The value of saccade metrics and VOR gain in detecting a vestibular stroke.

OBJECTIVE: A normal video Head Impulse Test is the gold standard in the emergency department to rule-in patients with an acute vestibular syndrome and a stroke. We aimed to compare the diagnostic accuracy of vHIT metrics regarding the vestibulo-ocular reflex gain and the corrective saccades in detecting vestibular strokes. METHODS: Prospective cross-sectional study (convenience sample) of patients presenting with acute vestibular syndrome in the emergency department of a tertiary referral centre between February 2015 and May 2020. We screened 1677 patients and enrolled 76 patients fulfilling the inclusion criteria of acute vestibular syndrome. All patients underwent video head impulse test with automated and manual data analysis. A delayed MRI served as a gold standard for vestibular stroke confirmation. RESULTS: Out of 76 patients, 52 were diagnosed with acute unilateral vestibulopathy and 24 with vestibular strokes. The overall accuracy of detecting stroke with an automated vestibulo-ocular reflex gain was 86.8%, compared to 77.6% for cumulative saccade amplitude and automatic saccade mean peak velocity measured by an expert and 71% for cumulative saccade amplitude and saccade mean peak velocity measured automatically. Gain misclassified 13.1% of the patients as false positive or false negative, manual cumulative saccade amplitude and saccade mean peak velocity 22.3%, and automated cumulative saccade amplitude and saccade mean peak velocity 28.9% respectively. CONCLUSIONS: We found a better accuracy of video head impulse test for the diagnosis of vestibular strokes when using the vestibulo-ocular reflex gain than using saccade metrics. Nevertheless, saccades provide an additional and important information for video head impulse test evaluation. The automated saccade detection algorithm is not yet perfect compared to expert analysis, but it may become a valuable tool for future non-expert video head impulse test evaluations.

Physiological oculo-auricular-facial-mandibular synkinesis elicited in humans by gaze deviations.

Integrated motor behaviors involving ocular motion-associated movements of the head, neck, pinna, and parts of the face are commonly seen in animals orienting to a visual target. A number of coordinated movements have also been observed in humans making rapid gaze shifts to horizontal extremes, which may be vestiges of these. Since such integrated mechanisms point to a nonpathological coactivation of several anatomically separate cranial circuits in humans, it is important to see how the different pairs of integrative motor behaviors with a common trigger (i.e., ocular motion) manifest in relation to one another. Here, we systematically examined the pattern of eye movement-induced recruitment of multiple cranial muscles in humans. Simultaneous video-oculography and bilateral surface electromyograms of transverse auricular, temporalis, frontalis, and masseter muscles were recorded in 15 healthy subjects (8 females; 29.3 ± 5.2 yr) while they made head-fixed, horizontal saccadic, pursuit, and optokinetic eye movements. Potential chin laterotrusion linked to contractions of masticator muscles was captured with a jaw-fixed accelerometer. Our findings objectively show an orchestrated aural-facial-masticatory muscle response to a range of horizontal eye movements (prevalence of 21%-93%). These responses were most prominent during eccentric saccades. We further reveal distinctions between the various observed activation patterns in terms of their profile (transient or sustained), laterality (with respect to direction of gaze), and timing (with respect to saccade onset). Possible underlying neural substrates, their atavistic behavioral significance, and potential clinical applications for monitoring sensory attention and designing attention-directed hearing aids in the future are discussed.NEW & NOTEWORTHY Healthy humans exhibit different combinations of nonpathological, synkinetic gaze-associated movements with aural, facial, and/or masticatory muscles during different types of voluntary and reflexive horizontal eye movements. The manifestations of these collective phenomena are strongest during large-scale horizontal saccades and accompanied by a detectable horizontal chin movement. Auricular muscle activations occur equally on both sides, whereas the activation of facial and masticatory muscles is predominantly ipsilateral (in regard to gaze direction).

Age-dependent perturbation of the perceptual and postural vertical by visual roll vection and susceptibility to motion sickness in children.

