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Background: The differentiation of Horner syndrome from physiological anisocoria is important yet clinically challenging. We investigated the diagnostic accuracy of pupillometry to discriminate Horner syndrome from physiological anisocoria compared to pharmacological testing with the alpha-2-agonist apraclonidine, which is considered the current gold standard., Methods: Forty-four adult patients, mostly referred to our neuro-ophthalmology service for evaluation of anisocoria, were included. Automated binocular pupillometry was performed under standardized light conditions before and >30 minutes after instillation of 1% apraclonidine eye drops. A positive apraclonidine test indicating unilateral Horner syndrome was defined as an increase of pupil size in the smaller pupil and decrease of size in the larger pupil. Receiver operator characteristic curves were calculated to find the best pupillometric parameter discriminating Horner syndrome from physiological anisocoria., Results: We found that the parameters measuring the pupillary dilation lag using pupillometry could reliably discriminate Horner syndrome from physiological anisocoria compared to pharmacological testing. Calculating the change of anisocoria at 3-4 seconds after light-off relative to the anisocoria at the end of the light-on period (Δ3-4) may be most suitable to rule out Horner syndrome reaching a sensitivity of 95% and specificity of 68% using a cutoff of 0.35 mm., Conclusions: Our results indicate that pupillometry is a robust tool to measure the dilation lag in Horner syndrome and, therefore, to distinguish pathological from physiological anisocoria obviating pharmacological testing. The high sensitivity of the test will allow to identify the patients with Horner syndrome requiring further investigation., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the North American Neuro-Ophthalmology Society.)

Patients with visual snow syndrome (VSS) experience uncountable flickering tiny dots in the entire visual field. Symptoms often persist over the years. Very little is known about altered perception in VSS. VSS is diagnosed based on subjective reports because there is no manual with objective measures. In this study, 20 patients with VSS and 17 healthy controls performed a battery of tests assessing visual acuity, contrast sensitivity, illusion perception, spatial-temporal vision, motion perception, visual attention, and selective attention. Surprisingly, except for one test, which is the honeycomb illusion, patients performed at the same level as controls. Patients reporting black and white visual snow performed better in the Stroop test compared to patients reporting other visual snow colours. In addition to a clinical visit, the 30-day clinical diary was administered to patients to broadly measure their symptom severity. We found that better performance in the tests, in particular in the contrast and coherent motion tests, was correlated with lower VSS symptoms, weaker VS characteristics (e.g. density and size) and lower VS severity. Our results suggest that, even if visual abilities are not deteriorated by VSS, they can determine how severe symptoms are, and show that VSS is an heterogenous disorder where symptoms and visual abilities vary between patients, for instance depending on the VS colour. The study was primarily designed to identify tests where performance differs between controls and patients. In addition, exploratory analyses were conducted to initiate an understanding of the overall pattern of relationships between patients' visual abilities and symptoms, which is of clinical relevance. Future studies with more power are necessary to validate our findings., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Unpreserved single-dose unit (SDU) eye drops are commonly used to avoid benzalkonium chloride-related toxicity. Although intended for single use, many patients report off-label repeated use of SDUs over a prolonged period. We investigated whether repeated use of dexamethasone 0.1% SDUs in the same patient increases the bacterial contamination rate., Methods: We prospectively enrolled patients scheduled for inpatient corneal and glaucoma surgery receiving dexamethasone 0.1% SDU four times per day from the same vial. To assess contamination rates, one drop from the vial was cultured immediately after opening the SDU (t0), 10 hours later after four drop applications (t10) and 24 hours after opening without further drop applications (t24). Conjunctival swabs were taken before and after drop application. Contamination rate was assessed with a standard clinical culturing protocol without introducing a positive control., Results: 110 eyes of 109 patients were evaluated. Drops collected immediately after opening the SDU (t0) were contaminated in 9/110 cultures (8.1%). At t10, 13/110 cultures were contaminated (11.8%; p=0.267) and 11/110 at t24 (10.0%; t24 vs t0; p=1.00). In 5 of 21 cases of contaminated drops at t10 and/or t24, the same isolates were cultured from the initial conjunctival swab and the SDU. In three cases, the same bacterial species was found in consecutive samples., Conclusion: The contamination rate of the SDU did not increase after multiple use within 24 hours. Contamination from fingertip flora was more likely than from ocular surface flora. Reuse of dexamethasone 0.1% SDU in the same patient within 24 hours appears to be safe., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: We developed repetitive ocular vestibular-evoked myogenic potentials (roVEMP) as an electrophysiologic test that allows us to elicit the characteristic decrement of extraocular muscles in patients with ocular myasthenia gravis (OMG). Case-control studies demonstrated that roVEMP reliably differentiates patients with OMG from healthy controls. We now aimed to evaluate the diagnostic accuracy of roVEMP for OMG diagnosis in patients with ptosis and/or diplopia., Methods: In this blinded prospective diagnostic accuracy trial, we compared roVEMP in 89 consecutive patients presenting with ptosis and/or diplopia suspicious of OMG with a multimodal diagnostic approach, including clinical examination, antibodies, edrophonium testing, repetitive nerve stimulation of accessory and facial nerves, and single-fiber EMG (SFEMG). We calculated the roVEMP decrement as the ratio between the mean of the first 2 responses compared with the mean of the sixth-ninth responses in the train and used cutoff of >9% (unilateral decrement) in a 30 Hz stimulation paradigm., Results: Following a complete diagnostic work-up, 39 patients (44%) were diagnosed with ocular MG, while 50 patients (56%) had various other neuro-ophthalmologic conditions, but not MG (non-MG). roVEMP yielded 88.2% sensitivity, 30.2% specificity, 50% positive predictive value (PPV), and 76.5% negative predictive value (NPV). For comparison, SFEMG resulted in 75% sensitivity, 56% specificity, 55.1% PPV, and 75.7% NPV. All other diagnostic tests (except for the ice pack test) also yielded significantly higher positive results in patients with MG compared with non-MG., Discussion: The study revealed a high sensitivity of 88.2% for roVEMP in OMG, but specificity and PPV were too low to allow for the OMG diagnosis as a single test. Thus, differentiating ocular MG from other neuro-ophthalmologic conditions remains challenging, and the highest diagnostic accuracy is still obtained by a multimodal approach. In this study, roVEMP can complement the diagnostic armamentarium for the diagnosis of MG., Classification of Evidence: This study provides Class I evidence that in patients with diplopia and ptosis, roVEMP alone does not accurately distinguish MG from non-MG disorders., Trial Registration Information: ClinicalTrials.gov: NCT03049956.

