A Landscape of Pharmacogenomic Interactions in Cancer.

Systematic studies of cancer genomes have provided unprecedented insights into the molecular nature of cancer. Using this information to guide the development and application of therapies in the clinic is challenging. Here, we report how cancer-driven alterations identified in 11,289 tumors from 29 tissues (integrating somatic mutations, copy number alterations, DNA methylation, and gene expression) can be mapped onto 1,001 molecularly annotated human cancer cell lines and correlated with sensitivity to 265 drugs. We find that cell lines faithfully recapitulate oncogenic alterations identified in tumors, find that many of these associate with drug sensitivity/resistance, and highlight the importance of tissue lineage in mediating drug response. Logic-based modeling uncovers combinations of alterations that sensitize to drugs, while machine learning demonstrates the relative importance of different data types in predicting drug response. Our analysis and datasets are rich resources to link genotypes with cellular phenotypes and to identify therapeutic options for selected cancer sub-populations.

cGAS-STING drives the IL-6-dependent survival of chromosomally instable cancers.

Chromosomal instability (CIN) drives cancer cell evolution, metastasis and therapy resistance, and is associated with poor prognosis1. CIN leads to micronuclei that release DNA into the cytoplasm after rupture, which triggers activation of inflammatory signalling mediated by cGAS and STING2,3. These two proteins are considered to be tumour suppressors as they promote apoptosis and immunosurveillance. However, cGAS and STING are rarely inactivated in cancer4, and, although they have been implicated in metastasis5, it is not known why loss-of-function mutations do not arise in primary tumours4. Here we show that inactivation of cGAS-STING signalling selectively impairs the survival of triple-negative breast cancer cells that display CIN. CIN triggers IL-6-STAT3-mediated signalling, which depends on the cGAS-STING pathway and the non-canonical NF-κB pathway. Blockade of IL-6 signalling by tocilizumab, a clinically used drug that targets the IL-6 receptor (IL-6R), selectively impairs the growth of cultured triple-negative breast cancer cells that exhibit CIN. Moreover, outgrowth of chromosomally instable tumours is significantly delayed compared with tumours that do not display CIN. Notably, this targetable vulnerability is conserved across cancer types that express high levels of IL-6 and/or IL-6R in vitro and in vivo. Together, our work demonstrates pro-tumorigenic traits of cGAS-STING signalling and explains why the cGAS-STING pathway is rarely inactivated in primary tumours. Repurposing tocilizumab could be a strategy to treat cancers with CIN that overexpress IL-6R.

The Mediterranean mussel Mytilus galloprovincialis: a novel model for developmental studies in mollusks.

A model organism in developmental biology is defined by its experimental amenability and by resources created for the model system by the scientific community. For the most powerful invertebrate models, the combination of both has already yielded a thorough understanding of developmental processes. However, the number of developmental model systems is still limited, and their phylogenetic distribution heavily biased. Members of one of the largest animal lineages, the Spiralia, for example, have long been neglected. In order to remedy this shortcoming, we have produced a detailed developmental transcriptome for the bivalve mollusk Mytilus galloprovincialis, and have expanded the list of experimental protocols available for this species. Our high-quality transcriptome allowed us to identify transcriptomic signatures of developmental progression and to perform a first comparison with another bivalve mollusk: the Pacific oyster Crassostrea gigas. To allow co-labelling studies, we optimized and combined protocols for immunohistochemistry and hybridization chain reaction to create high-resolution co-expression maps of developmental genes. The resources and protocols described here represent an enormous boost for the establishment of Mytilus galloprovincialis as an alternative model system in developmental biology.

Gain of gene regulatory network interconnectivity at the origin of vertebrates.

SignificanceIn this manuscript, we address an essential question in developmental and evolutionary biology: How have changes in gene regulatory networks contributed to the invertebrate-to-vertebrate transition? To address this issue, we perturbed four signaling pathways critical for body plan formation in the cephalochordate amphioxus and in zebrafish and compared the effects of such perturbations on gene expression and gene regulation in both species. Our data reveal that many developmental genes have gained response to these signaling pathways in the vertebrate lineage. Moreover, we show that the interconnectivity between these pathways is much higher in zebrafish than in amphioxus. We conclude that this increased signaling pathway complexity likely contributed to vertebrate morphological novelties during evolution.

