Novel Approaches to the Treatment of Idiopathic Intracranial Hypertension.

PURPOSE OF REVIEW: Idiopathic intracranial hypertension (IIH) typically affects women of childbearing age, is associated with recent weight gain, and can result in debilitating headache as well as papilledema that can cause vision loss. There have been advances in the medical and surgical treatment of affected patients with IIH that can improve outcomes and tolerability of therapy. RECENT FINDINGS: Medical treatment with agents that lower intracranial pressure through pathways other than carbonic anhydrase inhibition are being developed, and medically-directed weight loss as well as bariatric surgery now may be considered as primary therapy. New surgical options including venous sinus stenting have shown efficacy even with cases of severe vision loss. Our treatment options for IIH patients are becoming more diverse, and individualized treatment decisions are now possible to address specific components of the patient's disease manifestations and to lead to IIH remission.

Long-Term Efficacy of Teprotumumab in Thyroid Eye Disease: Follow-Up Outcomes in Three Clinical Trials.

Introduction: Thyroid eye disease (TED) is an autoimmune process characterized by extraocular muscle and orbital fat remodeling/expansion resulting in swelling, pain, redness, proptosis, and diplopia. Teprotumumab, an insulin-like growth factor-I receptor inhibitor, demonstrated improvements in TED signs and symptoms in three adequately powered clinical trials of 24 weeks duration. Here we analyze the long-term maintenance of responses with teprotumumab from these trials. Methods: A total of 112 patients who received 7 or 8 infusions of teprotumumab in the Phase 2, Phase 3 (OPTIC study), and OPTIC Extension (OPTIC-X) studies were included in this analysis. Responses, including clinical activity score (CAS ≥2-point improvement), the European Group of Graves' Orbitopathy ophthalmic composite outcome, diplopia (≥1 Gorman grade improvement), proptosis (≥2 mm improvement), Overall (improvement in proptosis + CAS), and disease inactivation (CAS ≤1), were assessed and pooled from study baseline to week 24 (formal study) and up to week 72 (formal follow-up). Graves' Ophthalmopathy quality-of-life (GO-QoL) scores were also assessed. Outcomes included the percentages of observed patient responses from the study baseline. Additional alternative treatments for TED were assessed as a surrogate of persistent benefit from week 24 through week 120 (extended follow-up). Studies differed in the timing of follow-up visits, and data from some visits were unavailable. Results: At week 72, 52/57 (91.2%), 51/57 (89.5%), 35/48 (72.9%), 38/56 (67.9%), and 37/56 (66.1%) of patients were responders for CAS, composite outcome, diplopia, proptosis, and Overall response, respectively. The mean reduction in proptosis was 2.68 mm (SD 1.92, n = 56), mean GO-QoL improvement was 15.22 (SE 2.82, n = 56), and disease inactivation (CAS ≤1) was detected in 40/57 (70.2%). Over 99 weeks following teprotumumab therapy, 19/106 (17.9%) patients reported additional TED therapy during formal and extended follow-up. Conclusion: The long-term response to teprotumumab as observed 51 weeks after therapy was similar to week 24 results in the controlled clinical trials. Inflammatory and ophthalmic composite outcome improvements were seen in 90% of patients with nearly 70% reporting improvement in diplopia and proptosis. Further, 82% of patients in this analysis did not report additional TED treatment (including surgery) over 99 weeks following the final teprotumumab dose.

A Study of Pupil Response to Light as a Digital Biomarker of Recent Cannabis Use.

Introduction: Given the traffic safety and occupational injury prevention implications associated with cannabis impairment, there is a need for objective and validated measures of recent cannabis use. Pupillary light response may offer an approach for detection. Method: Eighty-four participants (mean age: 32, 42% female) with daily, occasional, and no-use cannabis use histories participated in pupillary light response tests before and after smoking cannabis ad libitum or relaxing for 15 min (no use). The impact of recent cannabis consumption on trajectories of the pupillary light response was modeled using functional data analysis tools. Logistic regression models for detecting recent cannabis use were compared, and average pupil trajectories across cannabis use groups and times since light test administration were estimated. Results: Models revealed small, significant differences in pupil response to light after cannabis use comparing the occasional use group to the no-use control group, and similar statistically significant differences in pupil response patterns comparing the daily use group to the no-use comparison group. Trajectories of pupillary light response estimated using functional data analysis found that acute cannabis smoking was associated with less initial and sustained pupil constriction compared to no cannabis smoking. Conclusion: These analyses show the promise of pairing pupillary light response and functional data analysis methods to assess recent cannabis use.

