Frosted branch angiitis in a patient with systemic juvenile idiopathic arthritis: a case report.

BACKGROUND: Frosted branch angiitis is a retinal vascular condition that is associated with a viral infection or autoimmune disorders like Crohn's disease, systemic lupus erythematosus, and Behcet's disease. Frosted branch angiitis presents with vascular inflammation, retinal edema, and severe retinal vascular sheathing. We present a case of systemic juvenile idiopathic arthritis, an autoinflammatory disease, presenting with frosted branch angiitis. REPORT OF CASE: A 14-year-old female with systemic juvenile idiopathic arthritis and a history of bilateral anterior uveitis developed acute unilateral vision loss and was found to have frosted branch angiitis complicated by branch retinal vein occlusion. She underwent an extensive serology workup and aqueous viral PCR to rule out other possible autoimmune and viral etiologies for forested branch angiitis. She received systemic and intravitreal antiviral treatment due to positive CMV IgM initially. However, the clinical picture improved following the use of a higher dose of oral steroids and the switch of the immunosuppressive agent to a TNF-a inhibitor. CONCLUSION: To our knowledge, this would be the first case in the literature demonstrating a systemic juvenile idiopathic arthritis patient presenting with frosted branch angiitis. Infectious causes still must be ruled out, especially CMV, as it is the most common cause of secondary frosted branch angiitis.

POU6f1 Mediates Neuropeptide-Dependent Plasticity in the Adult Brain.

The mouse olfactory bulb (OB) features continued, activity-dependent integration of adult-born neurons, providing a robust model with which to examine mechanisms of plasticity in the adult brain. We previously reported that local OB interneurons secrete the neuropeptide corticotropin-releasing hormone (CRH) in an activity-dependent manner onto adult-born granule neurons and that local CRH signaling promotes expression of synaptic machinery in the bulb. This effect is mediated via activation of the CRH receptor 1 (CRHR1), which is developmentally regulated during adult-born neuron maturation. CRHR1 is a GS-protein-coupled receptor that activates CREB-dependent transcription in the presence of CRH. Therefore, we hypothesized that locally secreted CRH activates CRHR1 to initiate circuit plasticity programs. To identify such programs, we profiled gene expression changes associated with CRHR1 activity in adult-born neurons of the OB. Here, we show that CRHR1 activity influences expression of the brain-specific Homeobox-containing transcription factor POU Class 6 Homeobox 1 (POU6f1). To elucidate the contributions of POU6f1 toward activity-dependent circuit remodeling, we targeted CRHR1+ neurons in male and female mice for cell-type-specific manipulation of POU6f1 expression. Whereas loss of POU6f1 in CRHR1+ neurons resulted in reduced dendritic complexity and decreased synaptic connectivity, overexpression of POU6f1 in CRHR1+ neurons promoted dendritic outgrowth and branching and influenced synaptic function. Together, these findings suggest that the transcriptional program directed by POU6f1 downstream of local CRH signaling in adult-born neurons influences circuit dynamics in response to activity-dependent peptide signaling in the adult brain.SIGNIFICANCE STATEMENT Elucidating mechanisms of plasticity in the adult brain is helpful for devising strategies to understand and treat neurodegeneration. Circuit plasticity in the adult mouse olfactory bulb is exemplified by both continued cell integration and synaptogenesis. We previously reported that these processes are influenced by local neuropeptide signaling in an activity-dependent manner. Here, we show that local corticotropin-releasing hormone (CRH) signaling induces dynamic gene expression changes in CRH receptor expressing adult-born neurons, including altered expression of the transcription factor POU6f1 We further show that POU6f1 is necessary for proper dendrite specification and patterning, as well as synapse development and function in adult-born neurons. Together, these findings reveal a novel mechanism by which peptide signaling modulates adult brain circuit plasticity.

Case Report: Late Sequela of a Muslinoma Involving the Optic Chiasm.

