Publications

Neurotrophic Keratitis (NK) is a degenerative disorder of the cornea characterized by decreased or absent sensory corneal innervation, corneal epitheliopathy and impaired healing.The clinical presentation of NK can range from persistent epithelial defects to corneal perforation and management is often both challenging and protracted. Historically, the management of NK has consisted of non-specific strategies to facilitate corneal epithelial healing such as lubrication, bandage contact lenses and tarsorrhaphy. Recent advances in the development of therapeutics for NK have provided new and efficacious targeted strategies for its management.In this article, we review recombinant human nerve growth factor (Cenegermin), currently approved for clinical use in the United States and Europe, as well as other promising therapeutic options that are in pre-clinical development such as thymosine β4, connexin43 inhibitors, and artificial extracellular matrix components.

PURPOSE OF REVIEW: Orbital disease represents a diverse spectrum of pathology and can result in a variety of neuro-ophthalmic manifestations. The aim of this review is to provide updates on recent advances in our understanding of orbital disease secondary to thyroid eye disease, myositis, IgG4-related disease, sarcoidosis, granulomatosis with polyangiitis and various tumours. RECENT FINDINGS: With regards to thyroid eye disease, there have been recent advances in the development of steroid-sparing therapies, new modalities for objectively monitoring disease activity and increased understanding of the role of environmental risk factors. There has been interest in characterizing the clinical course and underlying mechanism of optic nerve disease secondary to orbital disorders, which has led to advances in how we monitor for and prevent permanent vision loss. Increased knowledge of orbital tumour subtype histopathology and the development of novel classification systems has had prognostic value and aided medical decision-making. SUMMARY: Orbital disease occurs secondary to a wide variety of diseases and can lead to neuro-ophthalmic manifestations with significant morbidity. Advances in our understanding of different subtypes of orbital disease have improved our ability to treat these potentially debilitating conditions.

Amniotic bands can lead to eyelid colobomas contiguous with facial clefts, resulting in severe and highly variable eyelid malformations. There is no known underlying genetic cause of amniotic band sequence. Here, the authors review the case of an infant born with large, 4-eyelid colobomatous defects in the setting of facial clefts, amniotic bands and an underlying SMOC1 mutation, which has not previously been linked to amniotic band sequence or eyelid colobomas. Reconstructive technique and the postoperative course are described, and underlying etiologic theories of amniotic band sequence are reviewed and expanded upon. Although amblyopia prevention in this patient with poor visual potential was not a consideration, the goals of improving the patient's ocular surface and maintaining eye contact were achieved.

Proliferative vitreoretinopathy (PVR) is a fibrotic eye disease that develops after rhegmatogenous retinal detachment surgery and open-globe traumatic injury. Idelalisib is a specific inhibitor of phosphoinositide 3-kinase (PI3K) δ. While PI3Kδ is primarily expressed in leukocytes, its expression is also considerably high in retinal pigment epithelial (RPE) cells, which play a crucial part in the PVR pathogenesis. Herein we show that GeoMx Digital Spatial Profiling uncovered strong expression of fibronectin in RPE cells within epiretinal membranes from patients with PVR, and that idelalisib (10 μM) inhibited Akt activation, fibronectin expression and collagen gel contraction induced by transforming growth factor (TGF)-β2 in human RPE cells. Furthermore, we discovered that idelalisib at a vitreal concentration of 10 μM, a non-toxic dose to the retina, prevented experimental PVR induced by intravitreally injected RPE cells in rabbits assessed by experienced ophthalmologists using an indirect ophthalmoscope plus a + 30 D fundus lens, electroretinography, optical coherence tomography and histological analysis. These data suggested idelalisib could be harnessed for preventing patients from PVR.

PURPOSE: Letter acuity, the predominant clinical assessment of vision, is relatively insensitive to slow vision loss caused by eye disease. While the contrast sensitivity function (CSF) has demonstrated the potential to monitor the slow progress of blinding eye diseases, current tests of CSF lack the reliability or ease-of-use to capture changes in vision timely. To improve the current state of home testing for vision, we have developed and validated a computerized adaptive test on a commercial tablet device (iPad) that provides an efficient and easy-to-use assessment of the CSF. METHODS: We evaluated the reliability, accuracy, and flexibility of tablet-based CSF assessment. Repeated tablet-based assessments of the spatial CSF, obtained from four normally-sighted observers, which each took 3 to 5 minutes, were compared to measures obtained on CRT-based laboratory equipment; additional tablet-based measures were obtained from six subjects under three different luminance conditions. RESULTS: A Bland-Altman analysis demonstrated that tablet-based assessment was reliable for estimating sensitivities at specific spatial frequencies (coefficient of repeatability 0.14-0.40 log units). The CRT- and tablet-based results demonstrated excellent agreement with absolute mean sensitivity differences <0.05 log units. The tablet-based test also reliably identified changes in contrast sensitivity due to different luminance conditions. CONCLUSIONS: We demonstrate that CSF assessment on a mobile device is indistinguishable from that obtained with specialized laboratory equipment. We also demonstrate better reliability than tests used currently for clinical trials of ophthalmic therapies, drugs, and devices.

