MOG Antibody-Associated Disease in the Setting of Metastatic Melanoma Complicated by Immune Checkpoint Inhibitor Use.

OBJECTIVES: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an autoimmune demyelinating disease rarely associated with malignancy. We report the clinical, MRI, immunopathology, and treatment response in a person with MOGAD and melanoma. METHODS: This is a case report of a person with a multidisciplinary evaluation at a tertiary referral center. RESULTS: A 52-year-old man presented with progressive encephalomyelitis that led to identification of metastatic melanoma. Investigations revealed positive MOG-IgG at high titers in serum (1:1,000; normal, <1:20) and CSF (1:4,096; normal, <1:2). MRI demonstrated multifocal T2 lesions with enhancement in the brain and spine. Brain biopsy showed demyelination and inflammation. MOG immunostaining was not present in the tumor tissue. He initially improved with methylprednisolone, plasmapheresis, prolonged oral steroid taper, and cancer-directed treatment with BRAF and MEK 1/2 inhibitors, but then developed bilateral optic neuritis. IV immunoglobulin (IVIG) was initiated. Five months later, he developed metastases and immune checkpoint inhibitor (ICI) treatment was started, which precipitated optic neuritis and myelitis despite IVIG and prednisone. Tocilizumab, an interleukin-6 receptor blocker, was started with excellent and sustained clinical and radiologic response. DISCUSSION: This case revealed a presentation of MOGAD concurrent with melanoma without tumor MOG immunostaining. We highlight tocilizumab as a dual-purpose treatment of MOGAD and the neurologic immune-related adverse effect of ICI.

Radiologic Lag and Brain MRI Lesion Dynamics During Attacks in MOG Antibody-Associated Disease.

BACKGROUND AND OBJECTIVES: Knowledge of the evolution of CNS demyelinating lesions within attacks could assist diagnosis. We evaluated intra-attack lesion dynamics in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) vs multiple sclerosis (MS) and aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorder (AQP4+NMOSD). METHODS: This retrospective observational multicenter study included consecutive patients from Mayo Clinic (USA) and Great Ormond Street Hospital for Children (UK). Inclusion criteria were as follows: (1) MOGAD, MS, or AQP4+NMOSD diagnosis; (2) availability of ≥2 brain MRIs (within 30 days of attack onset); and (3) brain involvement (i.e., ≥1 T2 lesion) on ≥1 brain MRI. The initial and subsequent brain MRIs within a single attack were evaluated for the following: new T2 lesions(s); resolved T2 lesion(s); both; or no change. This was compared between MOGAD, MS, and AQP4+NMOSD attacks. We used the Mann-Whitney U test and χ2/Fisher exact test for statistical analysis. RESULTS: Our cohort included 55 patients with MOGAD (median age, 14 years; interquartile range [IQR] 5-34; female sex, 29 [53%]) for a total of 58 attacks. The comparison groups included 38 patients with MS, and 19 with AQP4+NMOSD. In MOGAD, the initial brain MRI (median of 5 days from onset [IQR 3-9]) was normal in 6/58 (10%) attacks despite cerebral symptoms (i.e., radiologic lag). The commonest reason for repeat MRI was clinical worsening or no improvement (33/56 [59%] attacks with details available). When compared with the first MRI, the second intra-attack MRI (median of 8 days from initial scan [IQR 5-13]) showed the following: new T2 lesion(s) 27/58 (47%); stability 24/58 (41%); resolution of T2 lesion(s) 4/58 (7%); or both new and resolved T2 lesions 3/58 (5%). Findings were similar between children and adults. Steroid treatment was associated with resolution of ≥1 T2 lesion (6/28 [21%] vs 1/30 [3%], p = 0.048) and reduced the likelihood of new T2 lesions (9/28 vs 18/30, p = 0.03). Intra-attack MRI changes favored MOGAD (34/58 [59%]) over MS (10/38 [26%], p = 0.002) and AQP4+NMOSD (4/19 [21%], p = 0.007). Resolution of ≥1 T2 lesions was exclusive to MOGAD (7/58 [12%]). DISCUSSION: Radiologic lag is common within MOGAD attacks. Dynamic imaging with frequent appearance and occasional disappearance of lesions within a single attack suggest MOGAD diagnosis over MS and AQP4+NMOSD. These findings have implications for clinical practice, clinical trial attack adjudication, and understanding of MOGAD pathogenesis.