Importance: The current clinical criterion standard for measuring abnormal eyeball protrusion is still the historic Hertel exophthalmometer, which is prone to reading errors. Therefore, a smartphone application has been developed to measure exophthalmos., Objective: To evaluate a relatively simple noninvasive measurement method for exophthalmos using a smartphone., Design, Setting, and Participants: This cross-sectional study compared smartphone exophthalmometry with the existing reference standard, the Hertel exophthalmometer, or a professional high-resolution 3-dimensional scanner. Participants were patients with exophthalmos due to Graves orbitopathy and other intraorbital conditions and healthy volunteers who were recruited between June 2019 and January 2022 from the Department of Ophthalmology, University Hospital Zurich., Interventions: All participants were examined twice by 3 different operators using 3 different methods (smartphone, high-resolution scanner, or Hertel exophthalmometer) at an interval of a minimum of 2 weeks or after exophthalmos-changing treatment., Main Outcome Measures: Accuracy and precision, test-retest reliability, and interoperator reliability of eyeball protrusion measurements obtained with the smartphone compared to the Hertel exophthalmometer and the high-resolution face scanner., Results: Of 39 participants, 23 patients (median [IQR] age, 54 [44-59] years; 15 [65%] female and 8 [35%] male) showed a mean difference in eyeball protrusion of 3.3 mm and 16 healthy volunteers (median [IQR] age, 32 [30-37] years; 11 [69%] female and 5 [31%] male) of 0.8 mm without any significant difference between the 3 methods. Accuracy and precision agreement between exophthalmos measures with the smartphone and the Hertel exophthalmometer showed an intraclass correlation coefficient (ICC) of 0.89 (95% CI, 0.80-0.94) and 0.93 (95% CI, 0.83-0.97) for the high-resolution scanner. Interoperator agreement was highest for the high-resolution scanner (ICC, 0.99 [95% CI, 0.98-0.99]), followed by the smartphone (ICC, 0.95 [95% CI, 0.92-0.97]) and the Hertel exophthalmometer (ICC, 0.91 [95% CI, 0.85-0.95]). Test retest reliability was similarly high for the smartphone (ICC, 0.93 [95% CI, 0.82-0.95]), the Hertel exophthalmometer (ICC, 0.92 [95% CI, 0.83-0.96]), and the high-resolution scanner (ICC, 0.95 [95% CI, 0.89-0.97])., Conclusions and Relevance: The findings of this study demonstrate relatively high accuracy and precision, interoperator reliability, and test-retest reliability for smartphone exophthalmometry. These data support the use of a smartphone in place of a Hertel exophthalmometer for measuring exophthalmos in the future.

