The Risk of Optic Neuritis following mRNA Coronavirus Disease 2019 Vaccination Compared to Coronavirus Disease 2019 Infection and Other Vaccinations.

PURPOSE: To determine the risk of optic neuritis (ON) after mRNA Coronavirus Disease 2019 (COVID-19) vaccine administration. DESIGN: U.S. National aggregate database retrospective cohort study. PARTICIPANTS: Patients were placed into cohorts based on mRNA COVID-19 vaccination status (no vaccine and positive history of COVID-19 infection, 1 vaccine, or 2 vaccines received) from December 2020 to June 2022. Two control cohorts were created with patients vaccinated against influenza or tetanus diphtheria and pertussis (Tdap) from June 2018 to December 2019. Patients with any history of ON or significant risk factors for ON development including infectious, inflammatory, and neoplastic diseases were excluded. METHODS: A large deidentified database was queried for the Common Procedural Technology codes for immunization encounters specific to first dose and second dose of mRNA COVID-19 vaccine, influenza, or Tdap. Cohorts were 1:1 propensity score matched on age, sex, race, and ethnicity. The risk of ON development after vaccination was calculated and compared for all 5 cohorts with 95% confidence intervals (CIs) reported. MAIN OUTCOME MEASURES: Risk ratio (RR) of ON 21 days after vaccination (or COVID-19 infection) and incidence of ON per 100 000 individuals. RESULTS: After matching, the first dose COVID-19 and influenza vaccine cohorts (n = 1 678 598, mean age [standard deviation] at vaccination of 45.5 [23.3] years and 43.2 [25.5] years, 55% female) the RR of developing ON was 0.44 (95% CI, 0.28-0.80). The first dose of COVID-19 and Tdap vaccinations (n = 797 538, mean age 38.9 [20.0] years, 54.2% female) cohort had 10 and 16 patients develop ON (RR, 0.63; 95% CI, 0.28-1.38). Comparison of COVID-19-vaccinated patients (n = 3 698 848, 48.2 [21.5] years, 54.7% female) to unvaccinated and COVID-19-infected patients (n = 3 698 848, 49.6 [22.0] years, 55.2% female) showed 49 and 506 patients developing ON, respectively (RR, 0.09; 95% CI, 0.07-0.12). The incidence per 100 000 for ON was 1 in the first dose COVID-19 vaccine cohort, 2 in the influenza cohort, and 2 in the Tdap cohort, and 14 in the COVID-19-infected and unvaccinated cohorts. CONCLUSIONS: Risk of ON after mRNA COVID-19 vaccination is rare and comparable to Tdap vaccination, decreased compared with influenza vaccination, and decreased compared with COVID-19 infection in the absence of vaccination. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Characterisation and Visual Outcomes of Fulminant Idiopathic Intracranial Hypertension: A Narrative Review.

Fulminant idiopathic intracranial hypertension (IIH) is a rapid vision-degrading presentation of IIH with limited published studies. This study composed a narrative review of fulminant IIH with the aim of better characterising fulminant IIH presentation and visual outcomes. SCOPUS and PubMed were searched for papers referencing IIH, benign intracranial hypertension, or pseudotumour cerebri. Abstracts were screened for rapid degradation in vision. All studies were required to meet both the modified Dandy and fulminant IIH criteria. Thirty-six studies met the inclusion criteria. Demographics, treatments, and visual outcome data were collected. Case studies made up 69% of the studies and 31% were case series. In total, 72 patients with fulminant IIH were reported, of which 23.6% were paediatric and 96% were female. Surgical intervention occurred in 85% of patients. Anaemia was present in 11% of patients and 85.7% of paediatric patients had a sixth cranial nerve palsy. In conclusion, we propose the following practice guidelines to assist in diagnosing and treating fulminant IIH patients: 1) patients who present with optic disc oedema require urgent visual field testing to evaluate for vision loss; 2) a paediatric patient presenting with a sixth cranial nerve palsy should have a comprehensive eye examination; 3) fulminant IIH can occur in patients with a normal body mass index; and 4) anaemia should be tested for in the setting of fulminant IIH. As little is known about the optimal treatment mechanisms for this presentation, multi-institutional and international collaborations will be a critical step for future research.

Evaluating the Incidence and Neuro-Ophthalmic Manifestations of Carotid-Cavernous Fistulas.

