Internal Carotid Artery Dissection Presenting with Transient or Subclinical Horner Syndrome.

Introduction: The most frequently encountered symptoms in internal carotid artery dissection (ICAD) are head or neck pain and cerebral ischemia. Ocular symptoms or signs have been reported as the presenting feature in up to 50% of patients, with (painful) Horner syndrome being the most frequently associated. Horner syndrome is part of the classic triad that depicts the characteristic presentation of ICAD and that consists of pain in the ipsilateral neck, head and orbital regions, (partial) Horner syndrome, and cerebral or retinal ischemia. All patients presenting with painful Horner syndrome should therefore require prompt investigations to rule out carotid artery dissection. In patients with confirmed diagnosis, treatment should be started early to prevent permanent ocular or cerebral complications. Case Presentation: Case 1: A 61-year-old woman presented with right temporal headache, an episode of transient visual loss and drooping of the right upper eyelid. Examination revealed anisocoria, which was more important in darkness. Reversal of anisocoria was observed after instilling drops of apraclonidine 0.5%. Neuroimaging demonstrated intrapetrous ICAD. Headaches, eyelid ptosis, and anisocoria all had resolved the next day. Apraclonidine pharmacologic testing a few weeks later was no longer dilating the previously smaller pupil. Case 2: A 48-year-old man presented with drooping of the right upper eyelid and right occipital headache and facial pain that all started one day after an intense yoga workout. Anisocoria was noticed upon examination, with topical cocaine 10% pharmacologic testing confirming a right Horner syndrome. Neuroimaging revealed ICAD. The patient reported resolution of his eyelid ptosis a few days later. Eyelid ptosis and anisocoria had indeed resolved at a follow-up examination a few weeks later. However, cocaine drop testing still produced anisocoria, compatible with subclinical Horner syndrome. Conclusion: Transient or subclinical Horner syndrome can be the presenting feature in ICAD; in such cases, the characteristic eyelid ptosis and anisocoria may be short-lived and resolve in only a few days. If suspected by clinical history, pharmacologic testing may be helpful in identifying subclinical cases.

Ocular sarcoidosis in adults and children: update on clinical manifestation and diagnosis.

Sarcoidosis-associated uveitis, is the predominant ocular sarcoidosis presentation, which affects both adults and children. For adults, international ocular sarcoidosis criteria (IWOS) and sarcoidosis-associated uveitis criteria (SUN) are defined. However, for children they are not yet established internationally. Due to the specificity of pediatric manifestations of sarcoidosis, this task is even more challenging. In children, sarcoidosis is subdivided into Blau syndrome and early-onset sarcoidosis (BS/EOS) affecting younger children (< 5 years) and the one affecting older children with clinical presentation resembling adults. Differential diagnosis, clinical work-up as well as diagnostic criteria should be adapted to each age group. In this article, we review the clinical manifestation of sarcoidosis-associated uveitis in adults and children and the sensitivity and specificity of various ocular sarcoidosis diagnostic modalities, including chest X-ray and CT, FDG PET-CT, gallium-67 scintigraphy, bronchoalveolar lavage fluid, genetic testing for NOD2 mutations and serum biomarkers, such as ACE, lysozyme and IL2R.

Focal Pachymeningitis Induced Papilloedema as an Early Manifestation of Relapsing Polychondritis.

A 52-year-old male patient presented with longstanding non-specific symptoms of ocular redness and irritation. Clinical examination not only revealed bilateral anterior scleritis but also bilateral optic disc swelling. Additional history taking revealed headaches and tinnitus, both starting around the same time as the eye redness, as well as a prior episode of swelling and redness of both ears. The lumbar puncture opening pressure was 29 cm of cerebrospinal fluid (CSF). There were 11 white blood cells/µl in the CSF. Subsequent magnetic resonance imaging showed focal thickening of the dura mater over the left cerebral convexity, suggestive of focal pachymeningitis. 18F-fluorodeoxyglucose positron emission tomography demonstrated hypermetabolic abnormalities located at the auricles, the nostrils, the anterior part of the eyes, and the dura mater over the left cerebral convexity, suggestive of relapsing polychondritis (RPC). RPC is a rare systemic immune-mediated condition; diagnosis can sometimes be delayed or missed due to insidious disease onset with non-specific symptoms. Nevertheless, sight-threatening or even life-threatening complications may occur. Given the high prevalence of ocular involvement, one should be suspicious when faced with patients with recurrent ocular inflammation. Optic disc swelling is a more uncommon finding, and while different mechanisms have been reported, it has rarely been associated with raised intracranial pressure. Nevertheless, intracranial hypertension arising from inflammation of the CSF and/or surrounding meninges caused by the newly diagnosed RPC was identified as the most likely underlying mechanism for the bilateral optic disc swelling in our patient.

