Automated alternate cover test for 'HINTS' assessment: a validation study.

OBJECTIVE: The alternate cover test (ACT) in patients with acute vestibular syndrome is part of the 'HINTS' battery test. Although quantitative, the ACT is highly dependent on the examiner's experience and could theoretically vary greatly between examiners. In this study, we sought to validate an automated video-oculography (VOG) system based on eye tracking and dedicated glasses. METHODS: We artificially induced a vertical strabismus to simulate a skew deviation on ten healthy subjects, aged from 26 to 66, using different press-on Fresnel prisms on one eye while recording eye position with VOG of the contralateral eye. We then compared the system's performance to that of a blinded trained orthoptist using conventional, semi-quantitative method of skew measurement known as the alternate prism cover test (APCT) as a gold standard. RESULTS: We found a significant correlation between the reference APCT and the Skew VOG (Pearson's R2 = 0.606, p < 0.05). There was a good agreement between the two tests (intraclass correlation coefficient 0.852, 95 CI 0.728-0.917, p < 0.001). The overall accuracy of the VOG was estimated at 80.53% with an error rate of 19.46%. There was no significant difference in VOG skew estimations compared with the gold standard except for very small skews. CONCLUSIONS: VOG offers an objective and quantitative skew measurement and proved to be accurate in measuring vertical eye misalignment compared to the ACT with prisms. Precision was moderate, which mandates a sufficient number of tests per subject.

PATIENTS WITH EPIRETINAL MEMBRANES DISPLAY RETROGRADE MACULOPATHY AFTER SURGICAL PEELING OF THE INTERNAL LIMITING MEMBRANE.

PURPOSE: Intraretinal cystoid spaces are commonly found after surgical peeling of epiretinal membranes. In this study, we explored whether these cysts were associated with ganglion cell loss and thus might be a manifestation of retrograde maculopathy. The latter is a nonvascular edema with a characteristic morphology that is often found in the inner nuclear layer (INL) of patients with optic neuropathy. METHODS: In this retrospective case series, we identified consecutive patients who underwent surgical epiretinal membrane peeling. We determined the frequency of microcystic macular edema (MME), defined by vertical cystoid spaces in the INL, and we measured the thickness of individual macular layers before and after surgery. RESULTS: Epiretinal membrane peeling resulted in an improvement of visual acuity and a reduction of retinal thickness by about 15%. In total, 35% of patients with MME before surgery showed no sign of MME postoperatively, whereas edema persisted after surgery in 65% of patients. Interestingly, 29% of the patients without MME before surgery developed MME after surgery. Overall, we found MME in 35% of patients before peeling and in 42% after peeling. After surgery, the mean ganglion cell layer thickness was reduced compared with healthy control eyes. Ganglion cell layer thickness correlated inversely with thickness of the INL. Compared with patients without MME, individuals with MME had a thinner ganglion cell layer and a thicker INL in the affected eye. CONCLUSION: Our findings indicate that peeling of epiretinal membranes and internal limiting membranes is associated with atrophy of ganglion cells and thickening of the INL. The latter is associated with the presence of MME. Altogether, we assume that surgical treatment of epiretinal membranes induces a variant of a retrograde maculopathy.

Acetazolamide Reduces Retinal Inner Nuclear Layer Thickness in Microcystic Macular Edema Secondary to Optic Neuropathy.

Optic neuropathy (ON) is commonly complicated by microcystic macular edema (MME), that is, small vertical cystoid spaces in the inner nuclear layer (INL) of the macula. We performed a retrospective consecutive case series of 14 eyes from 11 patients with ON and MME that were treated with oral acetazolamide, acting on cellular water transport. Contralateral eyes without MME were used as controls. Segmentation of images obtained with OCT was used to determine changes of individual retinal layer thickness during treatment. Retinal INL thickness consistently decreased in all eyes after 2-3 weeks of treatment. Recurrence of MME was observed after treatment cessation. No significant change of retinal thickness was found in contralateral unaffected eyes. Visual function did not change with treatment. Acetazolamide significantly improved the MME in eyes with ON. However, visual function did not. Acetazolamide is a treatment option for MME associated with ON but without an impact on the visual function.