Accuracy and replicability of identifying eyelid tremor as an indicator of recent cannabis smoking.

INTRODUCTION: Cannabis intoxication may increase the risk of motor vehicle crashes. However, reliable methods of assessing cannabis intoxication are limited. The presence of eyelid tremors is among the signs of cannabis use identified under the Drug Evaluation and Classification Program of the International Association of Chiefs of Police. Our objectives were to assess the accuracy and replicability of identifying eyelid tremor as an indicator of recent cannabis smoking using a blinded, controlled study design. METHODS: Adult subjects (N = 103) were recruited into three groups based on their cannabis use history: daily, occasional, and no current cannabis use. Participants' closed eyelids were video recorded for 30 seconds by infrared videography goggles before and at a mean ± standard deviation time of 71.4 ± 4.6 minutes after the onset of a 15-minute interval of ad libitum cannabis flower smoking or vaping. Three observers with expertise in neuro-ophthalmology and medical toxicology were trained on exemplar videos of eyelids to reach a consensus on how to grade eyelid tremor. Without knowledge of subjects' cannabis use history or time point (pre- or post-smoking), observers reviewed each video for eyelid tremor graded as absent, slight, moderate, or severe. During subsequent data analysis, this score was further dichotomized as a consensus score of absent (absent/slight) or present (moderate/severe). RESULTS: Kappa and intraclass correlation coefficient statistics demonstrated moderate agreement among the coders, which ranged from 0.44-0.45 and 0.58-0.61, respectively. There was no significant association between recent cannabis use and the observers' consensus assessment that eyelid tremor was present, and cannabis users were less likely to have tremors (odds ratio: 0.75; 95 percent confidence interval: 0.25, 2.40). The assessment of eyelid tremor as an indicator of recent cannabis smoking had a sensitivity of 0.86, specificity of 0.18, and accuracy of 0.64. DISCUSSION: Eyelid tremor has fair sensitivity but poor specificity and accuracy for identification of recent cannabis use. Inter-rater reliability for assessment of eyelid tremor was moderate for the presence and degree of tremor. The weak association between recent cannabis use and eyelid tremor does not support its utility in identifying recent cannabis use. LIMITATIONS: Videos were recorded at only one time point after cannabis use. Adherence to abstinence could not be strictly supervised. Due to regulatory restrictions, we were unable to control the cannabis product used or administer a fixed Δ9-tetrahydrocannabinol dose. Participants were predominately non-Hispanic and White. CONCLUSIONS: In a cohort of participants with a range of cannabis use histories, acute cannabis smoking was not associated with the presence of eyelid tremor, regardless of cannabis use history, at 70 minutes post-smoking. Additional research is needed to identify the presence of eyelid tremor accurately, determine the relationship between cannabis dose and timeline in relation to last cannabis use to eyelid tremor, and determine how it should be, if at all, utilized for cannabis Drug Recognition Evaluator examinations.

A Video Segmentation Pipeline for Assessing changes in Pupil Response to Light After Cannabis Consumption.

Due to long-standing federal restrictions on cannabis-related research, the implications of cannabis legalization on traffic and occupational safety are understudied. Accordingly, there is a need for objective and validated measures of acute cannabis impairment that may be applied in public safety and occupational settings. Pupillary response to light may offer an avenue for detection that outperforms typical sobriety tests and THC concentrations. We developed a video processing and analysis pipeline that extracts pupil sizes during a light stimulus test administered with goggles utilizing infrared videography. The analysis compared pupil size trajectories in response to a light for those with occasional, daily, and no cannabis use before and after smoking. Pupils were segmented using a combination of image pre-processing techniques and segmentation algorithms which were validated using manually segmented data and found to achieve 99% precision and 94% F-score. Features extracted from the pupil size trajectories captured pupil constriction and rebound dilation and were analyzed using generalized estimating equations. We find that acute cannabis use results in less pupil constriction and slower pupil rebound dilation in the light stimulus test.

