Metabolic modeling of single Th17 cells reveals regulators of autoimmunity.

Metabolism is a major regulator of immune cell function, but it remains difficult to study the metabolic status of individual cells. Here, we present Compass, an algorithm to characterize cellular metabolic states based on single-cell RNA sequencing and flux balance analysis. We applied Compass to associate metabolic states with T helper 17 (Th17) functional variability (pathogenic potential) and recovered a metabolic switch between glycolysis and fatty acid oxidation, akin to known Th17/regulatory T cell (Treg) differences, which we validated by metabolic assays. Compass also predicted that Th17 pathogenicity was associated with arginine and downstream polyamine metabolism. Indeed, polyamine-related enzyme expression was enhanced in pathogenic Th17 and suppressed in Treg cells. Chemical and genetic perturbation of polyamine metabolism inhibited Th17 cytokines, promoted Foxp3 expression, and remodeled the transcriptome and epigenome of Th17 cells toward a Treg-like state. In vivo perturbations of the polyamine pathway altered the phenotype of encephalitogenic T cells and attenuated tissue inflammation in CNS autoimmunity.

Optical coherence tomography angiography in neuro-ophthalmology.

PURPOSE OF REVIEW: Optical coherence tomography angiography (OCTA) is a novel, noninvasive imaging technique, which provides depth resolved visualization of microvasculature of the retina and choroid. Although OCTA has been widely used for the evaluation of a number of retinal diseases, its use in the field of neuro-ophthalmology has been less studied. In this review, we provide an update on the utility of OCTA in neuro-ophthalmic conditions. RECENT FINDINGS: Peripapillary and macular microvasculature analyses have indicated that OCTA can be a promising tool for early detection of a number of neuro-ophthalmic diseases, differential diagnosis, and monitoring of disease progression. Recent studies have demonstrated that structural and functional impairment can develop at early stages in some conditions such as in multiple sclerosis and Alzheimer's disease even in the absence of overt clinical symptoms. Furthermore, this dye-less technique can be a valuable adjunct tool in the detection of complications commonly seen in some congenital entities such optic disc drusen. SUMMARY: Since its introduction, OCTA has emerged as an important imaging approach shedding light on unrevealed pathophysiological mechanisms of several ocular diseases. The use of OCTA as a biomarker in the field of neuro-ophthalmology has recently gained considerable attention with studies supporting its role in clinical setting while larger studies are warranted for correlating these findings with traditional diagnostic procedures and clinical features and outcomes.

Juxtapapillary Choroidal Neovascular Membrane as a Complication of Optic Disc Drusen: Multimodal Imaging With Swept Source-Optical Coherence Tomography and Optical Coherence Tomography Angiography.

ABSTRACT: A 55-year-old Caucasian man presented to the neuro-ophthalmology department for follow-up evaluation due to long-standing bilateral optic nerve head drusen (ONHD). On examination, the BCVA was 20/20-2 in both eyes. Dilated fundus examination revealed extensive ONHD in both eyes, retinal hemorrhages, exudates inferonasal to the macula, and macular edema inferotemporal to the disc margin. Automated visual field testing revealed generalized depression in both eyes. Late phase leakage was observed on fluorescein angiography (FA). Optical coherence tomography angiography identified a small juxtapapillary choroidal neovascular membrane inferonasal to the macula in the right eye correlating with the area of retinal hemorrhage and exudates.

Case 292: Lyme Neuroborreliosis.