Experimental Models to Study Epithelial-Mesenchymal Transition in Proliferative Vitreoretinopathy.

Proliferative vitreoretinal diseases (PVDs) encompass proliferative vitreoretinopathy (PVR), epiretinal membranes, and proliferative diabetic retinopathy. These vision-threatening diseases are characterized by the development of proliferative membranes above, within and/or below the retina following epithelial-mesenchymal transition (EMT) of the retinal pigment epithelium (RPE) and/or endothelial-mesenchymal transition of endothelial cells. As surgical peeling of PVD membranes remains the sole therapeutic option for patients, development of in vitro and in vivo models has become essential to better understand PVD pathogenesis and identify potential therapeutic targets. The in vitro models range from immortalized cell lines to human pluripotent stem-cell-derived RPE and primary cells subjected to various treatments to induce EMT and mimic PVD. In vivo PVR animal models using rabbit, mouse, rat, and swine have mainly been obtained through surgical means to mimic ocular trauma and retinal detachment, and through intravitreal injection of cells or enzymes to induce EMT and investigate cell proliferation and invasion. This review offers a comprehensive overview of the usefulness, advantages, and limitations of the current models available to investigate EMT in PVD.

Posterior segment spectral domain oct in the differential diagnosis of bilateral temporal optic neuropathy and its correlation with visual acuity.

PURPOSE: To identify the underlying etiologies and to evaluate the differential diagnostic value of posterior segment spectral domain OCT measurements and their correlation with best-corrected visual acuity (BCVA) in a group of patients with OCT documented bilateral optic neuropathy limited to the temporal quadrants. METHODS: Retrospective study. RESULTS: We included 61 patients: 35 presented with presumed "classic" acquired mitochondrial optic neuropathy (MON) (18 nutritional, 11 toxic, 6 mixed toxic-nutritional) and 2 with suspected hereditary MON. Nine patients were identified as 'MON mimickers' (especially multiple sclerosis), and 4 were found to have a mixed mechanism, while 11 remained undiagnosed. Across all etiologies, the strongest positive relationship between BCVA and tested OCT parameters was with macular GCL (ganglion cell layer) and GCIPL (combined ganglion cell and inner plexiform layer) volumes rather than peripapillary retinal nerve fiber layer (RNFL) thicknesses (all statistically significant). There was an inverse relationship between BCVA and inner nuclear layer (INL) volumes, with significant differences for BCVA and all tested OCT parameters between eyes with and without INL microcystoid lesions. OCT (absolute values and intereye differences) was not helpful in distinguishing between presumed acquired mitochondrial disease and patients with multiple sclerosis without optic neuritis. However, significantly greater intereye differences in global RNFL and inner plexiform layer and GCIPL volumes were found in patients with a previous history of unilateral optic neuritis. CONCLUSIONS: The strongest positive relationship with BCVA was found for macular GCL and GCIPL volumes. OCT could not differentiate between acquired mitochondrial disease and multiple sclerosis without optic neuritis.

Subretinal Therapy: Technological Solutions to Surgical and Immunological Challenges.

Recent advances in ocular gene and cellular therapy rely on precisely controlled subretinal delivery. Due to its inherent limitations, manual delivery can lead to iatrogenic damage to the retina, the retinal pigment epithelium, favor reflux into the vitreous cavity. In addition, it suffers from lack of standardization, variability in delivery and the need to maintain proficiency. With or without surgical damage, an eye challenged with an exogenous viral vector or transplanted cells will illicit an immune response. Understanding how such a response manifests itself and to what extent immune privilege protects the eye from a reaction can help in anticipating short- and long-term consequences. Avoidance of spillover from areas of immune privilege to areas which either lack or have less protection should be part of any mitigation strategy. In that regard, robotic technology can provide reproducible, standardized delivery which is not dependent on speed of injection. The advantages of microprecision medical robotic technology for precise targeted deliveries are discussed.

Sarcoidosis revealed by simultaneous optic nerve and eyelid involvement: A case report.