Orbital Compartment Syndrome in Severe Burns: Predictive Factors, Timing, and Complications of Intervention.

PURPOSE: Severe burn patients require high-volume fluid resuscitation, which increases risk for orbital compartment syndrome (OCS). We aimed to understand surgeons' practice patterns and to examine risk factors for OCS, timing of lateral canthotomy and cantholysis (LCC), and complications of intervention. METHODS: A survey of American Society of Ophthalmic Plastic and Reconstructive Surgery and North American Society of Academic Orbital Surgeons' practice patterns in burn patients was undertaken. In addition, a retrospective analysis was conducted of 107 patients with burns greater than 20% total body surface area at 1 institution from January 1, 2009, to June 1, 2018. Patients with Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis, frostbite, or no ophthalmologic consultation were excluded. Risk factors for OCS, timing of LCC, and complications of the intervention were examined. RESULTS: In the survey, 37 of 54 respondents had treated burn patients, of which 29 followed no protocol. Threshold intraocular pressure for intervention varied widely, and nearly all reported having seen complications from LCC in burn patients. For the retrospective analysis, 107 patients met criteria, of which 22 (20.6%) required LCC. Renal failure, inhalation injury, eyelid burns, higher total body surface area, elevated lactate, increased number of escharotomies, and greater total fluid required were significantly associated with the clinical decision that the patient was at risk for OCS requiring LCC. Fluid resuscitation in excess of the Ivy Index (250 ml/kg) increased odds of LCC 8.6 times. Average time of LCC was 15.8 hours after burn. LCC patients experienced higher rates of complications including eyelid retraction, exposure keratopathy, and corneal ulceration. CONCLUSIONS: Severe burn patients should be monitored closely by an ophthalmologist during the first 48 hours for signs of OCS. Further studies should aim to recommend protocols guiding evaluation and intervention.

Safety of Lenadogene Nolparvovec Gene Therapy Over 5 Years in 189 Patients With Leber Hereditary Optic Neuropathy.

PURPOSE: To evaluate the safety profile of lenadogene nolparvovec (Lumevoq) in patients with Leber hereditary optic neuropathy. DESIGN: Pooled analysis of safety data from 5 clinical studies. METHODS: A total of 189 patients received single unilateral or bilateral intravitreal injections of a recombinant adeno-associated virus 2 (rAAV2/2) vector encoding the human wild-type ND4 gene. Adverse events (AEs) were collected throughout the studies, up to 5 years. Intraocular inflammation and increased intraocular pressure (IOP) were ocular AEs of special interest. Other assessments included ocular examinations, vector bio-dissemination, and systemic immune responses against rAAV2/2. RESULTS: Almost all patients (95.2%) received 9 × 1010 viral genomes and 87.8% had at least 2 years of follow-up. Most patients (75.1%) experienced at least one systemic AE, but systemic treatment-related AEs occurred in 3 patients; none were serious. Intraocular inflammation was reported in 75.6% of lenadogene nolparvovec-treated eyes. Almost all intraocular inflammations occurred in the anterior chamber (58.8%) or in the vitreous (40.3%), and were of mild (90.3%) or moderate (8.8%) intensity; most resolved with topical corticosteroids alone. All IOP increases were mild to moderate in intensity. No AE led to study discontinuation. Bio-dissemination of lenadogene nolparvovec and systemic immune response were limited. The safety profile was comparable for patients treated bilaterally and unilaterally. CONCLUSIONS: Lenadogene nolparvovec had a good overall safety profile with excellent systemic tolerability, consistent with limited bio-dissemination. The product was well tolerated, with mostly mild ocular side effects responsive to conventional ophthalmologic treatments.