History A 24-year-old right-handed woman presented to a neuro-ophthalmology clinic in Massachusetts in the summer with acute binocular diplopia when looking down and to the left, which started about 1 month earlier. Her medical history was notable for Raynaud syndrome, recurrent streptococcal pharyngitis, and an allergy to amoxicillin. Three days prior to developing diplopia, she presented to an outside emergency department due to fever, chills, and back pain. She received ciprofloxacin for presumed urinary tract infection based on urinalysis, which demonstrated few bacteria and was negative for leukocyte esterase, nitrites, and white blood cells. She then presented again to an outside emergency department for diplopia evaluation. Initial MRI and MR angiography of the brain at that time did not demonstrate any relevant findings, and the patient was referred to our department for neuro-ophthalmic evaluation, where she was seen 4 weeks later. Neuro-ophthalmic examination revealed 20/20 visual acuity in both eyes, and a right hypertropia in left gaze, downgaze and right head tilt, with right eye excyclotorsion. There were no ocular signs of myasthenia gravis or thyroid eye disease, nor did the patient report ocular or systemic symptoms. She denied recent travel. High-spatial-resolution MRI of the brain and orbit were performed.

Case 292.

History A 24-year-old right-handed woman presented to a neuro-ophthalmology clinic in Massachusetts in the summer with acute binocular diplopia when looking down and to the left, which started about 1 month earlier. Her medical history was notable for Raynaud syndrome, recurrent streptococcal pharyngitis, and an allergy to amoxicillin. Three days prior to developing diplopia, she presented to an outside emergency department due to fever, chills, and back pain. She received ciprofloxacin for presumed urinary tract infection based on urinalysis, which demonstrated few bacteria and was negative for leukocyte esterase, nitrites, and white blood cells. She then presented again to an outside emergency department for diplopia evaluation. Initial MRI and MR angiography of the brain at that time did not demonstrate any relevant findings, and the patient was referred to our department for neuro-ophthalmic evaluation, where she was seen 4 weeks later. Neuro-ophthalmic examination revealed 20/20 visual acuity in both eyes, and a right hypertropia in left gaze, downgaze and right head tilt, with right eye excyclotorsion. There were no ocular signs of myasthenia gravis or thyroid eye disease, nor did the patient report ocular or systemic symptoms. She denied recent travel. High-spatial-resolution MRI of the brain and orbit were performed (Figs 1, 2).

Ophthalmic manifestations of dementing disorders.

PURPOSE OF REVIEW: Dementia is a term for loss of memory, language, problem-solving, and other thinking abilities, which significantly interferes with daily life. Certain dementing conditions may also affect visual function. The eye is an accessible window to the brain that can provide valuable information for the early diagnosis of people who suffer from Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies as well as from more rare causes of dementias, such as Creutzfeldt-Jacob and Huntington's diseases. Herein, we present the ocular manifestations of neurocognitive disorders focusing on the neuro-ophthalmic ones and further discuss potential ocular biomarkers that could help in early detection of these disorders. RECENT FINDINGS: Ophthalmic examination along with the recent developments in in-vivo testing have provided a strong foundation of useful knowledge about brain disorder in neurodegenerative diseases without the need for invasive studies. Currently, a number of visual measures, such as visual acuity, contrast sensitivity, pupil response, and saccades in addition to various ophthalmic tests, such as electroretinogram, visual evoked potential, optical coherence tomography (OCT), and OCT-angiography have been widely used and evaluated as potential biomarkers for different stages of dementia. SUMMARY: Ophthalmologic and neuro-ophthalmic evaluation is evolving as an important part of the early diagnosis and management of people with dementia. A particular focus on ocular biomarkers in dementing illnesses has arisen over the past few years and there are several promising measures and imaging tools that have been proposed as potential biomarkers for these diseases.

Optic nerve sheath meningioma.

PURPOSE OF REVIEW: Optic nerve sheath meningiomas (ONSMs) are rare benign tumors of the anterior visual pathway which present with slowly progressive and painless vision loss and account for approximately 2% of all orbital tumors. This article provides an overview as well as an update on the ONSMs with regards to cause, epidemiology, clinical presentation, diagnosis, and management in adults and pediatric population. RECENT FINDINGS: The clinical presentation and prognosis of ONSMs can vary and largely depend on the location of tumor as well as the histologic type. Overall, the diagnosis is based on clinical presentation, examination, and neuroimaging findings. Nevertheless, delays in diagnosis or misdiagnosis are not uncommon and can result in higher morbidity rates. Recent advances in diagnostic as well as more effective and less-invasive treatment options are discussed in this review. SUMMARY: ONSMs are a rare cause of slowly progressive and inexorable visual loss. Although ONSM diagnosis depends on the characteristic clinical and radiologic findings, prompt diagnosis, and appropriate management is critical for favorable visual outcomes. Thus, current focus is optimizing diagnostic as well-treatment methods for patients with ONSMs.