BACKGROUND: To determine the incidence of carotid-cavernous fistula (CCF) and describe the neuro-ophthalmic manifestations and eventual clinical outcomes. METHODS: This was a population-based, retrospective cohort study using the Rochester Epidemiology Project to identify patients aged 18 years or older residing in Olmsted County, MN, diagnosed with CCF from 1997 to 2019. The medical records were reviewed for ophthalmic signs and symptoms, including conjunctival chemosis, proptosis, orbital bruit, diplopia, ophthalmoplegia, orbital pain, ocular hypertension, and blurred vision. Also determined was the number of patients with CCF found incidentally on neuroimaging, without clinical manifestations. RESULTS: Ten patients were diagnosed with a CCF between 1997 and 2019 with an overall incidence rate of 0.37 per 100,000 per year (95% CI 0.20-0.68). The median age was 50.5 years (range 23-74 years), 6 (60%) were female, and 9 were White and 1 patient was Korean. Three patients (30%) were asymptomatic and found incidentally on imaging that was obtained for unrelated reasons, and one patient's ocular details were unavailable because she passed away from severe head trauma. The following neuro-ophthalmologic or ocular manifestations were identified in the remaining 6 patients: chemosis/conjunctival injection (n = 6), cranial nerve (CN) VI palsy (n = 6), CN III palsy (n = 2), proptosis (n = 4), ocular/orbital pain (n = 3), audible orbital bruit (n = 2), ocular hypertension (n = 1), and blurred vision (n = 1). Of those patients with symptomatic CCFs, all underwent treatment except for one that spontaneously resolved. None of the patients suffered a stroke or cerebral hemorrhage. The 3 patients with incidentally discovered CCFs were asymptomatic and did not require treatment. CONCLUSIONS: This is the first population-based study to show a low incidence rate of CCFs, supporting the notion that it is an uncommon condition. Neuro-ophthalmic manifestations are common, especially chemosis/conjunctival injection and CN VI palsy. Up to a third of patients with CCF can be asymptomatic and may be found incidentally on neuroimaging during the evaluation for unrelated symptoms.

Fluorescein Angiography Findings in Susac Syndrome: A Multicenter Retrospective Case Series.

BACKGROUND: Susac syndrome is a vasculopathy, resulting in the classic triad of branch retinal artery occlusion (BRAO), inner ear ischemia, and brain ischemia. In this retrospective chart review, we characterize fluorescein angiography (FA) findings and other ancillary studies in Susac syndrome, including the appearance of persistent disease activity and the occurrence of new subclinical disease on FA. METHODS: This multicenter, retrospective case series was institutional review board-approved and included patients with the complete triad of Susac syndrome evaluated with FA, contrasted MRI of the brain, and audiometry from 2010 to 2020. The medical records were reviewed for these ancillary tests, along with demographics, symptoms, visual acuity, visual field defects, and findings on fundoscopy. Clinical relapse was defined as any objective evidence of disease activity during the follow-up period after initial induction of clinical quiescence. The main outcome measure was the sensitivity of ancillary testing, including FA, MRI, and audiometry, to detect relapse. RESULTS: Twenty of the 31 (64%) patients had the complete triad of brain, retinal, and vestibulocochlear involvement from Susac syndrome and were included. Median age at diagnosis was 43.5 years (range 21-63), and 14 (70%) were women. Hearing loss occurred in 20 (100%), encephalopathy in 13 (65%), vertigo in 15 (75%), and headaches in 19 (95%) throughout the course of follow-up. Median visual acuity at both onset and final visit was 20/20 in both eyes. Seventeen (85%) had BRAO at baseline, and 10 (50%) experienced subsequent BRAO during follow-up. FA revealed nonspecific leakage from previous arteriolar damage in 20 (100%), including in patients who were otherwise in remission. Of the 11 episodes of disease activity in which all testing modalities were performed, visual field testing/fundoscopy was abnormal in 4 (36.4%), MRI brain in 2 (18.2%), audiogram in 8 (72.7%), and FA in 9 (81.8%). CONCLUSIONS: New leakage on FA is the most sensitive marker of active disease. Persistent leakage represents previous damage, whereas new areas of leakage suggest ongoing disease activity that requires consideration of modifying immunosuppressive therapy.

Collapsin Response-Mediator Protein 5-Associated Retinitis, Vitritis, and Optic Disc Edema.

