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BACKGROUND: Little is known about the characteristics and occurrence frequencies of rapid eye movements (REMs) during REM sleep in movement disorders. OBJECTIVES: The aim of this study was to detect and characterize REMs during polysomnographically defined REM sleep as recorded by electro-oculography (EOG) in 12 patients with progressive supranuclear palsy (PSP), 13 patients with Parkinson's disease (PD) and 12 healthy controls. METHODS: Using a modified EOG montage, we developed an algorithm that automatically detects and characterizes REMs during REM sleep based on their presumptive saccadic kinematics. RESULTS: Compared to PD and healthy controls, REM densities and REM peak velocities were significantly reduced in PSP. These effects were most pronounced in vertical REMs. CONCLUSION: Ocular motor dysfunction, one of the cardinal features of PSP, seems to be equally at play during REM sleep and wakefulness. For future studies, we provide a novel tool for the unbiased analysis of REMs during REM sleep in movement disorders.

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BACKGROUND: The harlequin syndrome is a rare disorder of the autonomic nervous system characterized by unilateral diminished flushing and sweating of the face following exposure to heat or physical activity. It results from sympathetic dysfunction and most commonly occurs idiopathically. A secondary development due to an underlying pathology (e.g., carotid artery dissection, tumors) must be excluded at first appearance. There is evidence that the cranial autonomic system is involved in the pathophysiology of trigeminal autonomic headaches like hemicrania continua. Therefore, an overlap in the pathophysiology of harlequin syndrome and trigeminal autonomic headache disorders seems plausible. However, the association of a harlequin syndrome with hemicrania continua was never reported. CASE PRESENTATION: This work describes the case of a 42-year-old female patient presenting to our headache unit. The patient reported persisting unilateral headache of the right side of dragging or squeezing character accompanied by trigeminal autonomic symptoms, including lacrimation, nasal congestion, conjunctival injection and Horner's syndrome, and was responsive to treatment with 75mg/d indomethacin. Five months after the initial consultation, the patient noted that the upper right quadrant of her face was pale after jogging. A harlequin syndrome was diagnosed. Further, she developed a short-lasting, bilateral headache of pulsatile character during strenuous exercise consistent with exertional headache. Comprehensive diagnostic evaluations, encompassing cranial and cervical MRI scans, laboratory tests, and biopsies, culminated in the diagnosis of Sjögren's syndrome. This finding suggests that the trigemino-autonomic dysfunction may either be idiopathic or a direct manifestation of Sjögren's syndrome. CONCLUSIONS: This report documents the case of a rare combination of a headache resembling probable hemicrania continua and the harlequin syndrome (and even exertional headache). It illustrates the underlying anatomy of the autonomic nervous system in a clinical context and emphasizes the hypothesis of a pathophysiological link between abnormal sympathetic activity and trigeminal autonomic headaches.

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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.

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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.

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BACKGROUND: Video-oculography (VOG) is used to quantify functional deficits in internuclear ophthalmoplegia (INO), whereas MRI can detect the corresponding structural lesions in the medial longitudinal fasciculus (MLF). This study investigates the diagnostic agreement of MRI compared to VOG measurements. METHODS: We prospectively compared structural MRI findings and functional VOG measures of 63 MS patients to assess their diagnostic agreement for INO. RESULTS: MRI detected 12 true-positive and 92 true-negative MLF lesions for INO compared to VOG (12 true-positive and 38 true-negative patients) but identified one-third of the MLF lesions on the wrong side. MRI ratings were specific (92.0%) to detect MLF lesions but not sensitive (46.2%) for diagnosing INO (86.4% and 63.2% by patient). Accordingly, MRI has a high positive likelihood ratio of 5.77 but a modest negative likelihood ratio of 0.59 for the probability of INO (4.63 and 0.43) with an accuracy of 82.5% (79.4%). CONCLUSION: MRI assessments are highly specific but not sensitive for detecting INO compared to VOG. While MRI identifies MLF lesions in INO, VOG quantifies the deficit. As a simple, quick, and non-invasive test for diagnosing and tracking functional INO deficits, it will hopefully find its place in the diagnostic and therapeutic pathways of MS.

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CME: Idiopathic Intracranial Hypertension Abstract. Idiopathic intracranial hypertension is a pressure-induced secondary headache disorder and optic neuropathy. It primarily affects obese women of childbearing age and poses an interdisciplinary challenge both diagnostically and therapeutically. The most common symptom of this disorder are headaches frequently accompanied by photo- and/or phonophobia, whose semiology often resembles that of migraine, followed by transient visual obscurations and pulsatile tinnitus. While protection of visual acuity and visual fields are of first therapeutical priority, adequate headache treatment also plays a key role. In the majority of cases, conservative treatment including weight loss and pharmacological therapy is sufficient. In case of a fulminant disease course or loss of visual function, interventional strategies can be applied additionally. Headache treatment is guided by the predominant semiology.