An 84-year-old woman presented with 3 months of vertical binocular diplopia and difficulty reading at near. She had a history of bilateral ophthalmic artery aneurysm repair involving use of muslin in the 1990s. The patient then developed bitemporal hemianopsia secondary to muslin-induced inflammation ("muslinoma") extending to the optic chiasm, which required surgical decompression. She had a persistent bitemporal hemianopsia but was stable for two decades after surgery. In 2017, the patient re-presented with double vision. Exam showed a non-paretic diplopia due to a small angle comitant right hypertropia attributed to the retinal hemi-field slide. Repeat imaging showed no new aneurysm or recurrent muslinoma. This case had originally been reported two decades ago and represents the longest duration of recurrent symptoms from muslin-related optochiasmatic arachnoiditis in the English language ophthalmic literature. Clinicians should be aware of the potential of delayed and recurrent symptoms or signs years or even decades after muslin wrapping of aneurysms.

Utility of No-Charge Panel Genetic Testing for Inherited Retinal Diseases in a Real-World Clinical Setting.

Purpose: To show the utility of genetic testing in inherited retinal disease (IRD) patients. Methods: This retrospective cohort study was performed at a single academic center and comprised 59 patients clinically diagnosed with IRD who had testing via the Invitae IRD Panel (Invitae Corp). Samples were collected from August 2019 to April 2021. The rates of genetic diagnosis and disease-category specific results (ie, positive, undetermined, negative) were assessed. Results: Testing results were returned a mean of 20 days (range, 14-28 days) after submission. Of the samples, 50.8% (30/59) had a diagnostic yield. By disease category, the yield was 46.4% (13/28) nonsyndromic retinitis pigmentosa (RP), 50.0% (4/8) syndromic RP, 46.2% (6/13) macular dystrophies, 75.0% (3/4) cone or cone-rod dystrophies, and 80.0% (4/5) other retinopathies; there were no cases of rod dystrophies. The results were undetermined in 47.5% of patients (28/59) because of identification of only 1 recessive mutation (5.1%; 3/59), 1 recessive mutation and at least 1 variant of uncertain significance (VUS) (13.6%; 8/59), or VUS only (28.8%; 17/59). One patient (1.7%) received negative testing results with no mutations or VUS identified. Conclusions: Open-access, no-charge panel testing offers a reasonable diagnostic yield. Accurate clinical diagnosis of IRD before testing and acknowledgment of the limitations of panel testing are critical. The results add to the current estimates of the value of genetic testing for retina specialists in the management of IRD.

Delineating the Clinical Phenotype of Patients With the c.629C>G, p.Pro210Arg Mutation in Peripherin-2.

Purpose: More than 200 different mutations in peripherin-2 (PRPH2) are associated with multiple subtypes of inherited retinal diseases (IRDs), including retinitis pigmentosa and cone or macular diseases. Our goal was to understand how the poorly characterized PRPH2 mutation p.Pro210Arg (P210R) affects visual function and retinal structure as well as gain insight into the mechanism driving the clinical pathology. Methods: Eleven patients had clinical assessments including best-corrected visual acuity (BCVA), full field and multifocal electroretinography (ERG), static (spot size V) and kinetic perimetry (Octopus 900), and dark-adapted chromatic (DAC; Medmont; spot size V) perimetry. Images were acquired with the Optos ultra-wide field camera and spectral-domain optical coherence tomography (SD-OCT). Molecular characteristics of the P210R mutant protein were evaluated in vitro. Results: Patients with the P210R mutation had BCVA (Snellen) ranging from 20/15 to 20/80. Perimetry showed a reduction in sensitivity, while ERG findings suggested that cone function was more impaired than rod function. Scotomas were identified corresponding to atrophic retinal lesions. Imaging revealed heterogeneous outer retinal changes such as hyperfluorescent flecks, hypo-autofluorescence (AF) regions of atrophy, and thinning of the photoreceptor layer on SD-OCT. In vitro findings suggested that P210R-Prph2 retains the ability to interact with binding partner Rom1 but abnormally accumulates in the endoplasmic reticulum (ER), suggesting the protein does not fold properly. Conclusions: Rod and cone sensitivities were decreased in subjects with the P210R mutation in PRPH2. There was scotomatous vision loss that occurred within the macula, likely due to atrophy that occurs after drusen have formed and have begun to resolve. This suggests that although rod and cone photoreceptors are dependent on PRPH2, preventing blindness in this specific subgroup of patients could involve therapeutics that impede the formation or lifecycle of drusen.