Randomized trial of bilateral gene therapy injection for m.11778G>A MT-ND4 Leber optic neuropathy.

Leber hereditary optic neuropathy (LHON) is an important example of mitochondrial blindness with the m.11778G>A mutation in the MT-ND4 gene being the most common disease-causing mtDNA variant worldwide. The REFLECT phase 3 pivotal study is a randomized, double-masked, placebo-controlled trial investigating the efficacy and safety of bilateral intravitreal injection of lenadogene nolparvovec in patients with a confirmed m.11778G>A mutation, using a recombinant adeno-associated virus vector 2, serotype 2 (rAAV2/2-ND4). The first-affected eye received gene therapy; the fellow (affected/not-yet-affected) eye was randomly injected with gene therapy or placebo. The primary end point was the difference in change from baseline of best-corrected visual acuity (BCVA) in second-affected/not-yet-affected eyes treated with lenadogene nolparvovec versus placebo at 1.5 years post-treatment, expressed in logarithm of the minimal angle of resolution (LogMAR). Forty-eight patients were treated bilaterally and 50 unilaterally. At 1.5 years, the change from baseline in BCVA was not statistically different between second-affected/not-yet-affected eyes receiving lenadogene nolparvovec and placebo (primary end point). A statistically significant improvement in BCVA was reported from baseline to 1.5 years in lenadogene nolparvovec-treated eyes: -0.23 LogMAR for the first-affected eyes of bilaterally treated patients (P < 0.01); and -0.15 LogMAR for second-affected/not-yet-affected eyes of bilaterally treated patients and the first-affected eyes of unilaterally treated patients (P < 0.05). The mean improvement in BCVA from nadir to 1.5 years was -0.38 (0.052) LogMAR and -0.33 (0.052) LogMAR in first-affected and second-affected/not-yet-affected eyes treated with lenadogene nolparvovec, respectively (bilateral treatment group). A mean improvement of -0.33 (0.051) LogMAR and -0.26 (0.051) LogMAR was observed in first-affected lenadogene nolparvovec-treated eyes and second-affected/not-yet-affected placebo-treated eyes, respectively (unilateral treatment group). The proportion of patients with one or both eyes on-chart at 1.5 years was 85.4% and 72.0% for bilaterally and unilaterally treated patients, respectively. The gene therapy was well tolerated, with no systemic issues. Intraocular inflammation, which was mostly mild and well controlled with topical corticosteroids, occurred in 70.7% of lenadogene nolparvovec-treated eyes versus 10.2% of placebo-treated eyes. Among eyes treated with lenadogene nolparvovec, there was no difference in the incidence of intraocular inflammation between bilaterally and unilaterally treated patients. Overall, the REFLECT trial demonstrated an improvement of BCVA in LHON eyes carrying the m.11778G>A mtDNA mutation treated with lenadogene nolparvovec or placebo to a degree not reported in natural history studies and supports an improved benefit/risk profile for bilateral injections of lenadogene nolparvovec relative to unilateral injections.

Cavernous Malformation of the Optic Nerve and Chiasm: Prompt Suspicion and Surgery Matter.