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BACKGROUND AND AIMS: ATP-dependent phosphofructokinases (PFKs) catalyse phosphorylation of the carbon-1 position of fructose-6-phosphate, to form fructose-1,6-bisphosphate. In the cytosol, this is considered a key step in channelling carbon into glycolysis. Arabidopsis thaliana has seven genes encoding PFK isoforms, two chloroplastic and five cytosolic. This study focuses on the four major cytosolic isoforms of PFK in vegetative tissues of A. thaliana. METHODS: We isolated homozygous knockout individual mutants (pfk1, pfk3, pfk6 and pfk7) and two double mutants (pfk1/7 and pfk3/6), and characterized their growth and metabolic phenotypes. KEY RESULTS: In contrast to single mutants and the double mutant pfk3/6 for the hypoxia-responsive isoforms, the double mutant pfk1/7 had reduced PFK activity and showed a clear visual and metabolic phenotype with reduced shoot growth, early flowering and elevated hexose levels. This mutant also has an altered ratio of short/long aliphatic glucosinolates and an altered root-shoot distribution. Surprisingly, this mutant does not show any major changes in short-term carbon flux and in levels of hexose-phosphates. CONCLUSIONS: We conclude that the two isoforms PFK1 and PFK7 are important for sugar homeostasis in leaf metabolism and apparently in source-sink relationships in A. thaliana, while PFK3 and PFK6 only play a minor role under normal growth conditions.

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OBJECTIVES: Quantitative vestibular testing in athletes after sports-related concussion (SRC) has become more popular due to accompanying injuries of the peripheral-vestibular organs that require targeted treatment. Sports-specific normative values are currently not available. Taking into account potential adaptational mechanisms, we obtained sports-specific, age- and peak-head-velocity-corrected normative values of peripheral-vestibular function and postural-stability in football (soccer, FB) and ice-hockey (IH) players. DESIGN: Retrospective single-center case-control study. METHOD: Pre-seasonal angular vestibulo-ocular reflex (aVOR) gains and cumulative-saccadic-amplitudes were obtained using the video-head-impulse test and performance in the balance-error-scoring-system (BESS) was recorded and compared in high-level FB-players (n = 510, 197 females) and IH-players (n = 210, males only) (age-range = 13-39y) and in healthy normals (n = 49, 22 females). Statistical analysis was performed using a generalized linear model. RESULTS: aVOR-gain values were significantly higher for FB-players than for IH-players (1.07 ±â€¯0.21 vs. 0.98 ±â€¯0.13, p < 0.001) and controls (1.07 ±â€¯0.21 vs. 0.97 ±â€¯0.17, p < 0.001). Significant age-related changes in aVOR-gains were only observed for the anterior and posterior canals in the IH-players. Cumulative-saccadic-amplitudes were clearly below established cut-off values (0.73°/trial). BESS scores were significantly higher in IH-players than in FB-players (15.4 ±â€¯5.1 vs. 11.2 ±â€¯4.9, p < 0.001). CONCLUSIONS: The significantly better performance of the FB players in the vertical aVOR-gains and the BESS compared to the IH-players could be related to sports-specific differences influencing visuo-vestibular and balance performance. Therefore, we recommend using the established normative aVOR-gain values for high-level FB-players, whereas in IH obtaining individual pre-seasonal (baseline) aVOR-gain values is proposed. Further studies should add sports-specific normative aVOR-gain values for IH and other sports.

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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.

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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.

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Numerous plants protect themselves from attackers by using specialized metabolites. The biosynthesis of these deterrent, often toxic metabolites is costly, as their synthesis diverts energy and resources on account of growth and development. How plants diversify investments into growth and defense is explained by the optimal defense theory. The central prediction of the optimal defense theory is that plants maximize growth and defense by concentrating specialized metabolites in tissues that are decisive for fitness. To date, supporting physiological evidence relies on the correlation between plant metabolite presence and animal feeding preference. Here, we use glucosinolates as a model to examine the effect of changes in chemical defense distribution on feeding preference. Taking advantage of the uniform glucosinolate distribution in transporter mutants, we show that high glucosinolate accumulation in tissues important to fitness protects them by guiding larvae of a generalist herbivore to feed on other tissues. Moreover, we show that the mature leaves of Arabidopsis thaliana supply young leaves with glucosinolates to optimize defense against herbivores. Our study provides physiological evidence for the central hypothesis of the optimal defense theory and sheds light on the importance of integrating glucosinolate biosynthesis and transport for optimizing plant defense.