Genetic Diagnosis for 64 Patients with Inherited Retinal Disease.

The overlapping genetic and clinical spectrum in inherited retinal degeneration (IRD) creates challenges for accurate diagnoses. The goal of this work was to determine the genetic diagnosis and clinical features for patients diagnosed with an IRD. After signing informed consent, peripheral blood or saliva was collected from 64 patients diagnosed with an IRD. Genetic testing was performed on each patient in a Clinical Laboratory Improvement Amendments of 1988 (CLIA) certified laboratory. Mutations were verified with Sanger sequencing and segregation analysis when possible. Visual acuity was measured with a traditional Snellen chart and converted to a logarithm of minimal angle of resolution (logMAR). Fundus images of dilated eyes were acquired with the Optos® camera (Dunfermline, UK). Horizontal line scans were obtained with spectral-domain optical coherence tomography (SDOCT; Spectralis, Heidelberg, Germany). Genetic testing combined with segregation analysis resolved molecular and clinical diagnoses for 75% of patients. Ten novel mutations were found and unique genotype phenotype associations were made for the genes RP2 and CEP83. Collective knowledge is thereby expanded of the genetic basis and phenotypic correlation in IRD.

Quantifying burden of intravitreal injections: questionnaire assessment of life impact of treatment by intravitreal injections (QUALITII).

AIM: To quantify the areas of burden experienced by patients requiring repeated intravitreal injections (IVI) in the management of exudative retinal diseases. METHODS: The validated Questionnaire to Assess Life Impact of Treatment by Intravitreal Injections survey was administered to patients at four retina clinical practices across four US states. The primary outcome measure was Treatment Burden Score (TBS), a single score assessing overall burden. RESULTS: Of 1416 (n=657 age-related macular degeneration; n=360 diabetic macular oedema/diabetic retinopathy; n=221 retinal vein occlusion; n=178 other/uncertain) patients, 55% were women with an average age of 70 years. Patients most frequently reported receiving IVI every 4-5 weeks (40%). The mean TBS was 16.1±9.2 (range 1-48; scale of 1-54), and the TBS was higher in patients with diabetic macular oedema and/or diabetic retinopathy (DMO/DR) (17.1) compared with those with age-related macular degeneration (15.5) or retinal venous occlusive (15.3) (p=0.028). Though the mean level of discomfort was quite low (1.86) (scale 0-6), 50% of patients reported experiencing side effects more than half of the visits. Patients having received fewer than 5 IVI reported higher mean anxiety levels before (p=0.026), during (p=0.050) and after (p=0.016) treatment compared with patients having received more than 50 IVI. After the procedure, 42% of patients reported restrictions from usual activities due to discomfort. Patients reported a high mean satisfaction rating of 5.46 (scale 0-6) with the care of their diseases. CONCLUSIONS: The mean TBS was moderate and highest among patients with DMO/DR. Patients with more total injections reported lower levels of discomfort and anxiety but higher disruption to daily life. Despite the challenges related to IVI, the overall satisfaction with treatment remained high.

Questionnaire to Assess Life Impact of Treatment by Intravitreal Injections (QUALITII): Development of a patient-reported measure to assess treatment burden of repeat intravitreal injections.

OBJECTIVE: To understand patient burden of treatment of repeated intravitreal injections (IVI) in the management of exudative retinal diseases. METHODS AND ANALYSIS: Participants were sampled from a large urban retina specialty practice in Houston, Texas, USA, based on history of ongoing receipt of IVI. The 50-item Questionnaire to Assess Life Impact of Treatment by Intravitreal Injections questionnaire was developed to evaluate the patient experience including discomfort, anxiety, inconvenience and satisfaction. Categorial principal components analysis (CATPCA) was performed to assess construct validity and internal consistency. A subset of these items was used to establish a measure of total treatment burden, referred to as the IVI Treatment Burden Score (TBS). RESULTS: 142 patients participated in this study. CATPCA analysis revealed five dimensions of patient burden: disruption of normal routine or capacity, anxiety, frequency of visits, chronicity of disease and perceived treatment value or satisfaction. Together, these dimensions accounted for 67% of variance explained. Cronbach's alpha was 0.97. The most frequently cited cause of discomfort was the feeling after anaesthetic wore off. The most common source of anxiety was fear of injection and associated discomfort or pain. Regarding inconvenience, patients reported temporary postinjection debilitation, requiring an average of 8 hours for recovery per treatment. The most frequently identified sources of satisfaction were confidence in the provider or treatment and interactions with staff. CONCLUSIONS: Understanding and quantifying the patient burden associated with repeated IVI for exudative retinal diseases can reveal opportunities to improve delivery methods. The TBS could serve to inform strategies to maximise treatment adherence and optimise patient experiences.