BACKGROUND: Cavernous malformations (CMs) of the optic nerve and chiasm are extremely rare, accounting for less than 1% of all intracranial CMs. Acute, subacute, or progressive visual loss from CM may occur with or without hemorrhage. Prompt surgical excision of the CM offers the best hope to improve or stabilize vision. Given its rarity, optic nerve and chiasm CMs may not be readily suspected. We provide 3 cases of optic nerve and chiasm CM, highlighting key neuroimaging features and the importance of expedited intervention. METHODS: Case records of the neuro-ophthalmology clinics of the Bascom Palmer Eye Institute and the University of Colorado, and literature review of reported cases of optic CM. RESULTS: A 49-year-old woman reported acute progressive painless vision loss in the right eye. MRI showed a suprasellar mass with heterogeneity in signal involving the right prechiasmatic optic nerve. Surgical excision of the CM 5 days after onset of visual loss improved vision from 20/300 to 20/30. A 29-year-old woman with acute painless blurred vision in the right eye had anterior chiasmal junctional visual field defects corresponding to a heterogeneously minimally enhancing mass with blood products enlarging the optic chiasm and proximal right optic nerve. Surgical excision of the CM 8 weeks after onset of visual loss improved vision from 20/40 to 20/15 with improved visual fields. A 33-year-old woman with a history of familial multiple CMs, diagnosed at age 18, reported new-onset severe headache followed by blurred vision. MRI showed a hemorrhagic lesion of the optic chiasm and right optic tract. She was 20/20 in each eye with a reported left superior homonymous hemianopia. No intervention was recommended. Vision of the right eye worsened to 20/400 2 months later. The patient was followed over 13 years, and the MRI and visual function remained unchanged. Literature review yielded 87 optic CM cases occurring across gender and nearly all ages with visual loss and headache as the most common presenting symptoms. Optic chiasm is the most common site of involvement (79%). Nearly 95% of reported CM cases were treated with surgery with 81% with improved vision and 1% with worsened vision. CONCLUSION: MRI features are critical to the diagnosis of optic nerve and chiasm CM and may mimic other lesions. A high index of suspicion by the neuro-ophthalmologist and neuroradiologist leads to early recognition and intervention. Given optic CM displaces and does not infiltrate neural tissue, expedited surgical resection by a neurosurgeon after consideration of other diagnostic possibilities improves visual function in most cases.

Mismatch in Supply and Demand for Neuro-Ophthalmic Care.

BACKGROUND: Previous research suggests the number of neuro-ophthalmologists in the United States may be below a level that provides sufficient access to neuro-ophthalmic care in much of the United States. However, national estimates of the amount of clinical time spent on neuro-ophthalmology are lacking. METHODS: The North American Neuro-Ophthalmology Society administered a survey on professional time allocation to its active members. Survey response was 95%. The survey characterized the hours each week each respondent allocated to overall work, clinical work, clinical work in ophthalmology/neurology, and clinical work in neuro-ophthalmology specifically. The survey additionally collected information regarding demographics, current wait times to be seen for new patients, and the difference in clinical time spent in neuro-ophthalmology spent between the current day compared with that shortly after completing clinical training. Linear regression was used to identify potential relationships between the above and average wait time. RESULTS: On average, responding physicians spent 70% of their clinical time on neuro-ophthalmology. In 6 states, there were no reported practicing neuro-ophthalmologists, and in only 8 states was the clinical full-time equivalent to population ratio below the suggested threshold of 1 for every 1.2 million. The median wait time for a new patient was 6 weeks. This wait time was associated with the fraction of clinical time spent in neuro-ophthalmology (0.2 weeks longer wait for a 10 percentage point increase in the fraction of time spent in neuro-ophthalmology; P = 0.02), and suggestively associated with training (training in ophthalmology was associated with 1.0 week shorter wait time; P = 0.06). CONCLUSION: The survey suggests that neuro-ophthalmologists are unable to see patients in a timely manner and a decreasing number of clinicians are entering the field. Future interventions should be considered to incentivize neuro-ophthalmology training in ophthalmology and neurology residents such that the United States population is able to appropriately access neuro-ophthalmic care.

Physician burnout in ophthalmology: U.S. survey.