Monoclonal antibody therapies for aquaporin-4-immunoglobulin G-positive neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein antibody-associated disease.

Monoclonal antibody therapies mark the new era of targeted treatment for relapse prevention in aquaporin-4 (AQP4)-immunoglobulin G (IgG)-positive neuromyelitis optica spectrum disorder (AQP4-IgG+NMOSD). For over a decade, rituximab, an anti-CD20 B-cell-depleting agent, had been the most effectiveness treatment for AQP4-IgG+NMOSD. Tocilizumab, an anti-interleukin-6 receptor, was also observed to be effective. In 2019, several randomized, placebo-controlled trials were completed that demonstrated the remarkable efficacy of eculizumab (anti-C5 complement inhibitor), inebilizumab (anti-CD19 B-cell-depleting agent), and satralizumab (anti-interleukin-6 receptor), leading to the Food and Drug Administration (FDA) approval of specific treatments for AQP4-IgG+NMOSD for the first time. Most recently, ravulizumab (anti-C5 complement inhibitor) was also shown to be highly efficacious in an open-label, external-controlled trial. Although only some patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) warrant immunotherapy, there is currently no FDA-approved treatment for relapse prevention in MOGAD. Observational studies showed that tocilizumab was associated with a decrease in relapses, whereas rituximab seemed to have less robust effectiveness in MOGAD compared to AQP4-IgG+NMOSD. Herein, we review the evidence on the efficacy and safety of each monoclonal antibody therapy used in AQP4-IgG+NMOSD and MOGAD, including special considerations in children and women of childbearing potential.

Characterizing regional drug delivery within the nasal airways.

INTRODUCTION: The nose has been receiving increased attention as a route for drug delivery. As the site of deposition constitutes the first point of contact of the body with the drug, characterization of the regional deposition of intranasally delivered droplets or particles is paramount to formulation and device design of new products. AREAS COVERED: This review article summarizes the recent literature on intranasal regional drug deposition evaluated in vivo, in vitro and in silico, with the aim of correlating parameters measured in vitro with formulation and device performance. We also highlight the relevance of regional deposition to two emerging applications: nose-to-brain drug delivery and intranasal vaccines. EXPERT OPINION: As in vivo studies of deposition can be costly and time-consuming, researchers have often turned to predictive in vitro and in silico models. Variability in deposition is high due in part to individual differences in nasal geometry, and a complete predictive model of deposition based on spray characteristics remains elusive. Carefully selected or idealized geometries capturing population average deposition can be useful surrogates to in vivo measurements. Continued development of in vitro and in silico models may pave the way for development of less variable and more effective intranasal drug products.

A Comparative Study of Responses to Retina Questions from Either Experts, Expert-Edited Large Language Models, or Expert-Edited Large Language Models Alone.

Objective: To assess the quality, empathy, and safety of expert edited large language model (LLM), human expert created, and LLM responses to common retina patient questions. Design: Randomized, masked multicenter study. Participants: Twenty-one common retina patient questions were randomly assigned among 13 retina specialists. Methods: Each expert created a response (Expert) and then edited a LLM (ChatGPT-4)-generated response to that question (Expert + artificial intelligence [AI]), timing themselves for both tasks. Five LLMs (ChatGPT-3.5, ChatGPT-4, Claude 2, Bing, and Bard) also generated responses to each question. The original question along with anonymized and randomized Expert + AI, Expert, and LLM responses were evaluated by the other experts who did not write an expert response to the question. Evaluators judged quality and empathy (very poor, poor, acceptable, good, or very good) along with safety metrics (incorrect information, likelihood to cause harm, extent of harm, and missing content). Main Outcome: Mean quality and empathy score, proportion of responses with incorrect information, likelihood to cause harm, extent of harm, and missing content for each response type. Results: There were 4008 total grades collected (2608 for quality and empathy; 1400 for safety metrics), with significant differences in both quality and empathy (P < 0.001, P < 0.001) between LLM, Expert and Expert + AI groups. For quality, Expert + AI (3.86 ± 0.85) performed the best overall while GPT-3.5 (3.75 ± 0.79) was the top performing LLM. For empathy, GPT-3.5 (3.75 ± 0.69) had the highest mean score followed by Expert + AI (3.73 ± 0.63). By mean score, Expert placed 4 out of 7 for quality and 6 out of 7 for empathy. For both quality (P < 0.001) and empathy (P < 0.001), expert-edited LLM responses performed better than expert-created responses. There were time savings for an expert-edited LLM response versus expert-created response (P = 0.02). ChatGPT-4 performed similar to Expert for inappropriate content (P = 0.35), missing content (P = 0.001), extent of possible harm (P = 0.356), and likelihood of possible harm (P = 0.129). Conclusions: In this randomized, masked, multicenter study, LLM responses were comparable with experts in terms of quality, empathy, and safety metrics, warranting further exploration of their potential benefits in clinical settings. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of the article.