BACKGROUND: The visual contribution to the perceptual and postural vertical is mediated by a multisensory integration process and may relate to children's susceptibility to motion sickness that is hypothesized to arise from intersensory conflicts. OBJECTIVE: To analyze the maturation of visual contribution to the perceptual and postural vertical in conjunction with the motion sickness susceptibility in childhood. METHODS: In 81 healthy children (aged 2-17 years; 57 females), adjustments of the subjective visual vertical and posturographically tested mediolateral displacements of body sway were measured during free upright stance and large-field visual motion stimulation in the roll plane (roll vection). Motion sickness susceptibility was assessed by taking the history of parents and children. RESULTS: Vection-induced tilts of the visual vertical showed a linear age-dependent decrease with largest tilts in the youngest (2-7 years; median of 20°) and smallest tilts in the oldest age group (13-17 years; median of 9-10°). Analogously, postural tilts as measured by mediolateral body sway were greatest in the youngest and smallest in the oldest age group. In contrast, motion sickness susceptibility was lowest in the youngest and highest in the oldest age group and exhibited an inverse correlation with vection-induced tilts of the visual vertical. CONCLUSION: Roll vection-induced tilts of the visual and postural vertical exhibited a similar age-dependent course with the greatest effects in the youngest and the least effects in the oldest age group, the latter of which exhibited the highest susceptibility to motion sickness.

Comparison of two methods based on one psychophysical paradigm to measure the subjective postural vertical in standing.

The perception of verticality can be altered with age or due to neurological diseases. Different procedures have been described to measure the subjective postural vertical (SPV). A deviation from the earth vertical was either described as a single position or as a sector defined by two positions representing the edges of the perceived verticality. In this study, for the first time, we investigated if these two methods produce equal values, and consequently can be merged to set normative values. SPV in standing was tested in 24 healthy young adults (28.4 (5.2) years of age, 12 women). Each participant performed both methods in the sagittal and the frontal plane. Absolute and constant error values were found to be similar for both methods in both planes with a mean difference of less than 0.3° (p > 0.148). The mean width of the SPV sector was 3.9° (0.9°) in the sagittal and 3.7° (1.4°) in the frontal plane, ranging in the mean from -5.5° to 8.1° in the sagittal and -5.3° to 4.3° in the frontal plane. SPV values significantly differed in range between both methods in both planes with a mean difference of more than 3.1° (p<0.002). Results show that both methods, SPVposition and SPVsector, produce equal error values when applied with otherwise similar methodological settings and can therefore be used alternatively or within the same meta-analysis. The SPVsector, however, led to wider range values and was less frequently rated as the preferred method to represent the participants' subjective verticality.

Eye movement biomarkers allow for the definition of phenotypes in Gaucher Disease.

BACKGROUND: Neurological forms of Gaucher disease, the inherited disorder of ß-Glucosylceramidase caused by bi-allelic variants in GBA1, is a progressive disorder which lacks a disease-modifying therapy. Systemic manifestations of disease are effectively treated with enzyme replacement therapy, however, molecules which cross the blood-brain barrier are still under investigation. Clinical trials of such therapeutics require robust, reproducible clinical endpoints to demonstrate efficacy and clear phenotypic definitions to identify suitable patients for inclusion in trials. The single consistent clinical feature in all patients with neuronopathic disease is the presence of a supranuclear saccadic gaze palsy, in the presence of Gaucher disease this finding serves as diagnostic of 'type 3' Gaucher disease. METHODS: We undertook a study to evaluate saccadic eye movements in Gaucher patients and to assess the role of the EyeSeeCam in measuring saccades. The EyeSeeCam is a video-oculography device which was used to run a protocol of saccade measures. We studied 39 patients with non-neurological Gaucher disease (type 1), 21 patients with type 3 (neurological) disease and a series of 35 healthy controls. Mean saccade parameters were compared across disease subgroups. RESULTS: We confirmed the saccadic abnormality in patients with type 3 Gaucher disease and identified an unexpected subgroup of patients with type 1 Gaucher disease who demonstrated significant saccade parameter abnormalities. These patients also showed subtle neurological findings and shared a GBA1 variant. CONCLUSIONS: This striking novel finding of a potentially attenuated type 3 Gaucher phenotype associated with a specific GBA1 variant and detectable saccadic abnormality prompts review of current disease classification. Further, this finding highlights the broad spectrum of neuronopathic Gaucher phenotypes relevant when designing inclusion criteria for clinical trials.