Neuro-ophthalmic manifestations of the phakomatoses.

PURPOSE OF REVIEW: The phakomatoses are a group of inherited disorders with variable clinical manifestations that are characterized by brain, cutaneous, ocular and other distinct lesions in multiple organs. Correctly recognizing the neuro-ophthalmic signs and symptoms can lead to early diagnosis and treatment. The group is composed of neurofibromatosis (type 1 and 2), tuberous sclerosis complex, von Hippel-Lindau, ataxia-telangiectasia and Sturge-Weber syndromes. However, more than 60 syndromes have been described in the medical literature. This review provides an update on the diagnosis and management of phakomatoses with a focus on their clinical neuro-ophthalmic manifestations. RECENT FINDINGS: Phakomatoses are a group of inherited syndromes with variable clinical manifestations that are characterized by brain, cutaneous, ocular and other distinct lesions in multiple organs. Recent advances in diagnostic and treatment options that have contributed to prompt recognition and management of these disorders are discussed with an emphasis on the beneficial effects on vision. SUMMARY: Phakomatoses, also known as neuro-oculo-cutaneous syndromes, are inherited disorders with characteristic lesions in multiple organs. Because of their frequent ocular involvement thorough ophthalmologic and neuro-ophthalmic evaluation is critical in this patient population in order to prevent vision loss and life-threatening complications that are often associated with these disorders.

Immune checkpoint inhibitors: what neuro-ophthalmologists need to know.

PURPOSE OF REVIEW: Immune checkpoint inhibitors are currently an exceedingly powerful tool in the management of hitherto incurable malignancies and their use in clinical practice is expected to increase in the near future. The purpose of this review is to discuss the current medical uses of checkpoint inhibitors with a focus on their neuro-ophthalmic side-effects. RECENT FINDINGS: Immune checkpoint inhibitors have emerged as a promising breakthrough in the treatment of several tumor types. However, these targeted therapies can induce a wide range of immune-related ophthalmic and neuro-ophthalmic toxicities. It is important for neuro-ophthamologists to promptly recognize and manage these adverse events that can potentially threaten vision. SUMMARY: There are currently seven FDA-approved immune checkpoint inhibitors and several ones are under investigation. In general, immunotherapy is considered a well tolerated, safe and efficacious treatment option for many cancer patients. Nevertheless, because of their unique mechanism of action, these molecules can alter the immune response and result in immune-related adverse effects in almost every organ with an estimated incidence of ophthalmic side effects in this patient population of less than 1%.

Shear-wave elastographic imaging in choroidal melanomas: clinical and hemodynamic correlations.

PURPOSE: This study evaluated the role of shear wave elastography imaging (SWEΙ) in uveal melanomas and the associations between SWEI and clinical and hemodynamic findings. STUDY DESIGN: Prospective, clinical study METHODS: Twelve patients with uveal melanomas, scheduled to undergo Ru-106 brachytherapy, were prospectively recruited from the Department of Ophthalmology of the University Hospital of Heraklion (September-December 2022). B-mode, hemodynamic and SWEI ultrasonography examinations were performed with the HiScan (OPTIKON 2000) and the LOGIQ E9 (GE Healthcare) sonographic systems, respectively. Differences in SWEI scores (kPa) between tumor (TS) and adjacent non-affected choroid (CS), as well as between TS and orbital fat (FS) were examined. Correlations between SWEI and intra-tumoral hemodynamic parameters, including peak systolic and end diastolic velocities and resistivity index (RI) were also examined. RESULTS: TS was significantly correlated with intra-tumoral RI (Pearson's bivariate correlation coefficient 0.681, p=0.015) and with maximal tumor height (Pearson's bivariate correlation coefficient 0.620, p=0.031). TS was significantly higher than both FS and CS scores (paired-samples t-test, p=0.003 and p=0.006, respectively). CONCLUSIONS: SWEI score is applicable as a quantitative biomechanical marker in the assessment of choroidal melanoma. Choroidal melanomas are stiffer than both adjacent choroid and orbital fat. Moreover, choroidal melanomas with higher RI as well as those with higher apical elevations display higher SWEI scores.