Posture, Gait, Quality of Life, and Hearing with a Vestibular Implant.

BACKGROUND: Bilateral vestibular hypofunction is associated with chronic disequilibrium, postural instability, and unsteady gait owing to failure of vestibular reflexes that stabilize the eyes, head, and body. A vestibular implant may be effective in alleviating symptoms. METHODS: Persons who had had ototoxic (7 participants) or idiopathic (1 participant) bilateral vestibular hypofunction for 2 to 23 years underwent unilateral implantation of a prosthesis that electrically stimulates the three semicircular canal branches of the vestibular nerve. Clinical outcomes included the score on the Bruininks-Oseretsky Test of Motor Proficiency balance subtest (range, 0 to 36, with higher scores indicating better balance), time to failure on the modified Romberg test (range, 0 to 30 seconds), score on the Dynamic Gait Index (range, 0 to 24, with higher scores indicating better gait performance), time needed to complete the Timed Up and Go test, gait speed, pure-tone auditory detection thresholds, speech discrimination scores, and quality of life. We compared participants' results at baseline (before implantation) with those at 6 months (8 participants) and at 1 year (6 participants) with the device set in its usual treatment mode (varying stimulus pulse rate and amplitude to represent rotational head motion) and in a placebo mode (holding pulse rate and amplitude constant). RESULTS: The median scores at baseline and at 6 months on the Bruininks-Oseretsky test were 17.5 and 21.0, respectively (median within-participant difference, 5.5 points; 95% confidence interval [CI], 0 to 10.0); the median times on the modified Romberg test were 3.6 seconds and 8.3 seconds (difference, 5.1; 95% CI, 1.5 to 27.6); the median scores on the Dynamic Gait Index were 12.5 and 22.5 (difference, 10.5 points; 95% CI, 1.5 to 12.0); the median times on the Timed Up and Go test were 11.0 seconds and 8.7 seconds (difference, 2.3; 95% CI, -1.7 to 5.0); and the median speeds on the gait-speed test were 1.03 m per second and 1.10 m per second (difference, 0.13; 95% CI, -0.25 to 0.30). Placebo-mode testing confirmed that improvements were due to treatment-mode stimulation. Among the 6 participants who were also assessed at 1 year, the median within-participant changes from baseline to 1 year were generally consistent with results at 6 months. Implantation caused ipsilateral hearing loss, with the air-conducted pure-tone average detection threshold at 6 months increasing by 3 to 16 dB in 5 participants and by 74 to 104 dB in 3 participants. Changes in participant-reported disability and quality of life paralleled changes in posture and gait. CONCLUSIONS: Six months and 1 year after unilateral implantation of a vestibular prosthesis for bilateral vestibular hypofunction, measures of posture, gait, and quality of life were generally in the direction of improvement from baseline, but hearing was reduced in the ear with the implant in all but 1 participant. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT02725463.).

Evidence for the differential efficacy of yaw and pitch gaze stabilization mechanisms in people with multiple sclerosis.

People with multiple sclerosis (PwMS) who report dizziness often have gaze instability due to vestibulo-ocular reflex (VOR) deficiencies and compensatory saccade (CS) abnormalities. Herein, we aimed to describe and compare the gaze stabilization mechanisms for yaw and pitch head movements in PwMS. Thirty-seven PwMS (27 female, mean ± SD age = 53.4 ± 12.4 years old, median [IQR] Expanded Disability Status Scale Score = 3.5, [1.0]. We analyzed video head impulse test results for VOR gain, CS frequency, CS latency, gaze position error (GPE) at impulse end, and GPE at 400 ms after impulse start. Discrepancies were found for median [IQR] VOR gain in yaw (0.92 [0.14]) versus pitch-up (0.71 [0.44], p < 0.001) and pitch-down (0.81 [0.44], p = 0.014]), CS latency in yaw (258.13 [76.8]) ms versus pitch-up (208.78 [65.97]) ms, p = 0.001] and pitch-down (132.17 [97.56] ms, p = 0.006), GPE at impulse end in yaw (1.15 [1.85] degs versus pitch-up (2.71 [3.9] degs, p < 0.001), and GPE at 400 ms in yaw (-0.25 [0.98] degs) versus pitch-up (1.53 [1.07] degs, p < 0.001) and pitch-down (1.12 [1.82] degs, p = 0.001). Compared with yaw (0.91 [0.75]), CS frequency was similar for pitch-up (1.03 [0.93], p = 0.999) but lower for pitch-down (0.65 [0.64], p = 0.023). GPE at 400 ms was similar for yaw and pitch-down (1.88 [2.76] degs, p = 0.400). We postulate that MS may have preferentially damaged the vertical VOR and saccade pathways in this cohort.

