James Sharpe's Contributions to Neurology and Neuro-ophthalmology: A Posthumous Tribute 10 Years On.

Dr. Sharpe was a leading eye movement researcher who had also been the editor of this journal. We wish to mark the 10th anniversary of his death by providing a sense of what he had achieved through some examples of his research.

Brain network dynamics in people with visual snow syndrome.

Visual snow syndrome (VSS) is a neurological disorder characterized by a range of continuous visual disturbances. Little is known about the functional pathological mechanisms underlying VSS and their effect on brain network topology, studied using high-resolution resting-state (RS) 7 T MRI. Forty VSS patients and 60 healthy controls underwent RS MRI. Functional connectivity matrices were calculated, and global efficiency (network integration), modularity (network segregation), local efficiency (LE, connectedness neighbors) and eigenvector centrality (significance node in network) were derived using a dynamic approach (temporal fluctuations during acquisition). Network measures were compared between groups, with regions of significant difference correlated with known aberrant ocular motor VSS metrics (shortened latencies and higher number of inhibitory errors) in VSS patients. Lastly, nodal co-modularity, a binary measure of node pairs belonging to the same module, was studied. VSS patients had lower modularity, supramarginal centrality and LE dynamics of multiple (sub)cortical regions, centered around occipital and parietal lobules. In VSS patients, lateral occipital cortex LE dynamics correlated positively with shortened prosaccade latencies (p = .041, r = .353). In VSS patients, occipital, parietal, and motor nodes belonged more often to the same module and demonstrated lower nodal co-modularity with temporal and frontal regions. This study revealed reduced dynamic variation in modularity and local efficiency strength in the VSS brain, suggesting that brain network dynamics are less variable in terms of segregation and local clustering. Further investigation of these changes could inform our understanding of the pathogenesis of the disorder and potentially lead to treatment strategies.

Visual contrast perception in visual snow syndrome reveals abnormal neural gain but not neural noise.

Visual snow syndrome is a neurological condition characterized by a persistent visual disturbance, visual snow, in conjunction with additional visual symptoms. Cortical hyperexcitability is a potential pathophysiological mechanism, which could be explained by increased gain in neural responses to visual input. Alternatively, neural noise in the visual pathway could be abnormally elevated. We assessed these two potential competing neural mechanisms in our studies of visual contrast perception. Cortical hyperexcitation also occurs in migraine, which commonly co-occurs with visual snow syndrome. Therefore, to determine whether the effect of visual snow syndrome can be distinguished from interictal migraine, we recruited four participant groups: controls, migraine alone, visual snow syndrome alone and visual snow syndrome with migraine. In the first experiment, we estimated internal noise in 20 controls, 21 migraine participants and 32 visual snow syndrome participants (16 with migraine) using a luminance increment detection task. In the second experiment, we estimated neural contrast gain in 21 controls, 22 migraine participants and 35 visual snow syndrome participants (16 with migraine) using tasks assessing sensitivity to changes in contrast from a reference. Contrast gain and sensitivity were measured for the putative parvocellular and 'on' and 'off' magnocellular pathways, respectively. We found that luminance increment thresholds and internal noise estimates were normal in both visual snow syndrome and migraine. Contrast gain measures for putative parvocellular processing and contrast sensitivity for putative off magnocellular processing were abnormally increased in visual snow syndrome, regardless of migraine status. Therefore, our results indicate that visual snow syndrome is characterized by increased neural contrast gain but not abnormal neural noise within the targeted pathways.

Tracking Eye Movements for Diagnosis in Myasthenia Gravis: A Comprehensive Review.