PURPOSE: Ocular disease can be the initial manifestation in patients with sarcoidosis. It is most often associated with uveitis, but eyelid or optic nerve disease can also be presenting features. Although uncommon and easy to overlook in a patient presenting with visual loss, paying attention to the presence of eyelid granulomas in our patient proved to be very helpful in our diagnostic work up for optic neuropathy. OBSERVATIONS: A young otherwise healthy patient was addressed with a 3 month history of bilateral painless visual loss. At presentation, best-corrected visual acuity was counting fingers in both eyes. Anterior segment slit-lamp examination was completely normal in both eyes. Eye fundus examination revealed subtle optic disc swelling in the left eye. Interestingly, flesh-colored nodular eyelid lesions were found bilaterally. Basic work-up for optic neuropathy showed elevated levels of serum lysozyme and serum angiotensin converting enzyme. More importantly, a biopsy specimen of an eyelid nodule demonstrated multiple non-necrotizing granulomas, a hallmark sign of sarcoidosis. Despite a delay in treatment of several months after onset of symptoms, response to systemic corticosteroids was prompt and important with visual acuity improving to 20/20 in both eyes as well as complete resorption of all eyelid lesions. CONCLUSION AND IMPORTANCE: In the diagnostic work-up for optic neuropathy, the answer can sometimes be hiding where it's least expected: the possible presence of eyelid lesions should not be overlooked as they may orient us towards sarcoidosis as an underlying etiology.

Subclinical Choroidal Inflammation Revealed by Indocyanine Green Angiography in Tubulointerstitial Nephritis and Uveitis Syndrome.

PURPOSE: To describe subclinical chorioretinal lesions revealed by indocyanine green angiography (ICGA) and their evolution under systemic treatment in tubulointerstitial nephritis and uveitis (TINU) patients. METHODS: Retrospective case series of three patients with TINU syndrome. Choroidal and retinal involvement were assessed by fluorescein angiography (FA) and ICGA. RESULTS: Three patients were analyzed. FA demonstrated hot disc, associated in two cases with retinal vascular leakage, and ICGA revealed subclinical chorioretinal dots in all three cases. Given the presence of posterior uveitis and deterioration of kidney function, asystemic treatment by oral methylprednisolone was started. Persistence of retinal and choroidal inflammations under systemic corticosteroids required association with immunosuppressive agent to control the disease activity. CONCLUSION: Multimodal imaging and more precisely ICGA is useful to assess subclinical choroidal inflammation and monitor treatment response in TINU syndrome. Immunosuppression needs to be revised and adapted when uveitis and/or kidney function are unresponsive to systemic steroids. ABBREVIATIONS: TINU: tubulointerstitial nephritis and uveitis; TIN: tubulointerstitial nephritis; ACE: angiotensin-converting enzyme; RF: rheumatoid factor; Uß2M: urinary ß-2microglobulin; AMPPE: acute multifocal placoid pigment epitheliopathy; FA: fluorescein angiography; ICGA: indocyanine green angiography; CT: computed tomography.

Multimodal Imaging in AIDS-Related Ocular Cryptococcosis.

PURPOSE: To report multimodal imaging findings in two cases of AIDS-related cryptococcal chorioretinitis associated with uveitis and vasculitis. METHODS: Findings on clinical examination, color fundus photography, fluorescein and indocyanine green angiographies, and optical coherence tomography. Patients. Both patients were diagnosed with Cryptococcus neoformans meningitis in the setting of untreated HIV infection with CD4+ T cell count < 100/mm3. Ocular manifestations occurred during the course of the antifungal therapy for meningitis. RESULTS: In both cases, fundus showed vitritis. Fluorescein angiography allowed the characterization of vasculitis lesions, and indocyanine green angiography indicated choroidal involvement. In combination with optical coherence tomography, ICG and FA allowed the assessment of treatment response. CONCLUSION: These two cases reveal the potential of C. neoformans to infect almost all ocular structures and the critical role of multimodal imaging in baseline evaluation and in the follow-up of patients.

Retinal endothelial cell phenotypic modifications during experimental autoimmune uveitis: a transcriptomic approach.

BACKGROUND: Blood-retinal barrier cells are known to exhibit a massive phenotypic change during experimental autoimmune uveitis (EAU) development. In an attempt to investigate the mechanisms of blood-retinal barrier (BRB) breakdown at a global level, we studied the gene regulation of total retinal cells and retinal endothelial cells during non-infectious uveitis. METHODS: Retinal endothelial cells were isolated by flow cytometry either in Tie2-GFP mice (CD31+ CD45- GFP+ cells), or in wild type C57BL/6 mice (CD31+ CD45- endoglin+ cells). EAU was induced in C57BL/6 mice by adoptive transfer of IRBP1-20-specific T cells. Total retinal cells and retinal endothelial cells from naïve and EAU mice were sorted and their gene expression compared by RNA-Seq. Protein expression of selected genes was validated by immunofluorescence on retinal wholemounts and cryosections and by flow cytometry. RESULTS: Retinal endothelial cell sorting in wild type C57BL/6 mice was validated by comparative transcriptome analysis with retinal endothelial cells sorted from Tie2-GFP mice, which express GFP under the control of the endothelial-specific receptor tyrosine kinase promoter Tie2. RNA-Seq analysis of total retinal cells mainly brought to light upregulation of genes involved in antigen presentation and T cell activation during EAU. Specific transcriptome analysis of retinal endothelial cells allowed us to identify 82 genes modulated in retinal endothelial cells during EAU development. Protein expression of 5 of those genes (serpina3n, lcn2, ackr1, lrg1 and lamc3) was validated at the level of inner BRB cells. CONCLUSION: Those data not only confirm the involvement of known pathogenic molecules but further provide a list of new candidate genes and pathways possibly implicated in inner BRB breakdown during non-infectious posterior uveitis.