Quorum-sensing agr system of Staphylococcus aureus primes gene expression for protection from lethal oxidative stress.

The agr quorum-sensing system links Staphylococcus aureus metabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of H2O2, a crucial host defense against S. aureus. We now report that protection by agr surprisingly extends beyond post-exponential growth to the exit from stationary phase when the agr system is no longer turned on. Thus, agr can be considered a constitutive protective factor. Deletion of agr resulted in decreased ATP levels and growth, despite increased rates of respiration or fermentation at appropriate oxygen tensions, suggesting that Δagr cells undergo a shift towards a hyperactive metabolic state in response to diminished metabolic efficiency. As expected from increased respiratory gene expression, reactive oxygen species (ROS) accumulated more in the agr mutant than in wild-type cells, thereby explaining elevated susceptibility of Δagr strains to lethal H2O2 doses. Increased survival of wild-type agr cells during H2O2 exposure required sodA, which detoxifies superoxide. Additionally, pretreatment of S. aureus with respiration-reducing menadione protected Δagr cells from killing by H2O2. Thus, genetic deletion and pharmacologic experiments indicate that agr helps control endogenous ROS, thereby providing resilience against exogenous ROS. The long-lived 'memory' of agr-mediated protection, which is uncoupled from agr activation kinetics, increased hematogenous dissemination to certain tissues during sepsis in ROS-producing, wild-type mice but not ROS-deficient (Cybb-/-) mice. These results demonstrate the importance of protection that anticipates impending ROS-mediated immune attack. The ubiquity of quorum sensing suggests that it protects many bacterial species from oxidative damage.

Diagnostic Utility of MOG Antibody Testing in Cerebrospinal Fluid.

OBJECTIVE: The aim of this study was to assess the diagnostic utility of cerebrospinal fluid (CSF) myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) testing. METHODS: We retrospectively identified patients for CSF MOG-IgG testing from January 1, 1996, to May 1, 2023, at Mayo Clinic and other medical centers that sent CSF MOG-IgG for testing including: controls, 282; serum MOG-IgG positive MOG antibody-associated disease (MOGAD), 74; serum MOG-IgG negative high-risk phenotypes, 73; serum false positive MOG-IgG with alternative diagnoses, 18. A live cell-based assay assessed CSF MOG-IgG positivity (IgG-binding-index [IBI], ≥2.5) using multiple anti-human secondary antibodies and end-titers were calculated if sufficient sample volume. Correlation of CSF MOG-IgG IBI and titer was assessed. RESULTS: The pan-IgG Fc-specific secondary was optimal, yielding CSF MOG-IgG sensitivity of 90% and specificity of 98% (Youden's index 0.88). CSF MOG-IgG was positive in: 4/282 (1.4%) controls; 66/74 (89%) serum MOG-IgG positive MOGAD patients; and 9/73 (12%) serum MOG-IgG negative patients with high-risk phenotypes. Serum negative but CSF positive MOG-IgG accounted for 9/83 (11%) MOGAD patients, and all fulfilled 2023 MOGAD diagnostic criteria. Subgroup analysis of serum MOG-IgG low-positives revealed CSF MOG-IgG positivity more in MOGAD (13/16[81%]) than other diseases with false positive serum MOG-IgG (3/15[20%]) (p = 0.01). CSF MOG-IgG IBI and CSF MOG-IgG titer (both available in 29 samples) were correlated (Spearman's r = 0.64, p < 0.001). INTERPRETATION: CSF MOG-IgG testing has diagnostic utility in patients with a suspicious phenotype but negative serum MOG-IgG, and those with low positive serum MOG-IgG results and diagnostic uncertainty. These findings support a role for CSF MOG-IgG testing in the appropriate clinical setting. ANN NEUROL 2024.