BACKGROUND: Around 60%--75% of myasthenia gravis (MG) patients initially present with nonspecific ocular symptoms. Failed recognition of these symptoms may delay the diagnosis of MG up to 5 years or more, leading to a reduced likelihood of remission and increased morbidity. Current diagnostic tests are either poorly sensitive for patients presenting with ocular symptoms alone or are time consuming, invasive, require a high level of technical expertise, and generally are universally difficult to obtain. This review will explore quantitative eye and pupil tracking as a potential noninvasive, time-effective, and less technically demanding alternative to current diagnostic tests of MG. EVIDENCE ACQUISITION: Comprehensive literature review. RESULTS: Thirty-two publications using oculography for the diagnosis of MG and 6 studies using pupillometry were evaluated. In MG patients, extra ocular muscle fatigue was evident in reports of intersaccadic, intrasaccadic and postsaccadic abnormalities, changes in optokinetic nystagmus, slow eye movements, disconjugate saccades, and pupillary constrictor muscle weakness. CONCLUSIONS: Our review identified several potentially useful variables that derive from oculography and pupillometry studies that could assist with a timely diagnosis of MG. Limitations of this review include heterogeneity in design, sample size, and quality of the studies evaluated. There is a need for larger, well-designed studies evaluating eye-tracking measures in the diagnosis of MG, especially for patients presenting with purely ocular symptoms.

Retinal ganglion cell loss in neuromyelitis optica: a longitudinal study.

OBJECTIVES: Neuromyelitis optica spectrum disorders (NMOSD) are inflammatory conditions of the central nervous system and an important differential diagnosis of multiple sclerosis (MS). Unlike MS, the course is usually relapsing, and it is unclear, if progressive neurodegeneration contributes to disability. Therefore, we aimed to investigate if progressive retinal neuroaxonal damage occurs in aquaporin4-antibody-seropositive NMOSD. METHODS: Out of 157 patients with NMOSD screened, 94 eyes of 51 patients without optic neuritis (ON) during follow-up (F/U) and 56 eyes of 28 age-matched and sex-matched healthy controls (HC) were included (median F/U 2.3 years). The NMOSD cohort included 60 eyes without (EyeON -) and 34 eyes with a history of ON prior to enrolment (EyeON+). Peripapillary retinal nerve fibre layer thickness (pRNFL), fovea thickness (FT), volumes of the combined ganglion cell and inner plexiform layer (GCIP) and the inner nuclear layer (INL) and total macular volume (TMV) were acquired by optical coherence tomography (OCT). RESULTS: At baseline, GCIP, FT and TMV were reduced in EyeON+ (GCIP p<2e-16; FT p=3.7e-4; TMV p=3.7e-12) and in EyeON - (GCIP p=0.002; FT p=0.040; TMV p=6.1e-6) compared with HC. Longitudinally, we observed GCIP thinning in EyeON- (p=0.044) but not in EyeON+. Seven patients had attacks during F/U; they presented pRNFL thickening compared with patients without attacks (p=0.003). CONCLUSION: This study clearly shows GCIP loss independent of ON attacks in aquaporin4-antibody-seropositive NMOSD. Potential explanations for progressive GCIP thinning include primary retinopathy, drug-induced neurodegeneration and retrograde neuroaxonal degeneration from lesions or optic neuropathy. pRNFL thickening in the patients presenting with attacks during F/U might be indicative of pRNFL susceptibility to inflammation.

Visual Snow: Visual Misperception.

BACKGROUND: Visual snow (VS) is a constant visual disturbance described as flickering dots occupying the entire visual field. Recently, it was characterized as the defining feature of a VS syndrome (VSS), which includes palinopsia, photophobia, photopsias, entoptic phenomena, nyctalopia, and tinnitus. Sixty percent of patients with VSS also experience migraine, with or without aura. This entity often is considered psychogenic in nature, to the detriment of the patient's best interests, but the high frequency of similar visual symptoms argues for an organic deficit. The purpose of this review is to clarify VSS as a true entity and elaborate the nature of individual symptoms and their relationship to each other. EVIDENCE ACQUISITION: The literature was reviewed with specific regard to the clinical presentation and psychophysical, neurophysiological, and functional imaging studies in patients with defined visual disturbances that comprise VSS. RESULTS: Consideration of the individual symptoms suggests that multiple factors are potentially involved in the development of VSS, including subcortical network malfunction and cortical hyperexcitation. Although there is substantial overlap between VSS and migraine syndromes in terms of co-occurring symptoms, both neurophysiological and neuroimaging studies provide substantial evidence of separate abnormalities of processing, supporting these as separate syndromes. CONCLUSIONS: VSS is likely associated with either hyperactive visual cortices or, alternatively, impaired processing of simultaneous afferent information projecting to cortex. VSS likely results from widespread disturbance of sensory processing resulting in sensory misperception. There may be a number of syndromes associated with impaired sensory processing resulting in sensory misperception, including migraine, persistent perceptual postural dizziness, and tinnitus, which overlap with VSS. Elucidation of abnormality in one defined syndrome may provide a path forward for investigating all.