Overlap between ophthalmology and psychiatry - A narrative review focused on congenital and inherited conditions.

A number of congenital and inherited diseases present with both ocular and psychiatric features. The genetic inheritance and phenotypic variants play a key role in disease severity. Early recognition of the signs and symptoms of those disorders is critical to earlier intervention and improved prognosis. Typically, the associations between these two medical subspecialties of ophthalmology and psychiatry are poorly understood by most practitioners so we hope to provide a narrative review to improve the identification and management of these disorders. We conducted a comprehensive review of the literature detailing the diseases with ophthalmic and psychiatric overlap that were more widely represented in the literature. Herein, we describe the clinical features, pathophysiology, molecular biology, diagnostic tests, and the most recent approaches for the treatment of these diseases. Recent studies have combined technologies for ocular and brain imaging such as optical coherence tomography (OCT) and functional imaging with genetic testing to identify the genetic basis for eye-brain connections. Additional work is needed to further explore these potential biomarkers. Overall, accurate, efficient, widely distributed and non-invasive tests that can help with early recognition of these diseases will improve the management of these patients using a multidisciplinary approach.

Transient Monocular Visual Loss (Amaurosis Fugax): How Does Age Impact Diagnosis?

Transient monocular visual loss (TMVL), also known as transient monocular blindness or amaurosis fugax ("fleeting blindness"), is a temporary loss of vision often due to ischemia to the retina. While acute TMVL should be considered an emergency that further requires exhaustive investigation, there are some cases in which TMVL arises secondary to benign causes. Age has a major impact in the diagnosis of ischemia and although the differential diagnosis of TMVL can be broad, timely and appropriate history, examination, diagnostic testing, and treatment can be vision- or life-saving. We review the causes of TMVL and the impact of age on the differential diagnoses and management.

The Epidemiology and Risk Factors for the Progression of Sympathetic Ophthalmia in the United States: An IRIS Registry Analysis.

PURPOSE: To investigate the demographic and clinical characteristics of patients with sympathetic ophthalmia (SO) and define the risk factors for its incidence following trauma and ophthalmic procedures. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients in the American Academy of Ophthalmology's (Academy) IRIS Registry (Intelligent Research in Sight) who were (n=1523) or were not diagnosed with SO following a documented procedure or trauma between January 1, 2013, and December 31, 2019. METHODS: Multiple demographic and clinical factors were collected, descriptive statistics and prevalence were calculated, and multivariate linear regression models were fit to the data. MAIN OUTCOME MEASURES: Prevalence of SO, demographic and clinical characteristics, and beta coefficient (ß) estimates of demographic and clinical characteristics impacting time to SO onset after procedure (Procedure Only cohort) or trauma (Trauma cohort). RESULTS: Of 65,348,409 distinct IRIS Registry patients, 1523 (0.0023%) were diagnosed with SO between 2013 and 2019, and also had a documented preceding trauma or procedure. Of these, 927 (60.87%) were female, 1336 (87.72%) belonged to the Procedure Only cohort, and 187 (12.28%) belonged to the Trauma cohort. The prevalence of SO after trauma was 0.0207%, whereas after procedures it was 0.0124%. The highest risk of procedure-related SO was seen in patients with history of "other anterior segment" (0.122%) followed by glaucoma (0.066%) procedures, whereas the lowest prevalence was noted with cataract surgeries (0.011%). The average time to onset of SO across both cohorts combined was 527.44 (±715.60) days, with statistically significant differences between the 2 cohorts (P < .001). On average, the time to onset from inciting event to SO was shorter with increasing age, by 9.02 (95% CI: -11.96, -6.08) days for every 1-year increase. CONCLUSIONS: SO following trauma and ophthalmic procedure is potentially rarer than previously reported, as measured in this large ophthalmic medical record database. Female sex may be a risk factor for SO. Older age may be a risk factor for quicker onset. These findings can guide clinical decision-making and management.