Timing of concurrent visual stimuli determines modulation of saccadic amplitude.

The temporal relation of competing visual stimuli may determine the corresponding oculomotor response. In this study we systematically varied the temporal coincidence of two conflicting stimuli and investigated saccades that were elicited from such stimuli. We varied the time of presentation of two identical spatially separated stimuli between 0 and +165 ms and measured the amplitude of the saccade elicited by these stimuli using infrared eye tracking. In the first experiment, all stimuli were shown for 36 ms only. In the second experiment, stimuli remained on the screen until the subsequent stimulus appeared, whereas in the third experiment all stimuli were removed after saccade onset. Up to an interstimulus interval of 82 ms, we found a significant shift of the saccadic endpoint toward the location of the second stimulus as compared to saccades toward the first stimulus alone. The strongest saccadic bias was observed if a stimulus was shown 36 ms after or before another stimulus. In contrast, time intervals longer than 82 ms elicited saccade adaptation-that is, the saccadic landing point gradually moved toward the second location over time. In more than 99% of trials, the second stimulus appeared before the saccade reached its endpoint. The timing of a conflicting stimulus determines the associated saccadic response: Simultaneous presentation of two stimuli results in a saccadic endpoint at an averaged intermediate position, short interstimulus intervals result in a strong shift of the saccadic endpoint toward the location of the second of two consecutive stimuli, and longer interstimulus intervals elicit saccade adaptation. The timing of two stimuli thus is associated with distinct processes, which complement each other in order to provide an optimal oculomotor response.

Characterization of two novel intronic OPA1 mutations resulting in aberrant pre-mRNA splicing.

BACKGROUND: We report two novel splice region mutations in OPA1 in two unrelated families presenting with autosomal-dominant optic atrophy type 1 (ADOA1) (ADOA or Kjer type optic atrophy). Mutations in OPA1 encoding a mitochondrial inner membrane protein are a major cause of ADOA. METHODS: We analyzed two unrelated families including four affected individuals clinically suspicious of ADOA. Standard ocular examinations were performed in affected individuals of both families. All coding exons, as well as exon-intron boundaries of the OPA1 gene were sequenced. In addition, multiplex ligation-dependent probe amplification (MLPA) was performed to uncover copy number variations in OPA1. mRNA processing was monitored using RT-PCR and subsequent cDNA analysis. RESULTS: We report two novel splice region mutations in OPA1 in two unrelated individuals and their affected relatives, which were previously not described in the literature. In one family the heterozygous insertion and deletion c.[611-37_611-38insACTGGAGAATGTAAAGGGCTTT;611-6_611-16delCATATTTATCT] was found in all investigated family members leading to the activation of an intronic cryptic splice site. In the second family sequencing of OPA1 disclosed a de novo heterozygous deletion c.2012+4_2012+7delAGTA resulting in exon 18 and 19 skipping, which was not detected in healthy family members. CONCLUSION: We identified two novel intronic mutations in OPA1 affecting the correct OPA1 pre-mRNA splicing, which was confirmed by OPA1 cDNA analysis. This study shows the importance of transcript analysis to determine the consequences of unclear intronic mutations in OPA1 in proximity to the intron-exon boundaries.

The interaction of pupil response with the vergence system.

PURPOSE: A gaze shift from a target at distance to a target at near leads to pupillary constriction. The regulation of this pupillary near response is ill known. We investigated the impact of accommodation, convergence, and proximity on the pupillary diameter. METHODS: We recorded pupil size and vergence eye movements with the use of an infrared eye tracker. We determined the pupillary response in four conditions: (1) after a gaze shift from far to near without accommodation, (2) after a gaze shift from far to near with neither accommodation nor convergence, (3) after accommodation alone, and (4) after accommodation with convergence without a gaze shift to near. These responses were compared to the pupil response of a full near response and to a gaze shift from one far target to another. RESULTS: We found a reliable pupillary near response. The removal of both accommodation and convergence in gaze shift from far to near abolished the pupillary near response. Accommodation alone did not induce pupillary constriction, while convergence and accommodation together induced a pupil response similar to the full near response. CONCLUSIONS: The main trigger for the pupillary response seems to be convergence. Neither accommodation nor proximity alone induce a significant pupillary constriction. This suggests that the miosis of the near triad is closely coupled to the vergence system rather than being independently regulated.