Saccade reprogramming in Friedreich ataxia reveals impairments in the cognitive control of saccadic eye movement.

Although cerebellar dysfunction has known effects on motor function in Friedreich ataxia (FRDA), it remains unclear the extent to which the reprogramming of eye movements (saccades) and inhibition of well-learned automatic responses are similarly compromised in affected individuals. Here we examined saccade reprogramming to assess the ability of people with FRDA to respond toward unexpected changes in either the amplitude or direction of an "oddball" target. Thirteen individuals with genetically confirmed FRDA and 12 age-matched controls participated in the study. The saccade reprogramming paradigm was used to examine the effect of an unpredictable "oddball" target on saccade latencies and accuracy when compared to a well-learned sequence of reciprocating movements. Horizontal eye movements were recorded using a scleral search coil eye tracking technique. The results showed a proportionally greater increase in latencies for reprogrammed saccades toward an oddball-direction target in the FRDA group when compared to controls. The FRDA group were also less accurate in primary saccade gain (i.e. ratio of saccade amplitude to target amplitude) when reprogramming saccades toward an unexpected change in direction. No significant group differences were found on any of the oddball-amplitude targets. Significant correlations were revealed between latency and disease severity as measured by the Friedreich Ataxia Rating Scale. These findings provide further support to the view that cognitive changes in FRDA may arise from disruption of cerebellar connections to cortical structures.

Movement planning and online control in multiple sclerosis: assessment using a Fitts law reciprocal aiming task.

OBJECTIVE: We sought to quantify subtle changes in motor control in multiple sclerosis (MS) using a Fitts law reciprocal aiming task presented on a computer touchscreen. BACKGROUND: Upper-limb motor control is impaired in MS. However, many commonly used motor assessments do not detect subtle changes in motor function or differentiate between aspects of movement such as planning and online control. Fitts law states that movement time varies as a function of task difficulty, with smaller targets and greater distances making the task more difficult. METHODS: We gave a Fitts aiming task to 22 patients with MS and 22 matched controls. We manipulated movement difficulty by changing the targets' size and distance apart. RESULTS: The patients spent a significantly longer time than the controls stationary in each target before starting the next movement, and had a lower peak velocity, suggesting deficits in movement planning. The patients also spent longer in the deceleration phase of each movement, indicating deficits in the online control of movement. CONCLUSIONS: The computerized Fitts task allows quick, easy, and sensitive measurement of subtle aspects of movement. This task should be useful in clinical and research settings for assessing MS motor symptoms, disease progression, and treatment efficacy.

Improving Understanding of Visual Snow by Quantifying its Appearance and Effect on Vision.

Purpose: Visual snow is the hallmark of the neurological condition visual snow syndrome (VSS) but the characteristics of the visual snow percept remain poorly defined. This study aimed to quantify its appearance, interobserver variability, and effect on measured visual performance and self-reported visual quality. Methods: Twenty-three participants with VSS estimated their visual snow dot size, separation, luminance, and flicker rate by matching to a simulation. To assess whether visual snow masks vision, we compared pattern discrimination thresholds for textures that were similar in spatial scale to visual snow as well as more coarse than visual snow, in participants with VSS, and with and without external noise simulating visual snow in 23 controls. Results: Mean and 95% confidence intervals for visual snow appearance were: size (6.0, 5.8-6.3 arcseconds), separation (2.0, 1.7-2.3 arcmin), luminance (72.4, 58.1-86.8 cd/m2), and flicker rate (25.8, 18.9-32.8 frames per image at 120 hertz [Hz]). Participants with finer dot spacing estimates also reported greater visibility of their visual snow (τb = -0.41, 95% confidence interval [CI] = -0.62 to -0.13, P = 0.01). In controls, adding simulated fine-scale visual snow to textures increased thresholds for fine but not coarse textures (F(1, 22) = 4.98, P = 0.036, ηp2 = 0.19). In VSS, thresholds for fine and coarse textures were similar (t(22) = 0.54, P = 0.60), suggesting that inherent visual snow does not act like external noise in controls. Conclusions: Our quantitative estimates of visual snow constrain its likely neural origins, may aid differential diagnosis, and inform future investigations of how it affects vision. Methods to quantify visual snow are needed for evaluation of potential treatments.