Understanding Factors Affecting Health Providers' Perceptions of Pharmacist Roles in HPV Vaccine Administration.

Human papillomavirus (HPV) is a viral infection that sexually active females and males may be exposed to in their lifetime. The HPV vaccine is highly recommended especially among children to protect them before their anticipated exposure to HPV, however, vaccination uptake in Hawai'i remains low. As of 2017, legislation allows pharmacists to vaccinate for adolescent vaccines with the potential to increase access and opportunities for patients to complete the HPV vaccine series. Physicians in Hawai'i were surveyed to examine physicians' awareness of this law, their perceptions of the role of pharmacists, and willingness to send adolescent patients to pharmacies; 137 responses were received and analyzed. Overall, 72% (n=99) of respondents were willing while 28% (n=38) were unwilling to send patients to pharmacies for vaccines. Physicians view pharmacists' role as helpful but have concerns regarding correct administration and tracking doses given. Results show potential for more physician-pharmacist collaborations through further education and trainings for pharmacists and health providers to increase physician referrals for adolescent vaccine services in pharmacies.

Appropriateness of Ophthalmology Recommendations From an Online Chat-Based Artificial Intelligence Model.

Objective: To determine the appropriateness of ophthalmology recommendations from an online chat-based artificial intelligence model to ophthalmology questions. Patients and Methods: Cross-sectional qualitative study from April 1, 2023, to April 30, 2023. A total of 192 questions were generated spanning all ophthalmic subspecialties. Each question was posed to a large language model (LLM) 3 times. The responses were graded by appropriate subspecialists as appropriate, inappropriate, or unreliable in 2 grading contexts. The first grading context was if the information was presented on a patient information site. The second was an LLM-generated draft response to patient queries sent by the electronic medical record (EMR). Appropriate was defined as accurate and specific enough to serve as a surrogate for physician-approved information. Main outcome measure was percentage of appropriate responses per subspecialty. Results: For patient information site-related questions, the LLM provided an overall average of 79% appropriate responses. Variable rates of average appropriateness were observed across ophthalmic subspecialties for patient information site information ranging from 56% to 100%: cataract or refractive (92%), cornea (56%), glaucoma (72%), neuro-ophthalmology (67%), oculoplastic or orbital surgery (80%), ocular oncology (100%), pediatrics (89%), vitreoretinal diseases (86%), and uveitis (65%). For draft responses to patient questions via EMR, the LLM provided an overall average of 74% appropriate responses and varied by subspecialty: cataract or refractive (85%), cornea (54%), glaucoma (77%), neuro-ophthalmology (63%), oculoplastic or orbital surgery (62%), ocular oncology (90%), pediatrics (94%), vitreoretinal diseases (88%), and uveitis (55%). Stratifying grades across health information categories (disease and condition, risk and prevention, surgery-related, and treatment and management) showed notable but insignificant variations, with disease and condition often rated highest (72% and 69%) for appropriateness and surgery-related (55% and 51%) lowest, in both contexts. Conclusion: This LLM reported mostly appropriate responses across multiple ophthalmology subspecialties in the context of both patient information sites and EMR-related responses to patient questions. Current LLM offerings require optimization and improvement before widespread clinical use.

The Prevalence of Hospitalized Parkinson's Disease Patients in All Case Hospitalization among Different Race/Ethnic Subgroups in Hawai'i.