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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.

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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.

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Background: Patients with vestibular schwannoma that show residual peripheral-vestibular function before surgery may experience sudden and substantial vestibular loss of function after surgical resection. To alleviate the sudden loss of peripheral-vestibular function after vestibular-schwannoma (VS) resection, pre-surgical intratympanic gentamicin application was proposed. Objective: We hypothesized that this approach allows for a controlled reduction of peripheral-vestibular function before surgery but that resulting peripheral-vestibular deficits may be canal-specific with anterior-canal sparing as observed previously in systemic gentamicin application. Methods: Thirty-four patients (age-range = 27-70 y) with unilateral VS (size = 2-50 mm) were included in this retrospective single-center trial. The angular vestibulo-ocular reflex (aVOR) was quantified before and after (29.7 ± 18.7 d, mean ± 1SD) a single or two sequential intratympanic gentamicin applications by use of video-head-impulse testing. Both aVOR gains, cumulative saccadic amplitudes, and overall aVOR function were retrieved. Statistical analysis was done using a generalized linear model. Results: At baseline, loss of function of the horizontal (20/34) and posterior (21/34) canal was significantly (p < 0.001) more frequent than that of the anterior canal (5/34). After gentamicin application, loss of function of the horizontal (32/34) or posterior (31/34) canal remained significantly (p ≤ 0.003) more frequent than that of the anterior canal (18/34). For all ipsilesional canals, significant aVOR-gain reductions and cumulative-saccadic-amplitude increases were noted after gentamicin. For the horizontal canal, loss of function was significantly larger (increase in cumulative-saccadic-amplitude: 1.6 ± 2.0 vs. 0.8 ± 1.2, p = 0.007) or showed a trend to larger changes (decrease in aVOR-gain: 0.24 ± 0.22 vs. 0.13 ± 0.29, p = 0.069) than for the anterior canal. Conclusions: Intratympanic gentamicin application resulted in a substantial reduction in peripheral-vestibular function in all three ipsilesional canals. Relative sparing of anterior-canal function noted at baseline was preserved after gentamicin treatment. Thus, pre-surgical intratympanic gentamicin is a suitable preparatory procedure for reducing the drop in peripheral-vestibular function after VS-resection. The reasons for relative sparing of the anterior canal remain unclear.

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In clinical practice, the head impulse test paradigm (HIMP) and the suppression head impulse paradigm (SHIMP) stimulate high-frequency head movements so that the visual system is temporarily suppressed. The two tests could also be useful tools for vestibular assessment at low frequencies: VVOR (visually enhanced vestibulo-ocular reflex) and VORS (vestibulo-ocular reflex suppression). The aim of this study is to analyze the eye movements typically found during VVOR and VORS testing in patients with unilateral and bilateral vestibular hypofunction. Twenty patients with unilateral vestibular hypofunction, three patients with bilateral vestibular hypofunction, and ten patients with normal vestibular function (control group) were analyzed through VVOR and VORS testing with an Otometrics ICS Impulse system. During the VVOR test, patients with unilateral vestibular hypofunction exhibited corrective saccades to the same direction of the nystagmus fast phase toward the healthy side when the head rotates toward the affected side, while patients with bilateral vestibular hypofunction exhibited corrective saccades to the opposite side of head movements to each side. During the VORS test, patients with unilateral vestibular hypofunction seem to exhibit larger corrective saccades to the healthy side when the head was moved to this side, while patients with bilateral vestibular hypofunction did not exhibit corrective saccades during head movements to either side. Our data suggest that the VVOR and VORS tests yield the same diagnostic information as the HIMP and SHIMP tests in unilateral and bilateral vestibular hypofunction, and can contribute to the diagnosis of a peripheral vestibular loss as well as the affected side.

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Oculomotor palsy with cyclic spasms is an extremely rare condition whose exact pathophysiology remains a mystery. We followed a boy from the onset of symptoms at the age of ten months until 15 years and documented the case with video oculography. In addition, he was diagnosed with hereditary motor and sensory neuropathy (Charcot-Marie-Tooth disease type 1). Although a pure coincidence cannot be ruled out, it is conceivable that the underlying demyelinating neuropathy of this patient rendered the oculomotor nerve more susceptible to damage.

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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.