Pharmacological testing with apraclonidine eye drops induces a typical reversal of anisocoria in patients with Horner's syndrome. Moreover, apraclonidine was observed to have an elevating effect on the upper eyelid in Horner's syndrome as well as in healthy subjects, which is thought to be mediated by alpha-1 adrenergic receptors present in the Muller's muscle. We aim to quantitatively investigate the effect of apraclonidine on eyelid position in patients with Horner's syndrome compared to physiological anisocoria based on infrared video recordings from pupillometry. We included 36 patients for analysis who underwent binocular pupillometry before and after apraclonidine 1% testing for the evaluation of anisocoria. Vertical eyelid measurements were taken from infrared videos and averaged from multiple pupillometry cycles. Receiver operating characteristic curves were calculated to determine the optimal cutoff value for change in eyelid aperture pre- and post-apraclonidine. A decrease of inter-eye difference in the aperture of >0.42 mm was discriminative of Horner's syndrome compared to physiological anisocoria with a sensitivity of 80% and a specificity of 75%. Our data confirm an eyelid- elevating effect of the apraclonidine test, more pronounced in eyes with a sympathetic denervation deficit. Measuring eyelid aperture on pupillometry recordings may improve the diagnostic accuracy of apraclonidine testing in Horner's syndrome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer KL declared a shared affiliation with the authors to the handling editor at the time of review., (Copyright © 2022 Fierz, Disse, Bockisch and Weber.)

Purpose: To quantitatively assess lateral geniculate nucleus (LGN) volume loss in the presence of lesions in the postgeniculate pathway and its correlation with optical coherence tomography retinal parameters., Methods: This was a case control study of patients recruited at the University Hospital Zurich, Switzerland. Nine patients who were suffering from lesions in the postgeniculate pathway acquired at least 3 months earlier participated. Retinal parameters were analyzed using spectral domain optical coherence tomography and a newly developed magnetic resonance imaging protocol with improved contrast to noise ratio was applied to measure LGN volume., Results: The affected LGN volume in the patients (mean volume 73.89 ± 39.08 mm3) was significantly smaller compared with the contralateral unaffected LGN (mean volume 131.43 ± 12.75 mm3), as well as compared with healthy controls (mean volume 107 ± 24.4 mm3). Additionally, the ganglion cell layer thickness corresponding with the affected versus unaffected side within the patient group differed significantly (mean thickness 40.5 ± 4.11 µm vs 45.7 ± 4.79 µm) compared with other retinal parameters. A significant linear correlation could also be shown between relative LGN volume loss and ganglion cell layer thickness decrease., Conclusions: Corresponding LGN volume reduction could be shown in patients with postgeniculate lesions using a newly developed magnetic resonance imaging protocol. LGN volume decrease correlated with ganglion cell layer thickness reduction as a sign of trans-synaptic retrograde neuronal degeneration.

Background: Brown syndrome is characterized by a restrictive elevation deficit of the affected eye in adduction. Besides the well-known congenital form, different acquired etiologies including inflammation, trauma, and surgery may prevent the superior oblique (SO) tendon from gliding freely through the trochlea on attempted upgaze. We present MRI findings in pediatric and adult patients with inflammatory acquired Brown syndrome., Methods: Retrospective review of clinical and MRI findings of 6 patients (4 children: median age 8.4 years [range 6.1-8.7]; 2 adults: age 46.4 and 51.1 years). Median follow-up was 23 months (range 1-52)., Results: In all 6 patients, orbital MRI demonstrated inflammatory changes of the SO tendon-trochlea complex. A striking feature was circumferential contrast enhancement of the trochlea with central sparing where the tendon passes, reminiscent of an eyelet. In all cases, the motility restriction improved either spontaneously or with systemic anti-inflammatory treatment. Although both adult patients had a history of known seronegative spondyloarthritis, there was no associated systemic condition in the children in our series., Conclusions: Both in children and in adults, MRI can provide evidence of inflammatory changes located at the trochlea-tendon complex in acquired Brown syndrome here referred to as the "eyelet sign," which may be helpful in confirming the clinical diagnosis and guide appropriate treatment., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by North American Neuro-Ophthalmology Society.)