Background: Little is known about the epidemiology of Parkinson's disease (PD) patients in Native Hawaiian Or Other Pacific Islander (NHPI) and Asian American (AA) subgroups. Objective: To determine if the prevalence of hospitalized PD patients is different across age groups and racial/ethnic subgroups in Hawai'i. Methods: We conducted a retrospective analysis of Hawai'i statewide registry (2016-2020) hospitalization data for patients who were 50 years or older. PD patients were identified using an ICD 10 code: Parkinson's Disease (G20) as their primary/secondary hospitalization discharge diagnosis code. Demographic and clinical characteristics among racial/ethnic subgroups (White, Japanese, Filipino, Chinese, NHPI, or Other) were compared. Results: Of 146,844 total hospitalized patients (n = 429,879 records), 1.6% (n = 2,401) had a PD diagnosis. The prevalence of hospitalized PD patients was 2.3% among Japanese and Chinese, followed by 1.7% for Whites, 1.2% for Filipinos and was lowest for NHPI with 0.9% (p <  0.001). As patient's age increased, the prevalence of hospitalized PD patients increased, with 80-84 years old for the highest age range (3.4%). The prevalence of hospitalized PD patients at 80-84 years old varied across the race/ethnic subgroups (Chinese 4.3%, Japanese 4.0%, Whites 3.7%, Filipinos 2.5%, NHPI 2.3%). Conclusions: The prevalence of hospitalized PD patients among all case hospitalizations were lower for NHPI and Filipino compared to that of Japanese, Chinese, and Whites. As patients' age increased, the prevalence of hospitalized patients with PD increased, but less so in NHPI and Filipino groups. Further research is warranted to understand the reason for these observed differences among racial/ethnic subgroups.

Super High Contrast USPIO-Enhanced Cerebrovascular Angiography Using Ultrashort Time-to-Echo MRI.

Background: Ferumoxytol (Ferahame, AMAG Pharmaceuticals, Waltham, MA) is increasingly used off-label as an MR contrast agent due to its relaxivity and safety profiles. However, its potent T2∗ relaxivity limits achievable T1-weighted positive contrast and leads to artifacts in standard MRI protocols. Optimization of protocols for ferumoxytol deployment is necessary to realize its potential. Methods: We present first-in-human clinical results of the Quantitative Ultrashort Time-to-Echo Contrast Enhanced (QUTE-CE) MRA technique using the superparamagnetic iron oxide nanoparticle agent ferumoxytol for vascular imaging of the head/brain in 15 subjects at 3.0T. The QUTE-CE MRA method was implemented on a 3T scanner using a stack-of-spirals 3D Ultrashort Time-to-Echo sequence. Time-of-flight MRA and standard TE T1-weighted (T1w) images were also collected. For comparison, gadolinium-enhanced blood pool phase images were obtained retrospectively from clinical practice. Signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and intraluminal signal heterogeneity (ISH) were assessed and compared across approaches with Welch's two-sided t-test. Results: Fifteen volunteers (54 ± 17 years old, 9 women) participated. QUTE-CE MRA provided high-contrast snapshots of the arterial and venous networks with lower intraluminal heterogeneity. QUTE-CE demonstrated significantly higher SNR (1707 ± 226), blood-tissue CNR (1447 ± 189), and lower ISH (0.091 ± 0.031) compared to ferumoxytol T1-weighted (551 ± 171; 319 ± 144; 0.186 ± 0.066, respectively) and time-of-flight (343 ± 104; 269 ± 82; 0.190 ± 0.016, respectively), with p < 0.001 in each comparison. The high CNR increased the depth of vessel visualization. Vessel lumina were captured with lower heterogeneity. Conclusion: Quantitative Ultrashort Time-to-Echo Contrast-Enhanced MR angiography provides approximately 5-fold superior contrast with fewer artifacts compared to other contrast-enhanced vascular imaging techniques using ferumoxytol or gadolinium, and to noncontrast time-of-flight MR angiography, for clinical vascular imaging. This trial is registered with NCT03266848.

A Comparative Study of Large Language Models, Human Experts, and Expert-Edited Large Language Models to Neuro-Ophthalmology Questions.