The neural network of saccadic foreknowledge.

Foreknowledge about upcoming events may be exploited to optimize behavioural responses. In a previous work, using an eye movement paradigm, we showed that different types of partial foreknowledge have different effects on saccadic efficiency. In the current study, we investigated the neural circuitry involved in processing of partial foreknowledge using functional magnetic resonance imaging. Fourteen subjects performed a mixed antisaccade, prosaccade paradigm with blocks of no foreknowledge, complete foreknowledge or partial foreknowledge about stimulus location, response direction or task. We found that saccadic foreknowledge is processed primarily within the well-known oculomotor network for saccades and antisaccades. Moreover, we found a consistent decrease in BOLD activity in the primary and secondary visual cortex in all foreknowledge conditions compared to the no-foreknowledge conditions. Furthermore we found that the different types of partial foreknowledge are processed in distinct brain areas: response foreknowledge is processed in the frontal eye field, while stimulus foreknowledge is processed in the frontal and parietal eye field. Task foreknowledge, however, revealed no positive BOLD correlate. Our results show different patterns of engagement in the saccade-related neural network depending upon precisely what type of information is known ahead.

Gaze-dependent phoria and vergence adaptation.

Incomitance is a condition with gaze-dependent deviations of ocular alignment and is common in strabismus patients. The physiological mechanisms that maintain equal horizontal ocular alignment in all gaze directions (concomitance) in healthy individuals are poorly explored. We investigate adaptive processes in the vergence system that are induced by horizontal incomitant vergence stimuli (stimuli that require a gaze-dependent vergence response in order to re-establish binocular single vision). We measured horizontal vergence responses elicited after healthy subjects shifted their gaze from a position that required no vergence to a position that required convergence. Repetitive saccades into a position with a convergence stimulus rapidly decreased phoria (defined as the deviation of ocular alignment in the absence of a binocular stimulus). This change of phoria was present in all viewing directions (from 0° to 0.86° ± 0.40°, p < 0.001) but was more pronounced in the gaze direction with a convergence stimulus (from 0.26° ± 0.13° to 1.39° ± 0.33°, p < 0.001). We also found that vergence velocity rapidly increased (p = 0.015) and vergence latency promptly decreased (p < 0.001). We found gaze-dependent modulation of phoria in combined saccade-vergence eye movements and also in pursuit-vergence eye movements. Thus, acute horizontal, gaze-dependent changes of vergence, such as may be encountered in new onset strabismus due to paralysis, can rapidly increase vergence velocity and decrease latency. Gaze-specific (concomitant) and gaze-independent (incomitant) phoria levels will adapt. These early adaptive processes increase the efficacy of binocular vision and maintain good ocular alignment in all directions of gaze.

[Visual training in children]. / Sehtraining für Kinder.

The visual system has a pivotal role in most human activities. Many health disorders and psychomotor deficits involve the visual system at some level. From this some therapists infer a causal relation and apply a variety of visual therapies and trainings to cure a variety of deficits. The most prominent example is dyslexia, a disorder not caused by a defect in the primary visual system. Worldwide various non-evidence based therapies are used to treat dyslexia. The great number of exercises and visual trainings is contrasted by scientific evidence, which shows that exercises are useful in only few and selected disorders. The human visual system seems to be optimized such that no improvement can be achieved with training.

Enhanced-depth optical coherence tomography for imaging horizontal rectus muscles in Graves' orbitopathy.