The epidemiology of pediatric dry eye disease in the United States: An IRIS® registry (Intelligent Research in Sight) analysis.

PURPOSE: Dry-eye disease (DED) is a chronic progressive ocular surface disorder with limited studies in the pediatric population. The Academy of Ophthalmology's IRIS® Registry was leveraged to investigate the prevalence of DED in the pediatric population (PDED, patients <18 years old) and the demographic differences of DED between pediatric and adult patients (ADED). METHODS: Retrospective cohort study. Patients with DED between January 1st, 2013 and December 31st, 2019 (N = 4,795,979) were included. Descriptive statistics, Pearson's chi-squared tests and two-sample proportions tests were conducted to compare key demographic distributions between the ADED and PDED cohorts. RESULTS: The average age at onset for ADED patients was 61.06 (±14.75) years and for PDED patients was 12.51 (±3.86). The overall tests for independence and the individual tests of proportions of each category were statistically significant for all demographic characteristics (p < 0.001). Characteristics with the largest discrepancies between patients of PDED and the IRIS Registry pediatric patient pool (PIRIS) included female sex (58.08 % vs. 50.60 %), male sex (41.58 % vs. 48.78 %) and Asian race (6.02 % vs. 3.11 %) respectively. Within the PDED cohort, females were at higher risk of PDED (58 % vs. 42 %). PDED was more prevalent in children with refractive errors (76 %) and eyelid/conjunctival disorders (41 %). Characteristics with the largest discrepancies between PDED and ADED patients included female sex (58.08 % vs. 68.12 %), male sex (41.58 % vs. 31.55 %) and Caucasian race (50.24 % vs. 67.06 %) respectively. CONCLUSIONS: Significant differences in the PDED cohort are demonstrated in this study. PDED was more prevalent in the female sex and Caucasian race compared to PIRIS and was more commonly associated with refractive errors and eyelid/conjunctival disorders.

Lower body negative pressure as a research tool and countermeasure for the physiological effects of spaceflight: A comprehensive review.

Lower Body Negative Pressure (LBNP) redistributes blood from the upper body to the lower body. LBNP may prove to be a countermeasure for the multifaceted physiological changes endured by astronauts during spaceflight related to cephalad fluid shift. Over more than five decades, beginning with the era of Skylab, advancements in LBNP technology have expanded our understanding of neurological, ophthalmological, cardiovascular, and musculoskeletal adaptations in space, with particular emphasis on mitigating issues such as bone loss. To date however, no comprehensive review has been conducted that chronicles the evolution of this technology or elucidates the broad-spectrum potential of LBNP in managing the diverse physiological challenges encountered in the microgravity environment. Our study takes a chronological perspective, systematically reviewing the historical development and application of LBNP technology in relation to the various pathophysiological impacts of spaceflight. The primary objective is to illustrate how this technology, as it has evolved, offers an increasingly sophisticated lens through which to interpret the systemic effects of space travel on human physiology. We contend that the insights gained from LBNP studies can significantly aid in formulating targeted and effective countermeasures to ensure the health and safety of astronauts. Ultimately, this paper aspires to promote a more cohesive understanding of the broad applicability of LBNP as a countermeasure against multiple bodily effects of space travel, thereby contributing to a safer and more scientifically informed approach to human space exploration.