PURPOSE: Collapsin response-mediator protein 5 (CRMP5) immunoglobulin G (IgG) has been associated with paraneoplastic optic neuritis, vitritis, retinitis, or a combination thereof, but few reports of these findings exist in the literature. We reviewed the neuro-ophthalmic findings and visual outcomes in a large series of CRMP5 IgG-positive patients to characterize further its clinical phenotype and response to treatment. DESIGN: Retrospective case series. PARTICIPANTS: Seventy-six patients with CRMP5 autoimmunity examined at the Mayo Clinic, Rochester, Minnesota. METHODS: Single academic medical center chart review of all CRMP5 IgG-positive (serum titer, >1:240) patients seen between 2001 and 2017. MAIN OUTCOME MEASURES: Neuro-ophthalmic manifestations and outcomes of CRMP5 autoimmunity, coexisting neural autoantibody presence and paraneoplastic associations, and the impact of immunosuppressant therapy. RESULTS: Twenty-nine of 76 patients (38%) demonstrated neuro-ophthalmic manifestations. Of the 29 patients with neuro-ophthalmic findings, the median age was 67 years (range, 33-88 years) and 20 (69%) were women. Cancer was diagnosed in 62% of the patients (small-cell carcinoma in 83%). Neuro-ophthalmic symptoms occurred before the diagnosis of cancer in 72%. Seventeen of 29 patients (59%) showed ocular (i.e., anterior visual pathway or intraocular) manifestations; presenting median visual acuity was 20/50 (range, 20/20-counting fingers) and the final median visual acuity was 20/40 (range, 20/20-hand movements). Fourteen of 17 patients (82%) demonstrated optic neuropathy, with 12 of these patients also showing retinitis or uveitis. Three of 17 patients (18%) showed retinitis or uveitis without optic neuropathy. All 12 patients with optic neuropathy and a documented fundus examination at visual symptom onset demonstrated optic disc edema. No patients showed optic nerve enhancement on magnetic resonance imaging. Twelve of 29 patients (41%) demonstrated ocular motility dysfunction consisting of central nystagmus and diplopia. Among those receiving immunosuppressive therapy, visual function improved in 50%. CONCLUSIONS: In our cohort of 29 CRMP5 IgG-positive patients with neuro-ophthalmic manifestations, optic neuropathy presented with optic disc edema, often associated with uveitis, retinitis, or both. The combination of retinitis, vitritis, and optic disc edema without optic nerve enhancement should prompt serologic testing for CRMP5 IgG to expedite vision-sparing immunosuppressant therapy and a targeted search for a systemic cancer.

Intracranial Pure Germinoma With Optic Nerve Infiltration.

A 19-year-old man presented with a 3-year history of episodic headaches, right hemiparesis, and progressive vision loss in both eyes. Initially, extensive laboratory testing was unrevealing. MRI later demonstrated progressive enlargement and enhancement of the left optic nerve poorly correlated with the timing of his clinical manifestations. There was no clinical or radiological response to treatment with corticosteroids, mycophenolate mofetil, or rituximab administered empirically for possible inflammatory processes. Later in the disease course, he developed diabetes insipidus (DI), worsening vision to light perception bilaterally, severe cognitive decline, and spastic quadriparesis. Cerebrospinal fluid (CSF) beta human chorionic gonadotropin (ß-hCG) was elevated. Eventually, a left optic nerve biopsy was performed, which was consistent with an intracranial pure germinoma with infiltration of the optic nerve and disseminated leptomeningeal disease. Although rare, intracranial germ cell tumors can primarily involve the anterior visual pathways and should be considered in the setting of DI and elevated CSF ß-hCG.

Characterization of ANKRD11 mutations in humans and mice related to KBG syndrome.

Mutations in ANKRD11 have recently been reported to cause KBG syndrome, an autosomal dominant condition characterized by intellectual disability (ID), behavioral problems, and macrodontia. To understand the pathogenic mechanism that relates ANKRD11 mutations with the phenotype of KBG syndrome, we studied the cellular characteristics of wild-type ANKRD11 and the effects of mutations in humans and mice. We show that the abundance of wild-type ANKRD11 is tightly regulated during the cell cycle, and that the ANKRD11 C-terminus is required for the degradation of the protein. Analysis of 11 pathogenic ANKRD11 variants in humans, including six reported in this study, and one reported in the Ankrd11 (Yod/+) mouse, shows that all mutations affect the C-terminal regions and that the mutant proteins accumulate aberrantly. In silico analysis shows the presence of D-box sequences that are signals for proteasome degradation. We suggest that ANKRD11 C-terminus plays an important role in regulating the abundance of the protein, and a disturbance of the protein abundance due to the mutations leads to KBG syndrome.