BACKGROUND: While large language models (LLMs) are increasingly used in medicine, their effectiveness compared with human experts remains unclear. This study evaluates the quality and empathy of Expert + AI, human experts, and LLM responses in neuro-ophthalmology. METHODS: This randomized, masked, multicenter cross-sectional study was conducted from June to July 2023. We randomly assigned 21 neuro-ophthalmology questions to 13 experts. Each expert provided an answer and then edited a ChatGPT-4-generated response, timing both tasks. In addition, 5 LLMs (ChatGPT-3.5, ChatGPT-4, Claude 2, Bing, Bard) generated responses. Anonymized and randomized responses from Expert + AI, human experts, and LLMs were evaluated by the remaining 12 experts. The main outcome was the mean score for quality and empathy, rated on a 1-5 scale. RESULTS: Significant differences existed between response types for both quality and empathy (P < 0.0001, P < 0.0001). For quality, Expert + AI (4.16 ± 0.81) performed the best, followed by GPT-4 (4.04 ± 0.92), GPT-3.5 (3.99 ± 0.87), Claude (3.6 ± 1.09), Expert (3.56 ± 1.01), Bard (3.5 ± 1.15), and Bing (3.04 ± 1.12). For empathy, Expert + AI (3.63 ± 0.87) had the highest score, followed by GPT-4 (3.6 ± 0.88), Bard (3.54 ± 0.89), GPT-3.5 (3.5 ± 0.83), Bing (3.27 ± 1.03), Expert (3.26 ± 1.08), and Claude (3.11 ± 0.78). For quality (P < 0.0001) and empathy (P = 0.002), Expert + AI performed better than Expert. Time taken for expert-created and expert-edited LLM responses was similar (P = 0.75). CONCLUSIONS: Expert-edited LLM responses had the highest expert-determined ratings of quality and empathy warranting further exploration of their potential benefits in clinical settings.

Thrombolytic Therapy for Central Retinal Artery Occlusion in an Academic Multi-Site Stroke Centre.

Central retinal artery occlusion (CRAO) is a subtype of acute ischaemic stroke leading to severe visual loss. A recent American Heart Association scientific statement proposed time-windows for thrombolysis in CRAO similar to acute ischaemic cerebral strokes. We aimed to review our academic multi-site stroke centre experience with intravenous (IVT) and intra-arterial thrombolysis (IAT) in CRAO between 1997 and 2022. Demographic, clinical characteristics, thrombolysis timeline, concurrent therapies, complications, and 3-month follow-up visual acuity (VA) were collected. The thrombolysed cohort follow-up VA was compared with an age, gender and baseline VA matched cohort of CRAO patients that received conservative therapies. Thrombolytic therapy was administered to 3.55% (n = 20) of CRAO admissions; 13 IVT (mean age 68, 61.5% male, 12 alteplase and 1 tenecteplase, all embolic aetiology, 1 CRAO mimic) and 7 IAT (mean age 55, 85.7% male, 3 post-operative and 3 embolic). Additional conservative CRAO-targeting therapies was received by 60%. The median time from onset of visual loss to IVT was 158 minutes (range 67-260). Improvement by at least two Snellen lines was achieved by 25% with 12.5% improving to 20/100 or better. Intracranial haemorrhage post IVT occurred in 1/13 (7.6%). The median time from onset of visual loss to IAT was 335 minutes. Improvement by at least two Snellen lines was achieved by 42%. No difference in 3-month VA was noted between patients that received thrombolysis, either alone (n = 8) or combined with other therapies, and those that received conservative therapies. Our results suggest that the management of acute CRAO remains heterogeneous. The lack of obvious benefit of thrombolysis in our small series supports the need for randomizsd clinical trials comparing thrombolysis to placebo to guide hyperacute CRAO management.

Paraneoplastic vision loss.

Paraneoplastic vision loss, which represents a small percentage of paraneoplastic neurologic syndromes, can be a blinding disease. Presenting visual symptoms are variable, making diagnosis challenging. History of the presenting illness, ocular examination, and utilization of various modalities, such as automated perimetry, ocular coherence tomography, and electroretinogram allow for localization of vision loss to the optic nerves or retina, guiding in diagnosis and management. Paraneoplastic vision loss is often painless, bilateral, and subacute, and accompanies other neurologic symptoms but can be the first presenting symptom. Paraneoplastic optic neuropathy has been described in association with several antibodies, but most commonly anti-CRMP5. Cancer-associated retinopathy is the most common paraneoplastic autoimmune retinopathy; however, melanoma-associated retinopathy and bilateral diffuse uveal melanocytic proliferation have also been described to be associated with a paraneoplastic process affecting the retina. Paraneoplastic visual loss is an expanding field and advances in research have improved phenotypic characterization; however, further work is needed to identify more reliable biomarkers of disease and to better understand the underlying mechanisms and management.