PURPOSE: To determine the prevalence of physician burnout among ophthalmologists in the United States and identify associated risks. SETTING: All practice types within the United States. DESIGN: Cross-sectional study. METHODS: A survey was distributed through email listservs to several national ophthalmology societies. Participants completed a modified Mini Z Burnout Survey, a 10-item questionnaire measured in 5-point Likert scales, followed by demographic questions. The Mini Z Burnout survey assessed 3 main outcomes: stress, burnout, and work satisfaction. The percentage of subgroups experiencing burnout were presented and comparisons made with odds ratios from logistic regression modeling. RESULTS: Of the 592 ophthalmologists responding to the survey, 37.8% (224) self-reported symptoms of burnout with a low of 30.8% (12/39) for vitreoretinal specialists to a high of 45.4% (30/66) for uveitis specialists. Most of those reporting burnout were categorized as mild (65.2% [146/224]), followed by moderate (29.5% [66/224]) and severe (5.4% [12/224]). Women had almost twice the odds of reporting burnout (odds ratio [OR] = 1.9 [95% CI: 1.3-2.7]; P = .0005). Physicians employed in academic (OR = 2.0 [95% CI: 1.2-3.2]; P = 0.007) and hospital facilities (OR = 2.4 [95% CI: 1.3-4.6]; P = .008) reported higher rates of burnout compared with those in large private groups. Burnout was associated with self-reported low work control, insufficient time for documentation, and misalignment with departmental leaders (P < .0001). CONCLUSIONS: Ophthalmologists exhibited a high degree of self-reported burnout in the U.S. This study highlights sex, employment autonomy, and practice type as major factors associated with burnout.

Targeted RNA Sequencing of Formalin-Fixed, Paraffin-Embedded Temporal Arteries From Giant Cell Arteritis Cases Reveals Viral Signatures.

BACKGROUND AND OBJECTIVES: Varicella zoster virus (VZV) antigen has been detected in temporal arteries (TAs) of individuals with giant cell arteritis (GCA), the most common systemic vasculitis in older adults. Thus, we explored the contribution of VZV to GCA pathogenesis. METHODS: Formalin-fixed, paraffin-embedded TA sections from biopsy-positive GCA participants with VZV antigen (GCA/VZV-positive; n = 20) and without (GCA/VZV-negative, n = 20) and from normal participants with VZV antigen (control/VZV-positive, n = 11) and without (control/VZV-negative, n = 20) were analyzed by targeted RNA sequencing of the whole human transcriptome (BioSpyder TempO-Seq). Ingenuity pathway analysis and R-computational program were used to identify differentially expressed genes and pathways between groups. RESULTS: Compared with control/VZV-negative TAs, GCA/VZV-negative and GCA/VZV-positive TAs were significantly enriched for human transcripts specific for pathways involved in viral infections, including viral entry, nuclear factor kappa B activation by viruses, and other pathogen-related immune activation pathways. Similarly, human gene sets supporting viral infection were found in control/VZV-positive TAs that showed no morphological signs of inflammation, suggesting that the enriched pathways were not nonspecific signatures of infiltrating immune cells. All GCA TAs and control/VZV-positive TAs showed enrichment of transcripts involved in vascular remodeling, including smooth muscle cell migration. DISCUSSION: The detection of viral and immune activation pathways in GCA TAs supports a role for virus infection in GCA pathogenesis. In addition, the detection of viral pathways in control/VZV-positive TAs, along with vascular remodeling pathways, suggests that these samples may represent early infection with progression to clinical disease, depending on host and other environmental factors.

Meningiomas of the Planum Sphenoidale and Tuberculum Sella.

Patients with meningiomas of the planum sphenoidale and tuberculum sella often present with insidious vision loss in one or both eyes as the only sign or symptom of their disease, although other sensory, oculomotor, and even endocrine abnormalities may be seen in a minority of cases. Incidentally discovered tumors also are common, as patients may undergo neuroimaging for unrelated symptoms or events. Depending on the size and orientation of the tumor, central vision loss from optic nerve compression may be a later sign, and loss of peripheral vision in one or both eyes may not be recognized until it has progressed to areas closer to fixation. A thorough neuroophthalmologic assessment including visual field testing will help to define the extent of optic pathway involvement. Both fundus examination and optical coherence tomography of the retinal nerve fiber layer and macular ganglion cell complex will aid in determining prognosis after treatment of the tumor. Orbital surgery rarely is indicated as primary therapy for meningiomas in this location, and surgical resection or debulking is usually pursued before consideration is given to radiation therapy. Because of the long-term risk of residual tumor growth or recurrence, neuroophthalmic surveillance along with serial neuroimaging is required for years after tumor resection and/or radiation therapy.