Exploring Factors That Prolong the Diagnosis of Myasthenia Gravis.

Background and Objectives: Myasthenia gravis (MG) is a condition with significant phenotypic variability, posing a diagnostic challenge to many clinicians worldwide. Prolonged diagnosis can lead to reduced remission rates and morbidity. This study aimed to identify factors leading to a longer time to diagnosis in MG that could be addressed in future to optimize diagnosis time. Methods: One hundred and ten patients from 3 institutions in Melbourne, Australia, were included in this retrospective cohort study. Demographic and clinical data were collected for these patients over the first 5 years from diagnosis and at 10 years. Nonparametric statistical analysis was used to identify factors contributing to a longer diagnosis time. Results: The median time for MG diagnosis was 102 (345) days. 90% of patients were diagnosed before 1 year. Female patients took longer than male patients to be diagnosed (p = 0.013). The time taken for first presentation after symptom onset contributed most to diagnosis time (median 17 [141] days), with female patients and not working as contributory factors. Neurology referral took longer if patients had diplopia (p = 0.022), respiratory (p = 0.026) symptoms, or saw an ophthalmologist first (p < 0.001). Outpatient management compared with inpatient was associated with a longer time to be seen by a neurologist from referral (p < 0.001), for the first diagnostic result to return (p = 0.001), and for the result to be reviewed (p < 0.001). Ocular MG had a median greater time to neurologist review than generalized MG (median 5 [25] days vs 1 [13] days, p = 0.035). Electrophysiology tests took longer for outpatients than inpatients (median 21 [35] days vs 2 [8] days, p < 0.001). Outpatients were also started on treatment later than inpatients (p < 0.001). There was no association of MG severity, ethnicity, age, medical and ocular comorbidities, and public or private health service on diagnosis time. There was also no impact of time to diagnosis on Myasthenia Gravis Foundation of America outcomes, number of follow-ups or hospitalizations, or prevalence of treatments used. This study is limited by low patient numbers and its retrospective nature. Discussion: This study identified several factors that can contribute to a prolonged diagnosis time of MG. Patient and clinician education about MG and outpatient diagnostic efficiency needs emphasis. Further studies are also needed to explore the delayed presentation time of women and nonworking patients in MG.

Ischaemic stroke: the ocular motor system as a sensitive marker for motor and cognitive recovery.

OBJECTIVE: To evaluate the sensitivity of measuring cognitive processing in the ocular motor system as a marker for recovery of deficit in post stroke patients. METHODS: 15 patients (mean age 60.6 years, mean National Institutes of Health Stroke Scale (NIHSS) score 2.25) and 10 age matched control subjects (mean age 63.3 years) participated in the study. We included mildly affected acute stroke patients without a visual field defect or gaze palsy. Patients were examined at onset and at 1 month and 3 months post stroke by testing ocular motor function, NIHSS, modified Rankin Scale (mRS) and standard cognitive function assessments. RESULTS: Significant differences were found in measures of ocular motor function between groups at stroke onset as well as between the first test and follow-up in patients. At 3 months, function had not returned to normal baseline. Ocular motor function was more sensitive in identifying cognitive dysfunction and improvement compared with NIHSS or mRS. CONCLUSIONS: Standard neurological assessments of stroke patients are weighted significantly towards motor and sensory function, underestimating cognitive deficits. Ocular motor assessment demonstrates cognitive effects of even mild stroke and may provide improved quantifiable measurements of cognitive recovery post stroke. We demonstrated abnormality in patients just after onset, extending beyond 3 months, when there was apparent full recovery of motor and sensory function, implying more widespread disruption of cognitive mechanisms, consistent with the subjective complaints received from patients. This may provide insight into cognitive rehabilitation strategies leading to improved functional outcomes.

Eye movement characteristics are not significantly influenced by psychiatric comorbidities in people with visual snow syndrome.