Utricular Dysfunction and Hearing Impairment Affect Spatial Navigation in Community-dwelling Healthy Adults: Analysis from the Baltimore Longitudinal Study of Aging.

INTRODUCTION: Spatial navigation, the ability to move through one's environment, is a complex skill utilized in everyday life. The effects of specific vestibular end-organ deficits and hearing impairments on spatial navigation have received little to no attention. We hypothesized that hearing impairment adversely affects spatial navigation and that bi-modal impairments (vestibular and hearing) further impair navigation ability. METHODS: Data from 182 participants in the Baltimore Longitudinal Study of Aging who had interpretable results for the video head impulse test (vHIT), cervical (cVEMP) and ocular (oVEMP) vestibular evoked myogenic potentials, audiometric testing, and the triangle completion test (TCT) were retrospectively analyzed. Multiple linear regression, controlling for age, sex, and cognition, was employed to identify predictors of TCT performance in terms of end-point error, angle deviation, and distance walked. RESULTS: oVEMP abnormalities were associated with larger end-point error (p=0.008) and larger angle deviation (p=0.002) but were not associated with distance walked (p=0.392). Abnormalities on cVEMP and vHIT were not associated with distance walked (p=0.835, p=0.300), end-point error (p=0.256, p=0.808), or angle deviation (p=0.192, p=0.966). Compared with normal hearing adults, hearing impaired adults walked a shorter distance during the TCT (p=0.049) but had similar end-point error (p=0.302) and angle deviation (p=0.466). There was no interaction between vestibular and hearing function for predicting spatial navigation ability. CONCLUSION: In this cohort analysis, utricular dysfunction and hearing impairment were associated with poorer spatial navigation performance. We postulate that hearing impairment negatively affects one's ability to use real-time, intrinsic auditory cues and/or prior experience to guide navigation.

Amphioxus functional genomics and the origins of vertebrate gene regulation.

Vertebrates have greatly elaborated the basic chordate body plan and evolved highly distinctive genomes that have been sculpted by two whole-genome duplications. Here we sequence the genome of the Mediterranean amphioxus (Branchiostoma lanceolatum) and characterize DNA methylation, chromatin accessibility, histone modifications and transcriptomes across multiple developmental stages and adult tissues to investigate the evolution of the regulation of the chordate genome. Comparisons with vertebrates identify an intermediate stage in the evolution of differentially methylated enhancers, and a high conservation of gene expression and its cis-regulatory logic between amphioxus and vertebrates that occurs maximally at an earlier mid-embryonic phylotypic period. We analyse regulatory evolution after whole-genome duplications, and find that-in vertebrates-over 80% of broadly expressed gene families with multiple paralogues derived from whole-genome duplications have members that restricted their ancestral expression, and underwent specialization rather than subfunctionalization. Counter-intuitively, paralogues that restricted their expression increased the complexity of their regulatory landscapes. These data pave the way for a better understanding of the regulatory principles that underlie key vertebrate innovations.

Double-strand break toxicity is chromatin context independent.