EVALUATION OF TUMOR NECROSIS FACTOR INHIBITOR THERAPY IN SUSAC SYNDROME.

PURPOSE: To evaluate the effect of tumor necrosis factor (TNF) inhibitor therapy on ocular relapses in patients with Susac syndrome. METHODS: Multicenter retrospective cohort study of patients diagnosed with Susac syndrome according to classical clinical criteria. We evaluated the disease activity before and after introduction of anti-TNF therapy and its value as a steroid-sparing agent. RESULTS: Five patients were included. All were initially treated with a combination of corticosteroids and classical immunosuppressive drugs. Infliximab was started in three patients, and adalimumab was started in two patients. Patients had on average 5 ocular relapses during a mean follow-up time of 2.59 years before introducing a TNF inhibitor, corresponding with on average 1.93 relapses per year. After the introduction of an anti-TNF agent, this number was reduced by factor 5.51 to an average of 0.35 relapses per year for a mean follow-up of 2.86 years (P = 0.10). Before anti-TNF introduction ocular relapses occurred at a mean daily dose of 34 mg of prednisone, whereas with anti-TNF treatment, corticosteroid administration could be completely stopped in four patients with one patient still needing 5 mg daily (P = 0.10). Infliximab and adalimumab generally were well tolerated, and no serious adverse events were reported. CONCLUSION: Although not statistically significant, our results suggest that anti-TNF therapy can be a valuable option for the treatment of ocular Susac syndrome and may especially be considered in those patients unresponsive to more conventional immunosuppressive treatment.

ACUTE FROSTED RETINAL PERIPHLEBITIS IN A PATIENT WITH MEDITERRANEAN FEVER.

PURPOSE: To present a case of frosted branch periphlebitis in a young Armenian patient with familial Mediterranean fever. METHODS: Case report. RESULTS: A 37-year-old man presented with a unilateral decreased visual acuity and floaters for 4 days on the left eye (LE). Visual acuity was 20/20 in the right eye (RE) and 20/28 in the LE. Anterior segment and fundus examinations of the RE were normal. Slit-lamp examination of LE revealed a mild nongranulomatous anterior uveitis and vitritis. Intraocular pressure was 19 mmHg in the RE and 12 mmHg in the LE. Fundoscopy of the LE showed typical appearance of frosted branch periphlebitis with perivascular sheathing of the retinal veins and scattered retinal hemorrhages. Fluorescein angiography of the RE was normal. The LE showed optic disk and segmented vascular staining without macular leakage. Optical coherence tomography of the RE was normal; LE demonstrated a localized macular thickening and few intraretinal cysts. The detailed ophthalmologic history was negative. The general history and workup were significant for familial Mediterranean fever and a positive lupus anticoagulant. One week later, the fundus findings worsened with a severe decrease of visual acuity of the LE to 20/200. A single intravitreal (IVT) injection of bevacizumab was performed. Three weeks after injection, fundus findings progressively improved with a decrease of the macular thickening and an improvement of the visual acuity to 20/25. Clinical improvement continued up to the last visit (19 weeks after the injection) with a visual acuity that reached back 20/20 with no signs of active inflammation. CONCLUSION: This case demonstrates a possible association between unilateral frosted branch periphlebitis and familial Mediterranean fever.

Differential Diagnosis of Viral-Induced Anterior Uveitis.

Diagnosis of uveitis is often challenging, but can be easy in typical viral-induced anterior uveitis (VIAU). Associated symptoms and signs are an important source of information. Certain classical clinical features such as keratic precipitates (KPs) distribution, iris atrophy, elevated intraocular pressure (IOP), and unilaterality are commonly used to support the diagnosis of VIAU. However, many etiologies of anterior uveitis may to a certain extent mimic VIAU, especially the ones with unilateral granulomatous KPs and elevated IOP. This review begins with how the clinician can differentiate viral from nonviral anterior uveitis, and subsequently focuses on the key features which may aid in differentiating among the different viruses that cause VIAU.