The fundamental role of the visual system is to guide behavior in natural environments. To optimize information transmission, many animals have evolved a non-homogeneous retina and serially sample visual scenes by saccadic eye movements. Such eye movements, however, introduce high-speed retinal motion and decouple external and internal reference frames. Until now, these processes have only been studied with unnatural stimuli, eye movement behavior, and tasks. These experiments confound retinotopic and geotopic coordinate systems and may probe a non-representative functional range. Here we develop a real-time, gaze-contingent display with precise spatiotemporal control over high-definition natural movies. In an active condition, human observers freely watched nature documentaries and indicated the location of periodic narrow-band contrast increments relative to their gaze position. In a passive condition under central fixation, the same retinal input was replayed to each observer by updating the video's screen position. Comparison of visual sensitivity between conditions revealed three mechanisms that the visual system has adapted to compensate for peri-saccadic vision changes. Under natural conditions we show that reduced visual sensitivity during eye movements can be explained simply by the high retinal speed during a saccade without recourse to an extra-retinal mechanism of active suppression; we give evidence for enhanced sensitivity immediately after an eye movement indicative of visual receptive fields remapping in anticipation of forthcoming spatial structure; and we demonstrate that perceptual decisions can be made in world rather than retinal coordinates.

: Amblyopia and strabismus affect 2%-5% of the population and cause a broad range of visual deficits. The response to treatment is generally assessed using visual acuity, which is an insensitive measure of visual function and may, therefore, underestimate binocular vision gains in these patients. On the other hand, the contrast sensitivity function (CSF) generally takes longer to assess than visual acuity, but it is better correlated with improvement in a range of visual tasks and, notably, with improvements in binocular vision. The present study aims to assess monocular and binocular CSFs in amblyopia and strabismus patients. : Both monocular CSFs and the binocular CSF were assessed for subjects with amblyopia ( = 11), strabismus without amblyopia ( = 20), and normally sighted controls ( = 24) using a tablet-based implementation of the quick CSF, which can assess a full CSF in <3 min. Binocular summation was evaluated against a baseline model of simple probability summation. : The CSF of amblyopic eyes was impaired at mid-to-high spatial frequencies compared to fellow eyes, strabismic eyes without amblyopia, and control eyes. Binocular contrast summation exceeded probability summation in controls, but not in subjects with amblyopia (with or without strabismus) or strabismus without amblyopia who were able to fuse at the test distance. Binocular summation was less than probability summation in strabismic subjects who were unable to fuse. : We conclude that monocular and binocular contrast sensitivity deficits define important characteristics of amblyopia and strabismus that are not captured by visual acuity alone and can be measured efficiently using the quick CSF.

PURPOSE: We previously reported that archetypal analysis (AA), a type of unsupervised machine learning, identified and quantified patterns of visual field (VF) loss in idiopathic intracranial hypertension (IIH), referred to as archetypes (ATs). We assessed whether AT weight changes over time are consistent with changes in conventional global indices. We explored whether visual outcome or treatment effects are associated with select ATs and whether AA reveals residual VF defects in eyes deemed "normal" after treatment. DESIGN: Analysis of data collected from a randomized controlled trial. PARTICIPANTS: 2,862 VFs taken from 165 participants during the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). METHODS: We applied a 14-AT model derived from IIHTT VFs. We examined changes in individual AT weights over time within all study eye VFs and evaluated differences between treatment groups. We created an AT Change score to assess overall VF change from baseline. We tested threshold baseline AT weights for association with VF outcome and treatment effect at six months. We determined the abnormal ATs with meaningful weight at outcome for VFs considered "normal" based on a mean deviation (MD) cutoff ≥-2.00 dB. MAIN OUTCOME MEASURES: Individual AT weighting coefficients, MD. RESULTS: AT1 (a normal VF pattern) showed the greatest weight change for all study eyes, increasing from 11.9% (interquartile range [IQR]: 0.44-24.1%) at baseline to 31.2% (IQR: 16.0-45.5%) at outcome (p<0.001). AT1 weight change (r=0.795, p<0.001) and a global score of AT change (r=0.988, p<0.001) correlated strongly with MD change. Study eyes with baseline AT2 (a mild diffuse VF loss pattern) weight ≥ 44% (≥1 standard deviation above the mean) showed higher AT2 weights at outcome than those with AT2 < 44% at baseline (p<0.001). Only the latter group showed a significant acetazolamide treatment effect. AA revealed residual VF loss patterns, most frequently representing mild diffuse loss and enlarged blind spot in 64 of 66 study eyes with MD ≥-2.00 dB at outcome. CONCLUSION: AA provides a quantitative approach to monitoring VF changes in IIH. Baseline AT features may be associated with treatment response and VF outcome. AA uncovers residual VF defects not otherwise revealed by MD.