Cells respond to double-strand breaks (DSBs) by activating DNA damage response pathways, including cell cycle arrest. We have previously shown that a single double-strand break generated via CRISPR/Cas9 is sufficient to delay cell cycle progression and compromise cell viability. However, we also found that the cellular response to DSBs can vary, independent of the number of lesions. This implies that not all DSBs are equally toxic, and raises the question if the location of a single double-strand break could influence its toxicity. To systematically investigate if DSB-location is a determinant of toxicity we performed a CRISPR/Cas9 screen targeting 6237 single sites in the human genome. Next, we developed a data-driven framework to design CRISPR/Cas9 sgRNA (crRNA) pools targeting specific chromatin features. The chromatin context was defined using ChromHMM states, Lamin-B1 DAM-iD, DNAseI hypersensitivity, and RNA-sequencing data. We computationally designed 6 distinct crRNA pools, each containing 10 crRNAs targeting the same chromatin state. We show that the toxicity of a DSB is highly similar across the different ChromHMM states. Rather, we find that the major determinants of toxicity of a sgRNA are cutting efficiency and off-target effects. Thus, chromatin features have little to no effect on the toxicity of a single CRISPR/Cas9-induced DSB.

Visual vertigo and motion sickness is different between persistent postural-perceptual dizziness and vestibular migraine.

INTRODUCTION: Persistent postural-perceptual dizziness (PPPD) and vestibular migraine (VM) share symptoms of visual vertigo and motion sickness that can be confusing for clinicians to distinguish. We compare the severity of these symptoms and dynamic subjective visual vertical (dSVV) in these two common vestibular conditions. METHOD: Twenty-nine patients with PPPD, 37 with VM, and 29 controls were surveyed for subjective symptoms using the visual vertigo analogue scale (VVAS) and motion sickness susceptibility questionnaire during childhood (MSA) and the past 10 years (MSB). dSVV is a measure of visual dependence measures perception of verticality against a rotating background (5 deg./s). RESULTS: VVAS revealed contextual differences for dizziness between those with PPPD and VM. Ratings of visual vertigo were most severe in PPPD, less in VM, and mild in controls (VVAS PPPD 27.1, VM 11.2, control 4.6, p < 0.001). MSA was more severe in VM than in PPPD or control (12.8 vs 7.6 vs 8.5, p = 0.01). MSB was more severe in VM than controls (MSB score 12.9 VS 8.1 p = 0.009) but was not different than PPPD (MSB score 10.0, p = 0.10). dSVV alignment was similar among the three groups (p = 0.83). Both VM and PPPD groups had greater simulator sickness than controls after completing the dSVV. CONCLUSIONS: Patients with PPPD report more visual vertigo than those with VM, but a history of motion sickness as a child is more common in VM. Additionally, the environmental context that induces visual vertigo is different between PPPD and VM.

Quantification of groundwater discharge into a shallow coastal lagoon applying a multi-tracer approach.

In many cases, shallow coastal lagoons are, on the one hand, vulnerable habitats for birds and marine ecosystems and, on the other hand, threatened by discharging nutrient-laden surface waters and groundwater. In particular, the localization and quantification of submarine groundwater discharge (SGD) is of key concern in this regard. The presented study aimed at investigating SGD into a vulnerable coastal lagoon that is strongly impacted by evaporation applying a multi-tracer approach. The joint application of radionuclides (222Rn, 223Ra, 224Ra), stable water isotopes (δ18O, δ2H) and the water salinity as environmental water tracers allowed evaluating the suitability of the individual parameters in this specific type of environment. Whilst stable isotope and salinity data were difficult to construe in terms of SGD occurrence due to the intense impact of evaporation, a radon mass balance allowed localising SGD areas within the lagoon and quantifying the related SGD flux rates. In addition, a 224Ra/223Ra ratio analysis revealed information on the apparent age of the discharged groundwater, and hence on the flushing intensity of the lagoon. Besides these site-specific results, the study allowed the following general conclusions regarding the suitability of the applied tracers: (i) we verified the suitability of a radon mass balance approach for proving/disproving SGD occurrence and quantifying SGD fluxes in shallow coastal lagoons strongly impacted by evaporation; (ii) we showed that the impact of evaporation may impede the use of water stable isotope and salinity data as SGD indicators in such specific environments; (iii) we demonstrated that the tidal impact on a lagoon water body during a sampling campaign can be compensated by adapting sampling schedule and cruise track to the tidal cycle.

Compensatory saccades differ between those with vestibular hypofunction and multiple sclerosis pointing to unique roles for peripheral and central vestibular inputs.