PURPOSE: Graves' orbitopathy (GO) is an extraocular eye disease with symptoms ranging from minor discomfort from dry eyes to strabismus and visual loss. One of the hallmarks of active GO is visible hyperemia at the insertion of the extraocular muscles. The aim of the present study was to evaluate the use of enhanced-depth imaging spectral domain anterior segment optical coherence tomography (EDI SD AS-OCT) for detecting pathological changes in horizontal recti muscles of patients with GO. METHODS: Prospective cross sectional study of 27 eyes. Only women were included. EDI AS-OCT was used to measure the thickness of the tendons of the horizontal recti muscles in a predefined area in patients with GO and healthy controls. RESULTS: EDI AS-OCT was able to image the tendons of the horizontal recti muscles in both healthy controls and patients suffering from GO. The mean thickness of the medial rectus muscle (MR) tendon was 256.4 µm [±17.13 µm standard deviation (SD)] in the GO group and, therefore, significantly thicker (p = 0.046) than in the healthy group which had a mean thickness of 214.7 µm (±5.516 µm SD). There was no significant difference in the mean thickness of the tendon of the lateral recti muscles (LRs) between these groups. CONCLUSION: This is the first report showing that EDI AS-OCT is suitable to detect swelling at the insertion site of the MR muscle in GO. MR tendon thickness may be a useful parameter to monitor activity in these patients.

Acute onset incomitant image disparity modifies saccadic and vergence eye movements.

New-onset impairment of ocular motility will cause incomitant strabismus, i.e., a gaze-dependent ocular misalignment. This ocular misalignment will cause retinal disparity, that is, a deviation of the spatial position of an image on the retina of both eyes, which is a trigger for a vergence eye movement that results in ocular realignment. If the vergence movement fails, the eyes remain misaligned, resulting in double vision. Adaptive processes to such incomitant vergence stimuli are poorly understood. In this study, we have investigated the physiological oculomotor response of saccadic and vergence eye movements in healthy individuals after shifting gaze from a viewing position without image disparity into a field of view with increased image disparity, thus in conditions mimicking incomitance. Repetitive saccadic eye movements into a visual field with increased stimulus disparity lead to a rapid modification of the oculomotor response: (a) Saccades showed immediate disconjugacy (p < 0.001) resulting in decreased retinal image disparity at the end of a saccade. (b) Vergence kinetics improved over time (p < 0.001). This modified oculomotor response enables a more prompt restoration of ocular alignment in new-onset incomitance.

Microcystic macular edema: retrograde maculopathy caused by optic neuropathy.

PURPOSE: To investigate retrograde axonal degeneration for its potential to cause microcystic macular edema (MME), a maculopathy that has been previously described in patients with demyelinating disease. To identify risk factors for MME and to expand the anatomic knowledge on MME. DESIGN: Retrospective case series. PARTICIPANTS: We included 117 consecutive patients and 180 eyes with confirmed optic neuropathy of variable etiology. Patients with glaucoma were excluded. METHODS: We determined age, sex, visual acuity, etiology of optic neuropathy, and the temporal and spatial characteristics of MME. Eyes with MME were compared with eyes with optic neuropathy alone and to healthy fellow eyes. With retinal layer segmentation we quantitatively measured the intraretinal anatomy. MAIN OUTCOME MEASURES: Demographic data, distribution of MME in the retina, and thickness of retinal layers were analyzed. RESULTS: We found MME in 16 eyes (8.8%) from 9 patients, none of whom had multiple sclerosis or neuromyelitis optica. The MME was restricted to the inner nuclear layer (INL) and had a characteristic perifoveal circular distribution. Compared with healthy controls, MME was associated with significant thinning of the ganglion cell layer and nerve fiber layer, as well as a thickening of the INL and the deeper retinal layers. Youth is a significant risk factor for MME. CONCLUSIONS: Microcystic macular edema is not specific for demyelinating disease. It is a sign of optic neuropathy irrespective of its etiology. The distinctive intraretinal anatomy suggests that MME is caused by retrograde degeneration of the inner retinal layers, resulting in impaired fluid resorption in the macula.

Unilateral corneal arcus and conjunctival vessel alterations in cranial autonomic dysregulation: A case report.

BACKGROUND: Cranial autonomic dysregulation is a common symptom of patients suffering from cluster headache or migraine. The peripheral vascular dysfunction may increase the risk for ischemic or hemorrhagic strokes, myocardial infarction, retinal vasculopathy, cardiovascular mortality, and peripheral artery diseases. Furthermore, it may also manifest with ocular symptoms, e.g., increased lacrimation, conjunctival injection, and facial swelling. CASE PRESENTATION: We here report a case of a patient with migraine and ocular signs of a vascular dysregulation that have led to persisting changes of conjunctival vessels and to a corneal arcus. CONCLUSIONS: Autonomic vascular dysregulation may not only cause headaches but also persisting changes of ocular tissues, e.g., conjunctival vessel alterations and a corneal arcus.