Neuropeptide Signaling Networks and Brain Circuit Plasticity.

The brain is a remarkable network of circuits dedicated to sensory integration, perception, and response. The computational power of the brain is estimated to dwarf that of most modern supercomputers, but perhaps its most fascinating capability is to structurally refine itself in response to experience. In the language of computers, the brain is loaded with programs that encode when and how to alter its own hardware. This programmed "plasticity" is a critical mechanism by which the brain shapes behavior to adapt to changing environments. The expansive array of molecular commands that help execute this programming is beginning to emerge. Notably, several neuropeptide transmitters, previously best characterized for their roles in hypothalamic endocrine regulation, have increasingly been recognized for mediating activity-dependent refinement of local brain circuits. Here, we discuss recent discoveries that reveal how local signaling by corticotropin-releasing hormone reshapes mouse olfactory bulb circuits in response to activity and further explore how other local neuropeptide networks may function toward similar ends.

Bilateral pseudo-internuclear ophthalmoplegia in a patient with myasthenia gravis.

PURPOSE: To report a case of myasthenia gravis presenting with a false localizing sign, a bilateral pseudo internuclear ophthalmoplegia. OBSERVATIONS: A 61 year-old male presented with a five-week history of painless binocular oblique diplopia that was associated with fatigue, vocal hoarseness and bilateral ptosis, the latter two of which worsened through the course of the day. Exam was remarkable for an apparent bilateral internuclear ophthalmoplegia (INO). MRI of the brain with and without contrast and MRA of the head and neck were within normal limits. Lab work was positive for anti-AChR binding, blocking, and modulating antibodies, as well as anti-striated muscle and anti-titin antibodies. The patient was initiated on therapy for myasthenia gravis. CONCLUSION AND IMPORTANCE: Although myasthenia gravis often presents with ptosis or diplopia, rarely patients may develop pseudo-INO secondary to extraocular muscle weakness. True INO occurs with damage to the medial longitudinal fasciculus, a myelinated tract of fibers that controls yoked horizontal eye movements. Clinicians should be suspicious of the false localizing sign of a pseudo-INO associated with myasthenia gravis when more common causes of INO have been excluded.

An Objective and Reproducible Test of Olfactory Learning and Discrimination in Mice.

Olfaction is the predominant sensory modality in mice and influences many important behaviors, including foraging, predator detection, mating, and parenting. Importantly, mice can be trained to associate novel odors with specific behavioral responses to provide insight into olfactory circuit function. This protocol details the procedure for training mice on a Go/No-Go operant learning task. In this approach, mice are trained on hundreds of automated trials daily for 2-4 weeks and can then be tested on novel Go/No-Go odor pairs to assess olfactory discrimination, or be used for studies on how odor learning alters the structure or function of the olfactory circuit. Additionally, the mouse olfactory bulb (OB) features ongoing integration of adult-born neurons. Interestingly, olfactory learning increases both the survival and synaptic connections of these adult-born neurons. Therefore, this protocol can be combined with other biochemical, electrophysiological, and imaging techniques to study learning and activity-dependent factors that mediate neuronal survival and plasticity.

Olfactory Cued Learning Paradigm.

Sensory stimulation leads to structural changes within the CNS (Central Nervous System), thus providing the fundamental mechanism for learning and memory. The olfactory circuit offers a unique model for studying experience-dependent plasticity, partly due to a continuous supply of integrating adult born neurons. Our lab has recently implemented an olfactory cued learning paradigm in which specific odor pairs are coupled to either a reward or punishment to study downstream circuit changes. The following protocol outlines the basic set up for our learning paradigm. Here, we describe the equipment setup, programming of software, and method of behavioral training.