Trends in Plasma Exchange Utilization in Optic Neuritis Hospitalizations in the United States.

PURPOSE: To report utilization trends of plasma exchange (PLEX) as well as sociodemographic and medical comorbidities associated with PLEX in the United States (US). DESIGN: Retrospective cross-sectional study. SUBJECTS: Adult patients (≥18 years old) admitted for inpatient hospitalization with a primary diagnosis of optic neuritis (ON). METHODS: Data from the National Inpatient Sample database was compiled to assess PLEX utilization rates between the year 2000 through 2020. The cohorts of patients receiving PLEX versus no PLEX were analyzed between quarter four of 2015 through 2020 (ICD-10 only) for patient sociodemographic variables, medical diagnoses, insurance types, hospital characteristics, etiology of disease, time-to-therapy, length of stay, and total charges incurred. MAIN OUTCOME MEASURES: Incidence of ON, incidence of PLEX, demographics, diagnoses associated with PLEX therapy, total charges, length of stay. RESULTS: From 2000 to 2020, 11209 patients hospitalized with a primary diagnosis of ON were identified with a significant majority managed at urban teaching hospitals. PLEX utilization increased steadily over two decades from .63% to 5.46%. Utilization was greatest in the Western US and least in the East. In the subset of ICD-10 cases, 3215 patients were identified. The median time to-therapy of PLEX was one day after admission, and PLEX utilization was highest in patients with neuromyelitis optica spectrum disorder (NMOSD) (21.21%) and lowest in multiple sclerosis-associated ON (3.80%). PLEX was associated with significantly longer length-of-stay and higher total charges incurred. Medical comorbidities associated with PLEX included adverse reaction to glucocorticoids (aOR, 31.50), hemiplegia (aOR = 28.48), neuralgia (aOR = 4.81), optic atrophy (aOR = 3.74), paralytic strabismus (aOR = 2.36), and psoriasis (aOR = 1.76). CONCLUSIONS: Over the last two decades in the US, PLEX therapy for ON has increased with the highest utilization in the Western US and for patients with the diagnosis NMOSD ON.

Ocular Manifestations of Multiple Sclerosis: A Population-Based Study.

BACKGROUND: To evaluate the population-based frequency and severity of multiple sclerosis (MS)-related ocular diseases. METHODS: Retrospective, population-based study examining patients with MS between January 1, 1998 and December 31, 2011. Patients were identified using the Rochester Epidemiology Project, which is a record-linkage system of medical records for all patient-physician encounters among Olmsted County, Minnesota residents. Diagnosis of MS was confirmed based on neuroimaging, cerebrospinal fluid studies, and serum studies for each patient according to the 2017 McDonald criteria. Patient data were obtained using the medical records and followed through April 1, 2018. RESULTS: Of the 116 patients with MS, 66% were female and the median age of onset was 36 years (interquartile range 27.5-43.5 years). About half (61/116, 53%) had MS-related neuro-ophthalmic manifestations during their disease course, and about one-fourth (33/116, 28%) had visual symptoms as their presenting symptom of MS, most commonly as optic neuritis (26/116, 22%). Optic neuritis was the leading MS-related ocular condition (37%), followed by internuclear ophthalmoplegia (16%) and nystagmus (13%). Optic neuritis was mostly unilateral (40/43, 93%), with 16% (6/43) having a visual acuity of 20/200 or worse at nadir but ultimately 95% (35/37) improving to a visual acuity of 20/40 or better. CONCLUSIONS: This study provides the population-based frequency of MS-related ocular disease, which demonstrates a high frequency of ocular manifestations in MS both at disease onset and during the disease course, emphasizing the utility of neuro-ophthalmologists, or collaboration between neurologists and ophthalmologists, in the care of patients with MS.

Immune Checkpoint Inhibitor-Associated Kelch-Like Protein-11 IgG Brainstem Encephalitis.