Visual snow syndrome (VSS) is a neurological disorder primarily affecting the processing of visual information. Using ocular motor (OM) tasks, we previously demonstrated that participants with VSS exhibit altered saccade profiles consistent with visual attention impairments. We subsequently proposed that OM assessments may provide an objective measure of dysfunction in these individuals. However, VSS participants also frequently report significant psychiatric symptoms. Given that that these symptoms have been shown previously to influence performance on OM tasks, the objective of this study was to investigate whether psychiatric symptoms (specifically: depression, anxiety, fatigue, sleep difficulties, and depersonalization) influence the OM metrics found to differ in VSS. Sixty-one VSS participants completed a battery of four OM tasks and a series of online questionnaires assessing psychiatric symptomology. We revealed no significant relationship between psychiatric symptoms and OM metrics on any of the tasks, demonstrating that in participants with VSS, differences in OM behaviour are a feature of the disorder. This supports the utility of OM assessment in characterising deficit in VSS, whether supporting a diagnosis or monitoring future treatment efficacy.

Cognition and eye movements: assessment of cerebral dysfunction.

BACKGROUND: Many neurological disorders show deficits in ocular motor function. In the past, evaluation has been limited to assessing abnormalities largely generated by pathology of the brainstem andcerebellum. In disorders that primarily or substantially, affect the cerebral hemispheres, disruption of cognitive processes occur, often early in the clinical course. While neuropsychological testing traditionally is used to measure cognitive performance, the cerebral influences on the ocular motor system provides another quantitative paradigm. This review explores the relationship between cognitive sensory processing and execution of planned ocular motor tests in Parkinson's disease, Huntington's disease and multiple sclerosis and explores areas of clinical utility. METHODS: Review of the literature regarding cognitive and ocular motor abnormalities in neurological disease. RESULTS: The literature indicates that in systems degeneration there are abnormalities of cognitive processing, defined both by conventional behavioural testing and by assessment of cognitive function utilizing ocular motor studies, which characterise those processes. Moreover, in diffuse disease, in processes such as multiple sclerosis, the assessment of cognitive processes involved in ocular motor function may well provide an added level of sensitivity indicating more widespread pathology than would be apparent with conventional clinical assessment. CONCLUSIONS: Assessment of cognitive function in the ocular motor system may provide insight into cerebral function, in health and disease, and may provide both diagnostic information and permit quantification of deficit in future.

Working Memory Phenotypes in Early Multiple Sclerosis: Appraisal of Phenotype Frequency, Progression and Test Sensitivity.

Working memory (WM) impairments are common and debilitating symptoms of multiple sclerosis (MS), often emerging early in the disease. Predominantly, WM impairments are considered in a binary manner, with patients considered either impaired or not based on a single test. However, WM is comprised of different activated subcomponents depending upon the type of information (auditory, visual) and integration requirements. As such, unique WM impairment phenotypes occur. We aimed to determine the most frequent WM phenotypes in early MS, how they progress and which WM test(s) provide the best measure of WM impairment. A total of 88 participants (63 early relapsing-remitting MS: RRMS, 25 healthy controls) completed five WM tests (visual-spatial, auditory, episodic, executive) as well as the symbol digit modalities test as a measure of processing speed. RRMS patients were followed-up for two years. Factors affecting WM (age/gender/intelligence/mood) and MS factors (disease duration/disability) were also evaluated. Some 61.9% of RRMS patients were impaired on at least one WM subcomponent. The most subcomponents impaired were visual,-spatial and auditory WM. The most common WM phenotypes were; (1) visual-spatial sketchpad + episodic buffer + phonological loop + central executive, (2) visual-spatial sketchpad + central executive. The test of visual-spatial WM provided the best diagnostic accuracy for detecting WM impairment and progression. The SDMT did not achieve diagnostic accuracy greater than chance. Although this may be unsurprising, given that the SDMT is a measure of cognitive processing speed in MS, this does highlight the limitation of the SDMT as a general screening tool for cognitive impairment in early MS.

Corrigendum: Editorial: Visual Snow: Old Problem, New Understanding.

[This corrects the article DOI: 10.3389/fneur.2022.884752.].

Longitudinal tracking of axonal loss using diffusion magnetic resonance imaging in multiple sclerosis.