MRI signs helpful in the differentiation of patients with anterior ischaemic optic neuropathy and optic neuritis.

BACKGROUND/AIMS: The aim of this study was to identify specific MRI characteristics of anterior ischaemic optic neuropathy (AION) and optic neuritis (ON) that would aid in the differentiation between these two diagnoses. METHODS: We retrospectively analysed a consecutive case series including all patients with an MRI study of brain and orbit and the clinical diagnosis of either ON or AION. We examined the scans for restricted diffusion of the optic nerve, optic sheath diameter, enhancement and location of enhancement of the optic nerve and distribution of the white matter lesions. RESULTS: Fifty patients met the inclusion criteria. We found an accuracy of 0.98 for the discrimination between AION and ON based solely on parameters extracted from MRI data. Dominance analysis to determine the most influential parameters showed that the enhancement pattern of the optic nerve and distribution of the white matter lesions had the biggest impact on the classification and led to a discrimination accuracy of 0.9 when used alone. CONCLUSION: In patients with an inconclusive clinical diagnosis, optic nerve enhancement pattern and distribution of white matter lesions can aid in the diagnosis and differentiation between AION and ON. Diffusion-weighted imaging did not add significant information to the diagnosis or help to differentiate between the two conditions.

Detection of Relative Afferent Pupillary Defects Using Eye Tracking and a VR Headset.

Purpose: The purpose of this study was to assess the feasibility of detecting relative afferent pupillary defects (RAPDs) using a commercial virtual reality headset equipped with an eye tracker. Methods: This is a cross-sectional study in which we compare the new computerized RAPD test with the traditional clinical standard using the swinging flashlight test. Eighty-two participants including 20 healthy volunteers aged 10 to 88 years were enrolled in this study. We present a bright/dark stimulus alternating between the eyes every 3 seconds using a virtual reality headset, and we simultaneously record changes in pupil size. To determine the presence of an RAPD, we developed an algorithm analyzing the pupil size differences. For the assessment of the performance of the automated and the manual measurement a post hoc impression based on all available data is created. The accuracy of the manual clinical evaluation and the computerized method is compared using confusion matrices and the gold standard of the post hoc impression. The latter is based on all available clinical information. Results: We found that the computerized method detected RAPD with a sensitivity of 90.2% and an accuracy of 84.4%, as compared to the post hoc impression. This was not significantly different from the clinical evaluation with a sensitivity of 89.1% and an accuracy of 88.3%. Conclusions: The presented method offers an accurate, easy to use, and fast method to measure an RAPD. In contrast to today's clinical practice, the measures are quantitative and objective. Translational Relevance: Computerized testing of Relative Afferent Pupillary Defects (RAPD) using a VR-headset and eye-tracking reaches non-inferior performance compared with senior neuro-ophthalmologists.

Trial history biases the spatial programming of antisaccades.

The historical context in which saccades are made influences their latency and error rates, but less is known about how context influences their spatial parameters. We recently described a novel spatial bias for antisaccades, in which the endpoints of these responses deviate towards alternative goal locations used in the same experimental block, and showed that expectancy (prior probability) is at least partly responsible for this 'alternate-goal bias'. In this report we asked whether trial history also plays a role. Subjects performed antisaccades to a stimulus randomly located on the horizontal meridian, on a 40° angle downwards from the horizontal meridian, or on a 40° upward angle, with all three locations equally probable on any given trial. We found that the endpoints of antisaccades were significantly displaced towards the goal location of not only the immediately preceding trial (n - 1) but also the penultimate (n - 2) trial. Furthermore, this bias was mainly present for antisaccades with a short latency of <250 ms and was rapidly corrected by secondary saccades. We conclude that the location of recent antisaccades biases the spatial programming of upcoming antisaccades, that this historical effect persists over many seconds, and that it influences mainly rapidly generated eye movements. Because corrective saccades eliminate the historical bias, we suggest that the bias arises in processes generating the response vector, rather than processes generating the perceptual estimate of goal location.