Individuals with peripheral or central vestibular dysfunction recruit compensatory saccades (CSs) in response to high acceleration, yaw head impulses. Although CSs have been shown to be an effective strategy for reducing gaze position error (GPE) in individuals with peripheral hypofunction, for individuals with central vestibular dysfunction, the effectiveness of CS is unknown. The purpose of our study was to compare the effectiveness of CS, defined as the ability to compensate for head velocity and eye position errors, between persons with central and peripheral vestibular dysfunction. We compared oculomotor responses during video head impulse testing between individuals with unilateral peripheral vestibular deafferentation, a disorder of the peripheral vestibular afferents, and individuals with multiple sclerosis, a condition affecting the central vestibular pathways. We hypothesized that relative to individuals with peripheral lesions, individuals with central dysfunction would recruit CSs that were delayed and inappropriately scaled to head velocity and GPE. We show that CSs recruited by persons with central vestibular pathology were not uniformly deficient but instead were of a sufficient velocity to compensate for reductions in VOR gain. Compared to those with peripheral vestibular lesions, individuals with central pathology also recruited earlier covert CS with amplitudes that were better corrected for GPE. Conversely, those with central lesions showed greater variability in the amplitude of overt CS relative to GPE. These data point to a unique role for peripheral and central vestibular inputs in the recruitment of CS and suggest that covert CSs are an effective oculomotor strategy for individuals with multiple sclerosis.NEW & NOTEWORTHY Compensatory saccades (CSs) are recruited by individuals with unilateral vestibular deafferentation (UVD) to compensate for an impaired vestibulo-ocular reflex (VOR). The effectiveness of CS in multiple sclerosis (MS), a central vestibular impairment, is unknown. We show that in UVD and in MS, covert CSs compensate for reduced VOR gain and minimize gaze position error (GPE), yet in >50% of individuals with MS, overt CS worsened GPE, suggesting unique roles for peripheral and central vestibular inputs.

A prospective study of Skeletal survey versus Low-dose whole-body CT for Osteolytic lesions in Multiple Myeloma.

Whole-body low-dose CT (WBLDCT) is recommended over classical skeletal surveys (CSS) for investigating bone disease in multiple myeloma (MM) based on retrospective studies. No prospective studies with serial follow-up scans exist. OBJECTIVE: To compare WBLDCT to CSS for identifying progressive bone disease in MM in a prospective setting. METHODS: Ninety-six patients with MM at Odense University Hospital and Stavanger Hospital were followed for up to four years. Patients were scanned with WBLDCT and CSS every year for the first two years and every six months thereafter or at suspicion of progression. RESULTS: Nineteen cases of progressive bone disease were found using WBLDCT vs eight cases using CSS (p < 0.001). All cases of progressive bone disease using CSS were also identified by WBLDCT. Progression not found by CSS was primarily in the spine, sternum, and pelvis. Of the 19 cases, five patients had progressive bone disease only without other criteria for clinical progression. WBLDCT consistently identified more bone lesions per patient, 8.2 CI(6.8;9.6) vs CSS, 3.6 CI(2.7;4.5). CONCLUSION: WBLDCT outperformed CSS for finding progressive bone disease and osteolytic lesions. More new lesions were found during follow-up by WBLDCT than CSS. Using CSS for lytic lesions will underestimate progression rates. Our data offer prospective evidence for the current recommendation using WBLDCT for skeletal evaluations in patients with multiple myeloma.

Prevalence of and Theoretical Explanation for Type 2 Benign Paroxysmal Positional Vertigo.