Axonal loss in the CNS is a key driver of progressive neurological impairments in people with multiple sclerosis. Currently, there are no established methods for tracking axonal loss clinically. This study aimed to determine the sensitivity of longitudinal diffusion MRI-derived fibre-specific measures of axonal loss in people with multiple sclerosis. Fibre measures were derived from diffusion MRI acquired as part of a standard radiological MRI protocol and were compared (i) to establish measures of neuro-axonal degeneration: brain parenchymal fraction and retinal nerve fibre layer thickness and (ii) between different disease stages: clinically isolated syndrome and early/late relapsing-remitting multiple sclerosis. Retrospectively identified data from 59 people with multiple sclerosis (18 clinically isolated syndrome, 22 early and 19 late relapsing-remitting) who underwent diffusion MRI as part of their routine clinical monitoring were collated and analysed. Twenty-six patients had 1-year and 14 patients had a 2-year follow-up. Brain parenchymal fraction was calculated from 3D MRI scans, and fibre-specific measures were calculated from diffusion MRI using multi-tissue constrained spherical deconvolution. At each study visit, patients underwent optical coherence tomography to determine retinal nerve fibre layer thickness, and standard neurological assessment expanded the disability status scale. We found a significant annual fibre-specific neuro-axonal degeneration (mean ± SD = -3.49 ± 3.32%, P < 0.001) that was ∼7 times larger than the annual change of brain parenchymal fraction (-0.53 ± 0.95%, P < 0.001), and more than four times larger than annual retinal nerve fibre layer thinning (-0.75 ± 2.50% P = 0.036). Only fibre-specific measures showed a significant difference in annual degeneration between the disease stages (P = 0.029). Reduced brain parenchymal fraction, retinal nerve fibre layer thickness and fibre-specific measures were moderately related to higher expanded disability status scale (rho = -0.368, rho = -0.408 and rho = -0.365, respectively). Fibre-specific measures can be measured from data collected within a standard radiological multiple sclerosis study and are substantially more sensitive to longitudinal change compared with brain atrophy and retinal nerve fibre layer thinning.

Microstructure in patients with visual snow syndrome: an ultra-high field morphological and quantitative MRI study.

Visual snow syndrome is a neurological condition characterized by continuous visual disturbance and a range of non-visual symptoms, including tinnitus and migraine. Little is known about the pathological mechanisms underlying visual snow syndrome. Here, we assessed brain morphometry and microstructure in visual snow syndrome patients using high-resolution structural and quantitative MRI. Forty visual snow syndrome patients (22 with migraine) and 43 controls underwent 7-Tesla MRI (MP2RAGE, 0.75 mm isotropic resolution). Volumetric and quantitative T1 values were extracted for white and grey matter regions and compared between groups. Where regions were significantly different between groups (false discovery rate corrected for multiple comparisons), post hoc comparisons were examined between patients with and without migraine. For visual snow syndrome patients, significant MRI variables were correlated with clinical severity (number of visual symptoms, perceived visual snow intensity, disruptiveness, fatigue and quality of life) and psychiatric symptoms prevalent in visual snow syndrome (depression, anxiety and depersonalization). Finally, cortical regions and individual thalamic nuclei were studied. Compared with controls, visual snow syndrome patients demonstrated a trend towards larger brain and white matter volumes and significantly lower T1 values for the entire cortex (P < 0.001), thalamus (P = 0.001) and pallidum (P = 0.001). For the patient group, thalamic T1 correlated with number of visual symptoms (P = 0.019, r = 0.390) and perceived disruptiveness of visual snow (P = 0.010, r = 0.424). These correlations did not survive multiple comparison corrections. As for specificity in visual snow syndrome group, T1 changes were most evident in caudal regions (occipital cortices) followed by parietal, temporal and prefrontal cortices. T1 values differed between groups for most individual thalamic nuclei. No differences were revealed between patients with and without migraine. In visual snow syndrome patients, we observed no changes in morphometry, instead widespread changes in grey matter microstructure, which followed a caudal-rostral pattern and affected the occipital cortices most profoundly. Migraine did not appear to independently affect these changes. Lower T1 values may potentially result from higher neurite density, myelination or increased iron levels in the visual snow syndrome brain. Further investigation of these changes may enhance our understanding of the pathogenesis of visual snow syndrome, ultimately leading to new treatment strategies.

Early predictors of visual and axonal outcomes after acute optic neuritis.