Changes in Prevalence of Idiopathic Intracranial Hypertension in the United States Between 2015 and 2022, Stratified by Sex, Race, and Ethnicity.

BACKGROUND AND OBJECTIVES: With the obesity epidemic within the United States, the prevalence of idiopathic intracranial hypertension (IIH) is predicted to rise. IIH prevalence and racial disparities have rarely been reported in the United States. The purpose of this study was to evaluate the prevalence of IIH in a large national database while stratifying by sex, age, race, and ethnicity. METHODS: This was a cross-sectional epidemiologic evaluation conducted in the TriNetX US Collaborative network using data from 2015 to 2022. Patients with an International Classification of Diseases code of IIH and papilledema or unspecified papilledema were included in the study. Any secondary cause of intracranial hypertension including cerebral neoplasms and hydrocephalus were excluded from the study. IIH trends were later compared with TriNetX cohort obesity trends. Prevalence and prevalence odds ratios (ORs) were calculated in Microsoft Excel and R Studio. RESULTS: Among 85 million patients in this database, a 1.35 times increase in the prevalence of IIH occurred between 2015 and 2022 from 7.3 (95% CI 6.9-7.7) individuals per 100,000 to 9.9 (95% CI 9.5-10.3) individuals per 100,000 in 2022. In 2022, Black female individuals had the highest prevalence of IIH with 22.7 individuals per 100,000 compared with the 13.7 White female individuals per 100,000. Patients aged 11-17 years showed the largest growth of IIH prevalence with female individuals increasing by 10 individuals per 100,000 by 2022. Overall, Black and Hispanic patients had the largest prevalence OR of IIH at 1.66 (95% CI 1.49-1.85) and 1.33 (95% CI 1.14-1.56), respectively, compared with White female patients. DISCUSSION: IIH is a rapidly increasing health care concern for the US population, particularly among adolescent patients. Black and Hispanic female individuals are most predominately affected by this incapacitating disorder.

Clinical Reasoning: An Unusual Cause of Diplopia and Ptosis in a 67-Year-Old Woman.

Diplopia is a relatively common chief complaint encountered in an outpatient neurology clinic and carries a broad differential diagnosis. In this case, a 67-year-old woman presented with new horizontal, binocular diplopia and ptosis of 8-month duration, which persisted without significant progression. This case highlights the need for a comprehensive list of differential diagnoses for patients with acquired ophthalmoplegia and ptosis. Key learning points include an illustration of the stepwise diagnostic approach to evaluate for common etiologies, the importance of interpreting test results in the appropriate clinical setting, and the significance of recognizing specific signs and symptoms in achieving the correct diagnosis.

Serum Biomarkers in Neuro-Ophthalmology: When to Test.

Discovery and characterization of serologic biomarkers has revolutionized the diagnostic framework of systemic and paraneoplastic autoimmune neuro-ophthalmic diseases. Expanding recognition of the multiple ocular and visual manifestations of these conditions highlights the important role of the referring provider in identifying potential cases. Increasing ease of access to serologic testing also enables these practitioners to initiate the diagnostic work-up in suspected cases. We aimed to provide an update on the current knowledge surrounding and use of relevant autoimmune biomarkers by correlating specific clinical neuro-ophthalmic manifestations with autoantibody biomarkers. The utility of select biomarkers for myasthenia gravis, neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein-IgG-associated disorder, opsoclonus-myoclonus syndrome, anti-collapsin-response mediator protein-5 optic neuropathy, and glial fibrillary acidic protein-IgG-associated disease are discussed with particular focus on the clinical contexts in which to consider testing.

Discordance Rate Among Bilateral Simultaneous and Sequential Temporal Artery Biopsies in Giant Cell Arteritis: Role of Frozen Sectioning Based on the Mayo Clinic Experience.