BACKGROUND AND PURPOSE: A variant of benign paroxysmal positional vertigo (BPPV) involves the subjective report of vertigo without the coinciding nystagmus. This presentation includes truncal retropulsion when sitting up from the ipsilesional provocative test (ie, Dix-Hallpike), which we term type 2 BPPV. The primary objective of this study is to prospectively determine the prevalence and describe the clinical course of type 2 BPPV. We offer a theoretical explanation for the absence of nystagmus. METHODS: Prospective, observational study carried out in 2 tertiary hospitals. One hundred eighty patients (134 women, 46 men) met the inclusion criteria and were included between January 10, 2018, and October 30, 2019. Efficacy of physical therapy maneuvers was determined at 1-week follow-up. Three-dimensional reconstructions of the planes of the semicircular canal cupula from histological preparations are offered as evidence for the theoretical explanation. RESULTS: One-third of the patients met the criteria for type 2 BPPV; the remainder had typical posterior or horizontal semicircular canal involvement. Symptoms from type 2 BPPV were longer in duration yet responded favorably to physical therapy maneuvers. Upon repeat testing, 19 patients treated for posterior canalithiasis developed a slight, persistent positional downbeat nystagmus in the Dix-Hallpike position that we propose as evidence the otoconia entered the short arm of the posterior semicircular canal. DISCUSSION AND CONCLUSIONS: Our data and 3-dimensional rendering suggest the report of vertigo, yet absent nystagmus in type 2 BPPV is from otoconia aligning with the gravitoinertial vector during provocative testing that precludes cupular stimulation. Type 2 BPPV appears to be a common and treatable form of vertigo.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1 available at: http://links.lww.com/JNPT/A372).

Head movement kinematics are altered during balance stability exercises in individuals with vestibular schwannoma.

BACKGROUND: Balance stabilization exercises are often prescribed to facilitate compensation in individuals with vestibular schwannoma (VS). However, both the assessment and prescription of these exercises are reliant on clinical observations and expert opinion rather than on quantitative evidence. The aim of this study was to quantify head motion kinematics in individuals with vestibular loss while they performed commonly prescribed balance stability exercises. METHODS: Using inertial measurement units, head movements of individuals with vestibular schwannoma were measured before and after surgical deafferentation and compared with age-matched controls. RESULTS: We found that individuals with vestibular schwannoma experienced more variable head motion compared to healthy controls both pre- and postoperatively, particularly in absence of visual input, but that there was little difference between preoperative and postoperative kinematic measurements for our vestibular schwannoma group. We further found correlations between head motion kinematic measures during balance exercises, performed in the absence of visual input, and multiple clinical measurements for preoperative VS subjects. Subjects with higher head motion variability also had worse DVA scores, moved more slowly during the Timed up and Go and gait speed tests, and had lower scores on the functional gait assessment. In contrast, we did not find strong correlations between clinical measures and postoperative head kinematics for the same VS subjects. CONCLUSIONS: Our data suggest that further development of such metrics based on the quantification of head motion has merit for the assessment and prescription of balance exercises, as demonstrated by the calculation of a "kinematic score" for identifying the most informative balance exercise (i.e., "Standing on foam eyes closed").

Radon (222Rn) as tracer for submarine groundwater discharge investigation-limitations of the approach at shallow wind-exposed coastal settings.

Mapping radon (222Rn) distribution patterns in the coastal sea is a widely applied method for localizing and quantifying submarine groundwater discharge (SGD). While the literature reports a wide range of successful case studies, methodical problems that might occur in shallow wind-exposed coastal settings are generally neglected. This paper evaluates causes and effects that resulted in a failure of the radon approach at a distinct shallow wind-exposed location in the Baltic Sea. Based on a simple radon mass balance model, we discuss the effect of both wind speed and wind direction as causal for this failure. We show that at coastal settings, which are dominated by gentle submarine slopes and shallow waters, both parameters have severe impact on coastal radon distribution patterns, thus impeding their use for SGD investigation. In such cases, the radon approach needs necessarily to allow for the impact of wind speed and wind direction not only during but also prior to the field campaign.

Amphioxus neuroglia: Molecular characterization and evidence for early compartmentalization of the developing nerve cord.

Glial cells play important roles in the development and homeostasis of metazoan nervous systems. However, while their involvement in the development and function in the central nervous system (CNS) of vertebrates is increasingly well understood, much less is known about invertebrate glia and the evolutionary history of glial cells more generally. An investigation into amphioxus glia is therefore timely, as this organism is the best living proxy for the last common ancestor of all chordates, and hence provides a window into the role of glial cell development and function at the transition of invertebrates and vertebrates. We report here our findings on amphioxus glia as characterized by molecular probes correlated with anatomical data at the transmission electron microscopy (TEM) level. The results show that amphioxus glial lineages express genes typical of vertebrate astroglia and radial glia, and that they segregate early in development, forming what appears to be a spatially separate cell proliferation zone positioned laterally, between the dorsal and ventral zones of neural cell proliferation. Our study provides strong evidence for the presence of vertebrate-type glial cells in amphioxus, while highlighting the role played by segregated progenitor cell pools in CNS development. There are implications also for our understanding of glial cells in a broader evolutionary context, and insights into patterns of precursor cell deployment in the chordate nerve cord.