Background: Visual snow is considered a disorder of central visual processing resulting in a perturbed perception of constant binocular flickering or pixilation of the whole visual field. The underlying neurophysiological and structural alterations remain elusive. Methods: In this study, we included patients (final n = 14, five dropouts; five females, mean age: 32 years) with visual snow syndrome (VSS) and age- and sex-matched controls (final n = 20, 6 dropouts, 13 females, mean age: 28.2 years). We applied diffusion tensor imaging to examine possible white matter (WM) alterations in patients with VSS. Results: The patient group demonstrated higher (p-corrected < 0.05, adjusted for age and sex) fractional anisotropy (FA) and lower mean diffusivity (MD) and radial diffusivity (RD) compared to controls. These changes were seen in the prefrontal WM (including the inferior fronto-occipital fascicle), temporal and occipital WM, superior and middle longitudinal fascicle, and sagittal stratum. When additionally corrected for migraine or tinnitus-dominant comorbidities in VSS-similar group differences were seen for FA and RD, but less pronounced. Conclusions: Our results indicate that patients with VSS present WM alterations in parts of the visual cortex and outside the visual cortex. As parts of the inferior fronto-occipital fascicle and sagittal stratum are associated with visual processing and visual conceptualisation, our results suggest that the WM alterations in these regions may indicate atypical visual processing in patients with VSS. Yet, the frequent presence of migraine and other comorbidities such as tinnitus in VSS makes it difficult to attribute WM disruptions solely to VSS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Michels, Stämpfli, Aldusary, Piccirelli, Freund, Weber, Fierz, Kollias and Traber.)

The Hess and the Harms screen test each have different testing distances. While the Harms screen test is usually performed at 2.5 m, the Hess screen test is performed at 0.5 m. The geometry of the closer testing distance of the Hess screen test requires an increase of the convergence angle by 6°. This study investigates the quantitative differences between the two frequently employed screen tests. Ocular deviation of 18 normal subjects and 36 patients with congenital or acquired paralytic or concomitant strabismus were assessed with a complete orthoptic examination including alternate prism cover testing at near (nPCT) and far (fPCT), as well as Hess and Harms screen testing. One-way ANOVA was used for statistical analysis. The Hess test recorded more overall exodeviation compared to the Harms test for patients (mean difference -3.50°, 95% limits of agreement (CI) = [-4.79, -2.21], p < .001), and controls (mean difference -1.78°, CI = [-2.99, -0.56], p = .004). For vertical deviations, there was no statistically significant difference between the two tests for patients (mean difference +0.75°, CI = [-0.41, +1.91], p = .251), and controls (mean difference -0.28°, CI = [-0.68, -0.11], p = 0.231). This study emphasizes the importance to consider the divergence bias when comparing the Hess to the Harms screen test, which is likely explained by the greater vergence demand dependent on the closer testing distance. The exodeviation shift tended to be more pronounced in patients than controls, which may imply that patients with strabismus have an impaired convergence drive.

Objective: Visual snow (VS) is a distressing, life-impacting condition with persistent visual phenomena. VS patients show cerebral hypermetabolism within the visual cortex, resulting in altered neuronal excitability. We hypothesized to see disease-dependent alterations in functional connectivity and gray matter volume (GMV) in regions associated with visual perception., Methods: Nineteen patients with VS and 16 sex- and age-matched controls were recruited. Functional magnetic resonance imaging (fMRI) was applied to examine resting-state functional connectivity (rsFC). Volume changes were assessed by means of voxel-based morphometry (VBM). Finally, we assessed associations between MRI indices and clinical parameters., Results: Patients with VS showed hyperconnectivity between extrastriate visual and inferior temporal brain regions and also between prefrontal and parietal (angular cortex) brain regions ( p < 0.05, corrected for age and migraine occurrence). In addition, patients showed increased GMV in the right lingual gyrus ( p < 0.05 corrected). Symptom duration positively correlated with GMV in both lingual gyri ( p < 0.01 corrected)., Conclusion: This study found VS to be associated with both functional and structural changes in the early and higher visual cortex, as well as the temporal cortex. These brain regions are involved in visual processing, memory, spatial attention, and cognitive control. We conclude that VS is not just confined to the visual system and that both functional and structural changes arise in VS patients, be it as an epiphenomenon or a direct contributor to the pathomechanism of VS. These in vivo neuroimaging biomarkers may hold potential as objective outcome measures of this so far purely subjective condition., (Copyright © 2020 Aldusary, Traber, Freund, Fierz, Weber, Baeshen, Alghamdi, Saliju, Pazahr, Mazloum, Alshehri, Landau, Kollias, Piccirelli and Michels.)