Purpose: Archetypal analysis, a form of unsupervised machine learning, identifies archetypal patterns within a visual field (VF) dataset such that any VF is described as a weighted sum of its archetypes (ATs) and has been used to quantify VF defects in glaucoma. We applied archetypal analysis to VFs affected by nonglaucomatous optic neuropathy caused by idiopathic intracranial hypertension (IIH). Methods: We created an AT model from 2862 VFs prospectively collected from 330 eyes in the IIH Treatment Trial (IIHTT). We compared baseline IIH AT patterns with their descriptive VF classifications from the IIHTT. Results: The optimum IIH AT model yielded 14 ATs resembling VF patterns reported in the IIHTT. Baseline VFs contained four or fewer meaningful ATs in 147 (89%) of study eyes. AT2 (mild general VF depression pattern) demonstrated the greatest number of study eyes with meaningful AT weight at baseline (n = 114), followed by AT1 (n = 91). Other ATs captured patterns of blind spot enlargement, hemianopia, arcuate, nasal defects, and more nonspecific patterns of general VF depression. Of all ATs, AT1 (normal pattern) had the strongest correlation with mean deviation (r = 0.69, P < 0.001). For 65 of the 93 VFs with a dominant AT, this AT matched the expert classification. Conclusions: Archetypal analysis identifies quantifiable, archetypal VF defects that resemble those commonly seen in IIH. Translational Relevance: Archetypal analysis provides a quantitative, objective method of measuring and monitoring disease-specific regional VF defects in IIH.

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.

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%.

The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China in the city of Wuhan in December of 2019 and since then more than 5,000,000 people have been infected, with approximately 338,000 deaths worldwide. The virus causes the coronavirus disease 2019 (COVID-19), which is characterized by fever, myalgia and cough, with severe acute respiratory syndrome being the most fearsome complication. Nevertheless, the vast majority of cases present mild symptoms or none. Central nervous system and cardiovascular manifestations have been reported. The range of ocular manifestations, either as a result of the infection or as a result of the treatment, has not yet been discussed. In this study, a systematic review of current literature relevant to COVID-19 was performed with focus on modes of transmission, ocular manifestations related to infection and medications, as well as the control of infection in ophthalmic practice.

BACKGROUND: Orbital myositis is an idiopathic, non-infectious condition, typically seen in young females and usually affecting one extraocular muscle. Orbital myositis mimicking cluster headache is a rare clinical entity, and this is the first description of a case of a secondary trigeminal autonomic cephalalgia from orbital myositis responsive to high-flow oxygen. CASE: A young woman presented with new-onset, oxygen-responsive headache, periorbital pain and autonomic features. She had associated vertical diplopia on downgaze and subtle ocular misalignment. An initial diagnosis of cluster headache was made. Initial brain MRI was unrevealing, but dedicated MRI of the orbits showed enhancement of orbital muscles. The diplopia and the imaging findings were consistent with orbital myositis. CONCLUSION: Orbital myositis mimicking cluster headache is rare, and not previously reported as an oxygen-responsive headache.

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.

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.

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.

ABSTRACT: A 44-year-old woman presented with 2 painful and self-limited episodes of binocular horizontal diplopia within 1 year that at the beginning were thought to be secondary to microvascular insult. Her medical history was significant for Cushing syndrome status post transsphenoidal resection with bilateral adrenalectomy 4 years prior, hypertension, and diabetes mellitus. Neuro-ophthalmic evaluation was significant for left abduction deficit and incomitant esotropia consistent with left abducens nerve palsy. Of note, the patient had experienced a similar episode but on the contralateral side a few months prior. Although initially MRI of the brain demonstrated stable residual postoperative finding in the sella, upon review, an heterogenous T-1 hypointense marrow in the clivus was noted. Hypermetabolism of the clivus was also noted on computed tomography positron emission tomography of the skull base. A clival biopsy demonstrated a corticotroph adenoma with elevated proliferation index and scattered mitoses. A corticotroph pituitary adenoma after adrenalectomy, also known as Nelson syndrome, was diagnosed. Radiation therapy was offered to the patient, and resolution of symptoms was gradually observed.