Potential Interplay between Hyperosmolarity and Inflammation on Retinal Pigmented Epithelium in Pathogenesis of Diabetic Retinopathy.

Diabetic retinopathy is a frequent eyesight threatening complication of type 1 and type 2 diabetes. Under physiological conditions, the inner and the outer blood-retinal barriers protect the retina by regulating ion, protein, and water flux into and out of the retina. During diabetic retinopathy, many factors, including inflammation, contribute to the rupture of the inner and/or the outer blood-retinal barrier. This rupture leads the development of macular edema, a foremost cause of sight loss among diabetic patients. Under these conditions, it has been speculated that retinal pigmented epithelial cells, that constitute the outer blood-retinal barrier, may be subjected to hyperosmolar stress resulting from different mechanisms. Herein, we review the possible origins and consequences of hyperosmolar stress on retinal pigmented epithelial cells during diabetic retinopathy, with a special focus on the intimate interplay between inflammation and hyperosmolar stress, as well as the current and forthcoming new pharmacotherapies for the treatment of such condition.

Diagnosis of Cytomegalovirus Anterior Uveitis in Two European Referral Centers.

PURPOSE: To evaluate diagnostic methods and clinical signs of CMV anterior uveitis (AU), a rarely described entity in Europe. METHODS: We included patients with clinical characteristics of CMV AU and positive PCR and/or Goldmann-Witmer coefficient (GWc) for CMV. RESULTS: We report 21 patients with unilateral uveitis (100%) and signs of Posner-Schlossman syndrome (PSS) (n = 20, 95.2%), Fuchs uveitis syndrome (FUS) (n = 1, 4.7%), and endotheliitis (n = 4, 19,04%). PCR was positive in 15/21 (71.4%) and GWc in 8/9 patients (88.9%) in aqueous for CMV. GWc was the only positive test in 6/9 patients (66,6%). When PCR alone was performed (without GWc) in the first tap, repeated aqueous taps were needed, twice in five cases and thrice in one case. CONCLUSION: Combining PCR and GWc were very helpful to confirm the clinical diagnosis of CMV AU. In case of very high clinical suspicion and negative results, repeated tap seems to be recommended.

MHC class II expression and potential antigen-presenting cells in the retina during experimental autoimmune uveitis.

BACKGROUND: Controversy exists regarding which cell types are responsible for autoantigen presentation in the retina during experimental autoimmune uveitis (EAU) development. In this study, we aimed to identify and characterize the retinal resident and infiltrating cells susceptible to express major histocompatibility complex (MHC) class II during EAU. METHODS: EAU was induced in C57BL/6 mice by adoptive transfer of autoreactive lymphocytes from IRBP1-20-immunized animals. MHC class II expression was studied by immunostainings on eye cryosections. For flow cytometry (FC) analysis, retinas were dissected and enzymatically digested into single-cell suspensions. Three MHC class II+ retinal cell populations were sorted by FC, and their RNA processed for RNA-Seq. RESULTS: Immunostainings demonstrate strong induction of MHC class II expression in EAU, especially in the inner retina at the level of inflamed vessels, extending to the outer retinal layers and the subretinal space in severely inflamed eyes. Most MHC class II+ cells express the hematopoietic marker IBA1. FC quantitative analyses demonstrate that MHC class II induction significantly correlates with disease severity and is associated with upregulation of co-stimulatory molecule expression. In particular, most MHC class IIhi cells express co-stimulatory molecules during EAU. Further phenotyping identified three MHC class II+ retinal cell populations: CD45-CD11b- non-hematopoietic cells with low MHC class II expression and CD45+CD11b+ hematopoietic cells with higher MHC class II expression, which can be further separated into Ly6C+ and Ly6C- cells, possibly corresponding to infiltrating macrophages and resident microglia. Transcriptome analysis of the three sorted populations leads to a clear sample clustering with some enrichment in macrophage markers and microglial cell markers in Ly6C+ and Ly6C- cells, respectively. Functional annotation analysis reveals that both hematopoietic cell populations are more competent in MHC class II-associated antigen presentation and in T cell activation than non-hematopoietic cells. CONCLUSION: Our results highlight the potential of cells of hematopoietic origin in local antigen presentation, whatever their Ly6C expression. Our work further provides a first transcriptomic study of MHC class II-expressing retinal cells during EAU and delivers a series of new candidate genes possibly implicated in the pathogenesis of retinal autoimmunity.