Timely and accurate diagnosis of myasthenia gravis, particularly in patients with fluctuating, isolated ocular involvement, remains challenging. Serological antibody testing and repetitive nerve stimulation of peripheral muscles usually have low sensitivity in these patients. Edrophonium testing may cause adverse events, single-fiber electromyography (SFEMG) is time-consuming and both tests are often unavailable outside specialized institutions. Repetitive ocular vestibular evoked myogenic potential (roVEMP) stimulation has recently been introduced to facilitate the diagnosis of myasthenia gravis. Similar to repetitive nerve stimulation, roVEMPs detect muscle decrements with the benefit of being non-invasive and allowing for direct measurement of the extraocular muscles. This review summarizes the clinical evidence of the diagnostic value of roVEMP for myasthenia. Prospective clinical trials have demonstrated high sensitivity and specificity. RoVEMPs are of particular interest in challenging myasthenia subgroups with isolated ocular involvement, negative serology, and/or negative conventional electrophysiological results. Optimal roVEMP repetition rates of 20-30 Hz have been identified. This promising novel diagnostic tool merits further attention and investigation to establish its value as a clinical test for myasthenia., (Copyright © 2020 Wirth, Fierz, Valko and Weber.)

Background: Evaluation of anisocoria including pharmacological testing for Horner's syndrome in the pediatric population is challenging in view of potential serious underlying disease. We describe cocaine test results, outcome of systemic investigation, and long-term follow-up in children with anisocoria., Methods: Retrospective review of medical records and phone interview of consecutive pediatric patients (<18 years old) who underwent cocaine testing from August 2007 to July 2015 at a tertiary referral centre., Results: A total of 35 patients were included with a positive, negative, or inconclusive cocaine test in 12/35, 19/35, and 4/35, respectively. Systemic investigation was performed in 11 of the patients with a positive and in 2 of the patients with an inconclusive cocaine test result. Mediastinal Hodgkin lymphoma was found in one patient with an inconclusive cocaine test result. Two other cases were presumably related to birth trauma and surgical trauma. None of the other children further developed any pathology during the follow-up period of 34.8 months (range 0-106.6)., Conclusions: In most children with anisocoria and a positive cocaine test result, systemic investigation did not reveal any underlying etiology. The only malignant disease was diagnosed in a patient with a suspicion of Horner's syndrome but with an inconclusive cocaine test result in our cohort.

Background. In advanced cutaneous melanoma, new systemic therapies include immunotherapy by checkpoint inhibition and targeted inhibition of the mitogen-activated protein kinase pathway; these are becoming increasingly well established. We describe the clinical presentation of uveitis in three patients with concomitant systemic melanoma treatment. History and Signs. Three patients with metastatic melanoma receiving systemic therapy (ipilimumab, vemurafenib) presented at our institution with a short history of ocular symptoms. Clinical findings included anterior uveitis, intermediate uveitis, disc swelling, inflammatory choroidal lesions and retinal vasculitis. Therapy and Outcome. All three patients responded well to local and/or systemic steroid treatment. In one case, the systemic anti-cancer drug was discontinued after the onset of uveitis. Conclusions. Ocular inflammation may occur in the setting of systemic melanoma therapy. Presentations of uveitis include Vogt-Koyanagi-Harada-like syndromes. Ocular inflammation can usually be controlled by topical and sometimes systemic corticosteroid therapy. However, treatment guidelines are not established and management of these patients demands close cooperation with the oncologist., (Georg Thieme Verlag KG Stuttgart · New York.)

Three-dimensional (3D) scaffolds with tailored pores ranging from the nanometer to millimeter scale can support the reconstruction of centimeter-sized osseous defects. Three-dimensional-printing processes permit the voxel-wise fabrication of scaffolds. The present study rests upon 3D-printing with nano-porous hydroxyapatite granulates. The cylindrical design refers to a hollow bone with higher density at the periphery. The millimeter-wide central channel follows the symmetry axis and connects the perpendicularly arranged micro-pores. Synchrotron radiation-based micro computed tomography has served for the non-destructive characterization of the scaffolds. The 3D data treatment is essential, since, for example, the two-dimensional distance maps overestimate the mean distances to the material by 33-50% with respect to the 3D analysis. The scaffolds contain 70% micrometer-wide pores that are interconnected. Using virtual spheres, which might be related to the cells migrating along the pores, the central channel remains accessible through the micro-pores for spheres with a diameter of up to (350+/-35)mum. Registering the tomograms with their 3D-printing matrices has yielded the almost isotropic shrinking of (27+/-2)% owing to the sintering process. This registration also allows comparing the design and tomographic data in a quantitative manner to extract the quality of the fabricated scaffolds. Histological analysis of the scaffolds seeded with osteogenic-stimulated progenitor cells has confirmed the suitability of the 3D-printed scaffolds for potential clinical applications.