Background: Predicting long-term visual outcomes and axonal loss following acute optic neuritis (ON) is critical for choosing treatment. Predictive models including all clinical and paraclinical measures of optic nerve dysfunction following ON are lacking. Objectives: Using a prospective study method, to identify 1 and 3 months predictors of 6 and 12 months visual outcome (low contrast letter acuity 2.5%) and axonal loss [retinal nerve fiber layer thickness and multifocal evoked potential (mfVEP) amplitude] following acute ON. Methods: In total, 37 patients of acute ON onset were evaluated within 14 days using between-eye asymmetry of visual acuity, color vision (Ishihara plates), optical coherence tomography, mfVEP, and optic nerve magnetic resonance imaging [magnetic transfer ratio (MTR) and diffusion tensor imaging (DTI)]. Results: Visual outcome at 6 and 12 months was best predicted by Ishihara asymmetry at 1 and 3 months following ON onset. Axonal loss at 6 and 12 months was reliably predicted by Ishihara asymmetry at 1 month. Optic nerve MTR and DTI at 3 months post-acute ON could predict axonal loss at 6 and 12 months. Conclusions: Simple Ishihara asymmetry testing 1 month after acute ON onset can best predict visual outcome and axonal loss at 6 and 12 months in a clinical or research setting.

The Psychiatric Symptomology of Visual Snow Syndrome.

Objective: To characterise the psychiatric symptoms of visual snow syndrome (VSS), and determine their relationship to quality of life and severity of visual symptoms. Methods: One hundred twenty-five patients with VSS completed a battery of questionnaires assessing depression/anxiety, dissociative experiences (depersonalisation), sleep quality, fatigue, and quality of life, as well as a structured clinical interview about their visual and sensory symptoms. Results: VSS patients showed high rates of anxiety and depression, depersonalisation, fatigue, and poor sleep, which significantly impacted quality of life. Further, psychiatric symptoms, particularly depersonalisation, were related to increased severity of visual symptoms. The severity/frequency of psychiatric symptoms did not differ significantly due to the presence of migraine, patient sex, or timing of VSS onset (lifelong vs. later onset). Conclusion: Psychiatric symptoms are highly prevalent in patients with VSS and are associated with increased visual symptom severity and reduced quality of life. Importantly, patients with lifelong VSS reported lower levels of distress and milder self-ratings of visual symptoms compared to patients with a later onset, while being equally likely to experience psychiatric symptoms. This suggests that the psychiatric symptoms of VSS are not solely due to distress caused by visual symptoms. While no consistently effective treatments are available for the visual symptomology of VSS, psychiatric symptoms offer an avenue of treatment that is likely to significantly improve patient quality of life and ability to cope with visual symptoms.

Eye movement characteristics provide an objective measure of visual processing changes in patients with visual snow syndrome.

Visual snow syndrome (VSS) is a poorly understood neurological disorder that features a range of disabling sensory changes. Visual processing changes revealed previously in VSS appear consistent with poor attentional control, specifically, with difficulty controlling environmentally driven shifts of attention. This study sought to confirm this proposal by determining whether these changes were similarly evident where attention is internally driven. Sixty seven VSS patients and 37 controls completed two saccade tasks: the endogenously cued saccade task and saccadic Simon task. The endogenously cued saccade task correctly (valid trial) or incorrectly (invalid trial) pre-cues a target location using a centrally presented arrow. VSS patients generated significantly shorter saccade latencies for valid trials (p = 0.03), resulting in a greater magnitude cue effect (p = 0.02), i.e. the difference in latency between valid and invalid trials. The saccadic Simon task presents a peripheral cue which may be spatially congruent or incongruent with the subsequent target location. Latencies on this task were comparable for VSS patients and controls, with a normal Simon effect, i.e. shorter latencies for saccades to targets spatially congruent with the preceding cue. On both tasks, VSS patients generated more erroneous saccades than controls towards non-target locations (Endogenously cued saccade task: p = 0.02, saccadic Simon task: p = 0.04). These results demonstrate that cued shifts of attention differentially affect saccade generation in VSS patients. We propose that these changes are not due to impairment of frontally-mediated inhibitory control, but to heightened saccade-related activity in visual regions. These results contribute to a VSS ocular motor signature that may provide clinical utility as well as an objective measure of dysfunction to facilitate future research.