Rapid adaptation of visual search in simulated hemianopia.

Patients with homonymous hemianopia have altered visual search patterns, but it is unclear how rapidly this develops and whether it reflects a strategic adaptation to altered perception or plastic changes to tissue damage. To study the temporal dynamics of adaptation alone, we used a gaze-contingent display to simulate left or right hemianopia in 10 healthy individuals as they performed 25 visual search trials. Visual search was slower and less accurate in hemianopic than in full-field viewing. With full-field viewing, there were improvements in search speed, fixation density, and number of fixations over the first 9 trials, then stable performance. With hemianopic viewing, there was a rapid shift of fixation into the blind field over the first 5-7 trials, followed by continuing gradual improvements in completion time, number of fixations, and fixation density over all 25 trials. We conclude that in the first minutes after onset of hemianopia, there is a biphasic pattern of adaptation to altered perception: an early rapid qualitative change that shifts visual search into the blind side, followed by more gradual gains in the efficiency of using this new strategy, a pattern that has parallels in other studies of motor learning.

Pharmacological and Behavioral Strategies to Improve Vision in Acquired Pendular Nystagmus.

BACKGROUND Acquired pendular nystagmus (APN) is a back and forth, oscillatory eye movement in which the 2 oppositely directed slow phases have similar waveforms. APN occurs commonly in multiple sclerosis and causes a disabling oscillopsia that impairs vision. Previous studies have proven that symptomatic therapy with gabapentin or memantine can reduce the nystagmus amplitude or frequency. However, the effect of these medications on visual acuity (VA) is less known and to our knowledge the impact of non-pharmacological strategies such as blinking on VA has not been reported. This is a single observational study without controls (Class IV) and is meant to suggest a future strategy for study of vision in patients with disabling nystagmus and impaired vision. CASE REPORT A 49-year-old woman with primary progressive multiple sclerosis with spastic paraparesis and a history of optic atrophy presented with asymmetrical binocular APN and bothersome oscillopsia. We found that in the eye with greater APN her visual acuity improved by 1 line (from 0.063 to 0.08 decimals) immediately after blinking. During treatment with memantine, her VA without blinking increased by 2 lines, from 0.063 to 0.12, but improved even more (from 0.12 to 0.16) after blinking. In the contralateral eye with a barely visible nystagmus, VA was reduced by 1 line briefly (~500 ms) after blinking. CONCLUSIONS In a patient with APN, blinking transiently improved vision. The combination of pharmacological treatment with memantine and the blinking strategy may induce better VA and less oscillopsia than either alone.

Evaluation of the Reddesa Chart, a New Red Desaturation Testing Method, for Optic Neuritis Screening and Grading in Clinical Routine.

Background: Optic neuritis usually leads to reduced color sensitivity. Most often, the change of red color, the so-called red desaturation, is tested in clinical routine. The aim of this study was to test the feasibility of the Reddesa chart, a new red desaturation test based on polarization, as a screening method for optic neuropathy. Methods: A total of 20 patients with unilateral optic neuritis and 20 healthy controls were included in this prospective pilot study. Ophthalmological examination included assessment of best corrected visual acuity (BCVA), slit lamp examination, fundoscopy, testing of relative afferent pupillary defect (RAPD) and red desaturation with the red cup test and the Reddesa chart. Results: The mean BCVA in the optic neuritis group was 0.76 ± 0.36 in the affected eye (95% of eyes with RAPD, 75% of eyes with difference in the Reddesa test) and 1.28 ± 0.24 in the healthy eye, whereas in the control group, BCVA was 1.14 ± 0.11 in the right eye and 1.15 ± 0.14 in the left eye (none of the eyes with RAPD or abnormal Reddesa test). In our study, the Reddesa test showed a positive predictive value of 100% and a negative predictive value of 80% for detecting optic neuritis. Conclusion: The Reddesa chart allows to quantify red desaturation and has the potential to be implemented as a screening test in clinical routine.