Towards computerized diagnosis of neurological stance disorders: data mining and machine learning of posturography and sway.

We perform classification, ranking and mapping of body sway parameters from static posturography data of patients using recent machine-learning and data-mining techniques. Body sway is measured in 293 individuals with the clinical diagnoses of acute unilateral vestibulopathy (AVS, n = 49), distal sensory polyneuropathy (PNP, n = 12), anterior lobe cerebellar atrophy (CA, n = 48), downbeat nystagmus syndrome (DN, n = 16), primary orthostatic tremor (OT, n = 25), Parkinson's disease (PD, n = 27), phobic postural vertigo (PPV n = 59) and healthy controls (HC, n = 57). We classify disorders and rank sway features using supervised machine learning. We compute a continuous, human-interpretable 2D map of stance disorders using t-stochastic neighborhood embedding (t-SNE). Classification of eight diagnoses yielded 82.7% accuracy [95% CI (80.9%, 84.5%)]. Five (CA, PPV, AVS, HC, OT) were classified with a mean sensitivity and specificity of 88.4% and 97.1%, while three (PD, PNP, and DN) achieved a mean sensitivity of 53.7%. The most discriminative stance condition was ranked as "standing on foam-rubber, eyes closed". Mapping of sway path features into 2D space revealed clear clusters among CA, PPV, AVS, HC and OT subjects. We confirm previous claims that machine learning can aid in classification of clinical sway patterns measured with static posturography. Given a standardized, long-term acquisition of quantitative patient databases, modern machine learning and data analysis techniques help in visualizing, understanding and utilizing high-dimensional sensor data from clinical routine.

No Evidence of a Contribution of the Vestibular System to Frequent Falls in Progressive Supranuclear Palsy.

BACKGROUND AND PURPOSE: Conflicting results about vestibular function in progressive supranuclear palsy (PSP) prompted a systematic examination of the semicircular canal function, otolith function, and postural stability. METHODS: Sixteen patients with probable PSP [9 females, age=72±6 years (mean±SD), mean disease duration=3.6 years, and mean PSP Rating Scale score=31] and 17 age-matched controls were examined using the video head impulse test, caloric testing, ocular and cervical vestibular evoked myogenic potentials (o- and cVEMPs), video-oculography, and posturography. RESULTS: There was no evidence of impaired function of the angular vestibulo-ocular reflex (gain=1.0±0.1), and caloric testing also produced normal findings. In terms of otolith function, there was no significant difference between PSP patients and controls in the absolute peakto-peak amplitude of the oVEMP (13.5±7.2 µV and 12.5±5.6 µV, respectively; p=0.8) or the corrected peak-to-peak amplitude of the cVEMP (0.6±0.3 µV and 0.5±0.2 µV, p=0.3). The total root-mean-square body sway was significantly increased in patients with PSP compared to controls (eyes open/head straight/hard platform: 9.3±3.7 m/min and 6.9±2.1 m/min, respectively; p=0.032). As expected, the saccade velocities were significantly lower in PSP patients than in controls: horizontal, 234±92°/sec and 442±66°/sec, respectively; downward, 109±105°/sec and 344±72°/sec; and upward, 121±110°/sec and 348±78°/sec (all p<0.01). CONCLUSIONS: We found no evidence of impairment of either high- or low-frequency semicircular function or otolith organ function in the examined PSP patients. It therefore appears that other causes such as degeneration of supratentorial pathways lead to postural imbalance and falls in patients with PSP.

Resting in darkness improves downbeat nystagmus: evidence from an observational study.

Resting in an upright position during daytime decreases downbeat nystagmus (DBN). When measured in brightness only, that is, without intermitting exposure to darkness, it does not make a significant difference whether patients have previously rested in brightness or in darkness. In real-world scenarios, people are often exposed to brightness and darkness intermittently. The aim of this study was to analyze whether resting in brightness or resting in darkness was associated with a lower post-resting DBN after intermitting exposures to brightness and darkness. Eight patients were recorded with three-dimensional video-oculography in brightness and darkness conditions, each following two 2-h resting intervals under either brightness or darkness resting conditions. The dependent variable was DBN intensity, measured in mean slow phase velocity. A repeated measures ANOVA with the factors measurement condition (brightness vs. darkness), resting condition (brightness vs. darkness), and time (after first vs. second resting interval) showed a significant effect for the factor resting condition, where previous resting in darkness was associated with a significantly lower DBN relative to previous resting in brightness (P < 0.01). The clinical relevance is to advise patients with DBN to rest in darkness.