IMPORTANCE: Frozen section temporal artery biopsy (TAB) may prevent a contralateral biopsy from being performed. OBJECTIVE: To evaluate the sensitivity and specificity of TAB frozen vs permanent section pathology results for giant cell arteritis (GCA) and determine the discordance rate of bilateral TABs. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study, medical records were reviewed from 795 patients 40 years or older who underwent TAB from January 1, 2010, to December 1, 2018, treated at a single tertiary care center with the ability to perform both frozen and permanent histologic sections. Data were analyzed from January 2019 to December 2020. MAIN OUTCOMES AND MEASURES: Sensitivity and specificity of frozen section TAB for detecting GCA, and discordance rates of bilateral permanent section TAB. RESULTS: Of the 795 included participants, 329 (41.4%) were male, and the mean (SD) age was 72 (10) years. From the 795 patients with 1162 TABs, 119 patients (15.0%) and 138 TABs had positive findings on permanent section. Of these 119 patients, 103 (86.6%) also had positive results on the frozen section, with 4 false-positives (0.6%) and 20 false-negatives (16.8%). Frozen section had a specificity of 99.4% (95% CI, 98.5-99.8), sensitivity of 83.2% (95% CI, 75.2-89.4), positive predictive value of 96.1% (95% CI, 90.4-98.9), negative predictive value of 96.6% (95% CI, 94.9-97.8), positive likelihood ratio of 140.6 (95% CI, 72.7-374.8), and a negative likelihood ratio of 0.17 (95% CI, 0.11-0.25). Simultaneous bilateral TABs were performed in 60 patients (7.5%) with a 5% discordance rate on permanent section. In comparison, bilateral frozen section-guided sequential TABs were performed in 307 patients (38.6%) with 5.5% discordance based on permanent section. In multivariate models, there was a greater odds of positive findings with age (odds ratio [OR], 1.04; 95% CI, 1.01-1.07; P = .008), vision loss (OR, 2.72; 95% CI, 1.25-5.75; P = .01), diplopia (OR, 3.33; 95% CI, 1.00-10.29; P = .04), headache (OR, 2.32; 95% CI, 1.25-4.53; P = .01), weight loss (OR, 2.37; 95% CI, 1.26-4.43; P = .007), and anorexia (OR, 5.65; 95% CI, 2.70-11.89; P < .001). CONCLUSIONS AND RELEVANCE: These results support the hypothesis that negative findings from frozen sections should not be solely relied on to refute the diagnosis of GCA, whereas positive findings from frozen sections can be reliably used to defer a contralateral biopsy pending the permanent section results.

It is not your eyes.

A 55-year-old woman reported blurred vision while walking, numbness and tingling, contact allodynia, and gait imbalance. Visual acuity was 20/20 in both eyes, but there was a loss of 4 lines with horizontal dynamic visual acuity testing. Ocular motility examination demonstrated spontaneous downbeat nystagmus that increased in lateral gaze with a torsional component and impaired smooth pursuits. Head impulse test was positive, and electromyography demonstrated a sensory neuropathy/neuronopathy. Vestibular testing confirmed both central ocular motor pathway and bilateral peripheral vestibular system involvement. The constellation of clinical findings and paraclinical testing was consistent with a recently recognized neurodegenerative disorder termed cerebellar ataxia with neuropathy and vestibular areflexia syndrome.

A comprehensive library of familial human amyotrophic lateral sclerosis induced pluripotent stem cells.

Amyotrophic lateral sclerosis is a progressive disease characterized by the loss of upper and lower motor neurons, leading to paralysis of voluntary muscles. About 10% of all ALS cases are familial (fALS), among which 15-20% are linked to Cu/Zn superoxide dismutase (SOD1) mutations, usually inherited in an autosomal dominant manner. To date only one FDA approved drug is available which increases survival moderately. Our understanding of ALS disease mechanisms is largely derived from rodent model studies, however due to the differences between rodents and humans, it is necessary to have humanized models for studies of disease pathogenesis as well as drug development. Therefore, we generated a comprehensive library of a total 22 of fALS patient-specific induced pluripotent stem cell (iPSC) lines. These cells were thoroughly characterized before being deposited into the library. The library of cells includes a variety of C9orf72 mutations, sod1 mutations, FUS, ANG and FIG4 mutations. Certain mutations are represented with more than one line, which allows for studies of variable genetic backgrounds. In addition, these iPSCs can be successfully differentiated to astroglia, a cell type known to play a critical role in ALS disease progression. This library represents a comprehensive resource that can be used for ALS disease modeling and the development of novel therapeutics.