An Algorithm for the Diagnosis of Vestibular, Cerebellar, and Oculomotor Disorders Using a Systematized Clinical Bedside Examination.

The bedside examination associated with their clinical history remains the most critical means to accurately diagnose the cause for most of the signs and symptoms related to pathology of the cerebellum and vestibular system in patients presenting with dizziness and imbalance. This paper focuses on those critical bedside examinations, suggests when laboratory testing might be useful to confirm the clinical suspicion, and considers the shared neural circuitry within the visual and vestibular systems to offer an algorithmic approach in conducting the clinical bedside examination.

Vergence increases the amplitude of lateral ocular vestibular evoked myogenic potentials.

The angular and linear vestibulo-ocular reflex responses are greater when viewing near targets to compensate for the relatively larger translation of the eyes with respect to the target. Our aim was to measure vestibular evoked myogenic potentials using a lateral ocular electrode montage (oVEMP) with a laterally applied stimulus using a mini-shaker during both far- and near-viewing (vergence) distances to determine whether vergence affects the oVEMP response as it does the semicircular canal vestibulo-ocular reflex response. Our results show that during vergence, the p1 and n1-p1 amplitude of the lateral oVEMP response increases significantly, whereas the latencies do not change significantly. We suggest that the physiological basis for this vergence-mediated amplitude increase in potentials may be the same as those already documented using transient linear head accelerations. Our data also suggest that irregular vestibular afferents are likely mediating the vergence-mediated gain increase during linear head accelerations because only irregular afferents are stimulated during short, transient 500 Hz stimuli.

Convergence Vestibulo-ocular Reflex in Unilateral Vestibular Hypofunction: Behavioral Evidence in Support of a Novel Gaze Stability Exercise.

BACKGROUND AND PURPOSE: Convergence of the eyes during head rotation increases the gain (eye velocity/head velocity) of the vestibulo-ocular reflex (VOR). We sought to know whether convergence would increase the VOR gain (mean + SD) in unilateral vestibular hypofunction (UVH). METHODS: Vestibulo-ocular reflex gain during ipsi- and contralesional horizontal head rotation at near (15 cm) and far (150 cm) targets was measured in 22 subjects with UVH and 12 healthy controls. Retinal slip was estimated (retinal slip index [RSI]) as the difference between ideal VOR gain (no retinal slip) and the actual VOR gain. RESULTS: Convergence did not significantly enhance VOR gain for ipsilesional rotation (mean difference, 0.04; 95% confidence interval [CI], -0.01 to 0.09), near viewing (0.77 ± 0.34) versus far viewing (0.72 ± 0.29), yet the VOR gain during contralesional rotation was greater for near viewing (1.20 ± 0.23) than for far viewing (0.97 ± 0.21; mean difference, 0.23; 95% CI, 0.13-0.32). In the 36% of subjects with recovery of their ipsilesional VOR gain, the vergence effect trended to recover (far VOR gain: 1.06 ± 0.17 vs near VOR gain 1.16 ± 0.21; mean difference, 0.10; 95% CI, -0.02 to 0.22). Ipsilesional head rotation induced greater retinal slip for near (RSI = 0.90 ± 0.34) targets than for far targets (RSI = 0.35 ± 0.29; mean difference, 0.56; 95% CI, 0.51-0.61). DISCUSSION AND CONCLUSIONS: The convergence-mediated VOR gain enhancement is preserved during contralesional but impaired during ipsilesional head rotation. Recovery of ipsilesional passive VOR gain does not equate to restored convergence enhancement, although it did increase ∼10%. These data suggest head motion viewing near targets will increase retinal slip, which warrants consideration as a gaze stability exercise for subjects with UVH.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A325).