The subjective postural vertical in standing: reliability and normative data for healthy subjects.

Impaired verticality perception can cause falls, or even the inability to stand, due to lateropulsion or retropulsion. The internal estimate of verticality can be assessed through the subjective visual, haptic, or postural vertical (SPV). The SPV reflects impaired upright body orientation, but has primarily been assessed in sitting position. The internal representations of body orientation might be different between sitting and standing, mainly because of differences in somatosensory input for the estimation of SPV. To test the SPV during standing, we set up a paradigm using a device that allows movement in three dimensions (the Spacecurl). This study focused on the test-retest and interrater reliabilities of SPV measurements (n = 25) and provides normative values for the age range 20-79 years (n = 60; 10 healthy subjects per decade). The test-retest and interrater reliabilities for SPV measurements in standing subjects were good. The normality values ranged from -1.7° to 2.3° in the sagittal plane, and from -1.6° to 1.2° in the frontal plane. Minor alterations occurred with aging: SPV shifted backward with increasing age, and the variability of verticality estimates increased. Assessment of SPV in standing can be done with reliable results. SPV should next be used to test patients with an impaired sense of verticality, to determine its diagnostic value in comparison to established tools.

Dalfampridine in patients with downbeat nystagmus--an observational study.

We investigated the effects of dalfampridine, the sustained-release form of 4-aminopyridine, on slow phase velocity (SPV) and visual acuity (VA) in patients with downbeat nystagmus (DBN) and the side effects of the drug. In this proof-of-principle observational study, ten patients received dalfampridine 10 mg bid for 2 weeks. Recordings were conducted at baseline, 180 min after first administration, after 2 weeks of treatment and after 4 weeks of wash-out. Mean SPV decreased from a baseline of 2.12 deg/s ± 1.72 (mean ± SD) to 0.51 deg/s ± 1.00 180 min after first administration of dalfampridine 10 mg and to 0.89 deg/s ± 0.75 after 2 weeks of treatment with dalfampridine (p < 0.05; post hoc both: p < 0.05). After a wash-out period of 1 week, mean SPV increased to 2.30 deg/s ± 1.6 (p < 0.05; post hoc both: p < 0.05). The VA significantly improved during treatment with dalfampridine. Also, 50 % of patients did not report any side effects. The most common reported side effects were abdominal discomfort and dizziness. Dalfampridine is an effective treatment for DBN in terms of SPV. It was well-tolerated in all patients.

Human brain dynamics accompanying use of egocentric and allocentric reference frames during navigation.

Maintaining spatial orientation while travelling requires integrating spatial information encountered from an egocentric viewpoint with accumulated information represented within egocentric and/or allocentric reference frames. Here, we report changes in high-density EEG activity during a virtual tunnel passage task in which subjects respond to a postnavigation homing challenge in distinctly different ways--either compatible with a continued experience of the virtual environment from a solely egocentric perspective or as if also maintaining their original entrance orientation, indicating use of a parallel allocentric reference frame. By spatially filtering the EEG data using independent component analysis, we found that these two equal subject subgroups exhibited differences in EEG power spectral modulation during tunnel passages in only a few cortical areas. During tunnel turns, stronger alpha blocking occurred only in or near right primary visual cortex of subjects whose homing responses were compatible with continued use of an egocentric reference frame. In contrast, approaching and during tunnel turns, subjects who responded in a way compatible with use of an allocentric reference frame exhibited stronger alpha blocking of occipito-temporal, bilateral inferior parietal, and retrosplenial cortical areas, all areas implicated by hemodynamic imaging and neuropsychological observation in construction and maintenance of an allocentric reference frame. We conclude that in these subjects, stronger activation of retrosplenial and related cortical areas during turns support a continuous translation of egocentrically experienced visual flow into an allocentric model of their virtual position and movement.