OBJECTIVES: Kelch-like protein-11 (KLHL11)-IgG is associated with rhombencephalitis and seminoma. It has not previously been described as a neurologic immune checkpoint inhibitor (ICI)-related adverse event (nirAE) or in association with esophageal adenocarcinoma. METHODS: We describe a 61-year-old man with metastatic esophageal adenocarcinoma treated with folinic acid, fluorouracil, oxaliplatin (FOLFOX), and nivolumab, who subsequently developed diplopia, vertigo, and progressive gait ataxia after 8 weeks of treatment. RESULTS: Owing to a concern for ICI-associated myasthenia gravis, nivolumab was held and he was treated with prednisone and pyridostigmine. EMG showed no neuromuscular junction dysfunction, and acetylcholine-receptor antibodies were negative. Brain MRI was unrevealing. Murine brain tissue immunofluorescence assay revealed KLHL11-IgG in both serum and CSF, confirmed by cell-based assay. Tumor histopathology demonstrated poorly differentiated, highly proliferative adenocarcinoma with increased mitotic figures and cytoplasmic KLHL11 immunoreactivity. He was initiated on 6 months of cyclophosphamide in addition to FOLFOX for post-ICI-associated KLHL11-IgG rhombencephalitis. DISCUSSION: We report KLHL11-IgG rhombencephalitis associated with poorly differentiated esophageal cancer as a novel nirAE. Tumor staining revealed KLHL11 immunoreactivity, supporting a cancer-antigen-driven ICI-associated paraneoplastic syndrome. Recognition of novel nirAEs can expedite treatment and potentially prevent progressive neurologic disability.

Acute Optic Neuropathy in Older Adults: Differentiating Between MOGAD Optic Neuritis and Nonarteritic Anterior Ischemic Optic Neuropathy.

BACKGROUND AND OBJECTIVES: Myelin oligodendrocyte glycoprotein antibody-associated disease optic neuritis (MOGAD-ON) and nonarteritic anterior ischemic optic neuropathy (NAION) can cause acute optic neuropathy in older adults but have different managements. We aimed to determine differentiating factors between MOGAD-ON and NAION and the frequency of serum MOG-IgG false positivity among patients with NAION. METHODS: In this international, multicenter, case-control study at tertiary neuro-ophthalmology centers, patients with MOGAD presenting with unilateral optic neuritis as their first attack at age 45 years or older and age-matched and sex-matched patients with NAION were included. Comorbidities, clinical presentations, acute optic disc findings, optical coherence tomography (OCT) findings, and outcomes were compared between MOGAD-ON and NAION. Multivariate analysis was performed to find statistically significant predictors of MOGAD-ON. A separate review of consecutive NAION patients seen at Mayo Clinic, Rochester, from 2018 to 2022, was conducted to estimate the frequency of false-positive MOG-IgG in this population. RESULTS: Sixty-four patients with unilateral MOGAD-ON were compared with 64 patients with NAION. Among patients with MOGAD-ON, the median age at onset was 56 (interquartile range [IQR] 50-61) years, 70% were female, and 78% were White. Multivariate analysis showed that eye pain was strongly associated with MOGAD-ON (OR 32.905; 95% CI 2.299-473.181), while crowded optic disc (OR 0.033; 95% CI 0.002-0.492) and altitudinal visual field defect (OR 0.028; 95% CI 0.002-0.521) were strongly associated with NAION. On OCT, peripapillary retinal nerve fiber layer (pRNFL) thickness in unilateral MOGAD-ON was lower than in NAION (median 114 vs 201 µm, p < 0.001; median pRNFL thickening 25 vs 102 µm, p < 0.001). MOGAD-ON had more severe vision loss at nadir (median logMAR 1.0 vs 0.3, p < 0.001), but better recovery (median logMAR 0.1 vs 0.3, p = 0.002). In the cohort of consecutive NAION patients, 66/212 (31%) patients with NAION were tested for MOG-IgG and 8% (95% CI 1%-14%) of those had false-positive serum MOG-IgG at low titers. DISCUSSION: Acute unilateral optic neuropathy with optic disc edema in older adults can be caused by either MOGAD-ON or NAION. Detailed history, the degree of pRNFL swelling on OCT, and visual outcomes can help differentiate the entities and prevent indiscriminate serum MOG-IgG testing in all patients with acute optic neuropathy.