Vestibular damage affects the precision and accuracy of navigation in a virtual visual environment.

Vestibular information is available to the brain during navigation, as are the other self-generated (idiothetic) and external (allothetic) sensorimotor cues that contribute to central estimates of position and motion. Rodent studies provide strong evidence that vestibular information contributes to navigation but human studies have been less conclusive. Furthermore, sex-based differences have been described in human navigation studies performed with the head stationary, a situation where dynamic vestibular (and other idiothetic) information is absent, but sex differences in the utilization of vestibular information have not been described. Here, we studied men and women with severe bilateral vestibular damage as they navigated through a visually barren virtual reality environment and compared their performance to normal men and women. Two navigation protocols were employed, which either activated dynamic idiothetic cues ('dynamic task', navigate by turning, walking in place) or eliminated them ('static task', navigate with key presses, head stationary). For both protocols, we employed a standard 'triangle completion task' in which subjects moved to two visual targets in series and then were required to return to their perceived starting position without localizing visual information. The angular and linear 'accuracy' (derived from response error) and 'precision' (derived from response variability) were calculated. Comparing performance 'within tasks', navigation on the dynamic paradigm was worse in male vestibular-deficient patients than in normal men but vestibular-deficient and normal women were equivalent; on the static paradigm, vestibular-deficient men (but not women) performed better than normal subjects. Comparing performance 'between tasks', normal men performed better on the dynamic than the static paradigm while vestibular-deficient men and both normal and vestibular-deficient women were equivalent on both tasks. Statistical analysis demonstrated that for the angular precision metric, sex had a significant effect on the interaction between vestibular status and the test paradigm. These results provide evidence that humans use vestibular information when they navigate in a virtual visual environment and that men and women may utilize vestibular (and visual) information differently. On our navigation paradigm, men used vestibular information to improve navigation performance, and in the presence of severe vestibular damage, they utilized visual information more effectively. In contrast, we did not find evidence that women used vestibular information while navigating on our virtual task, nor did we find evidence that they improved their utilization of visual information in the presence of severe vestibular damage.

Vestibular dysfunction in neurofibromatosis type 2-related schwannomatosis.

Neurofibromatosis type 2-related schwannomatosis is a genetic disorder characterized by neurologic tumours, most typically vestibular schwannomas that originate on the vestibulo-cochlear nerve(s). Although vestibular symptoms can be disabling, vestibular function has never been carefully analysed in neurofibromatosis type 2-related schwannomatosis. Furthermore, chemotherapy (e.g. bevacizumab) can reduce tumour volume and improve hearing in neurofibromatosis type 2-related schwannomatosis, but nothing is known about its vestibular effects. In this report, we studied the three primary vestibular-mediated behaviours (eye movements, motion perception and balance), clinical vestibular disability (dizziness and ataxia), and imaging and hearing in eight untreated patients with neurofibromatosis type 2-related schwannomatosis and compared their results with normal subjects and patients with sporadic, unilateral vestibular schwannoma tumours. We also examined how bevacizumab affected two patients with neurofibromatosis type 2-related schwannomatosis. Vestibular schwannomas in neurofibromatosis type 2-related schwannomatosis degraded vestibular precision (inverse of variability, reflecting a reduced central signal-to-noise ratio) but not vestibular accuracy (amplitude relative to ideal amplitude, reflecting the central signal magnitude) and caused clinical disability. Bevacizumab improved vestibular precision and clinical disability in both patients with neurofibromatosis type 2-related schwannomatosis but did not affect vestibular accuracy. These results demonstrate that vestibular schwannoma tumours in our neurofibromatosis type 2-related schwannomatosis population degrade the central vestibular signal-to-noise ratio, while bevacizumab improves the signal-to-noise ratio, changes that can be explained mechanistically by the addition (schwannoma) and suppression (bevacizumab) of afferent neural noise.

Your Vestibular Thresholds May Be Lower Than You Think: Cognitive Biases in Vestibular Psychophysics.

PURPOSE: Recently, there has been a surge of interest in measuring vestibular perceptual thresholds, which quantify the smallest motion that a subject can reliably perceive, to study physiology and pathophysiology. These thresholds are sensitive to age, pathology, and postural performance. Threshold tasks require decisions to be made in the presence of uncertainty. Since humans often rely on past information when making decisions in the presence of uncertainty, we hypothesized that (a) perceptual responses are affected by their preceding trial; (b) perceptual responses tend to be biased opposite of the "preceding response" because of cognitive biases but are not biased by the "preceding stimulus"; and (c) when fits do not account for this cognitive bias, thresholds are overestimated. To our knowledge, these hypotheses are unaddressed in vestibular and direction-recognition tasks. CONCLUSIONS: Results in normal subjects supported each hypothesis. Subjects tended to respond opposite of their preceding response (not the preceding stimulus), indicating a cognitive bias, and this caused an overestimation of thresholds. Using an enhanced model (MATLAB code provided) that considered these effects, average thresholds were lower (5.5% for yaw, 7.1% for interaural). Since the results indicate that the magnitude of cognitive bias varies across subjects, this enhanced model can reduce measurement variability and potentially improve the efficiency of data collection.

Visuospatial Cognitive Dysfunction in Patients with Vestibular Loss.

OBJECTIVE: To characterize visuospatial and nonvisuospatial cognitive domains affected by vestibular loss and determine whether patient-reported outcomes measures (PROMs) correlate with performance on neuropsychological tests. STUDY DESIGN: Cross-sectional study. SETTING: University-based tertiary medical center. PATIENTS: Sixty-nine age-matched subjects: 25 patients with bilateral vestibular loss (BVL), 14 patients with unilateral vestibular loss (UVL), and 30 normal controls (NC). INTERVENTIONS: Neuropsychological tests used to assess visuospatial and auditory short-term and working memory, number magnitude representation, executive function, and attention. Validated PROMs used to evaluate quality of life and subjective cognitive impairment. MAIN OUTCOME MEASURES: Performance on neuropsychological tests and scores on PROM surveys. RESULTS: BVL and UVL patients performed significantly worse than NC subjects on tasks requiring visuospatial representation compared with NC subjects ( p < 0.01). BVL patients demonstrated decreased performance on spatial representation tasks compared with UVL and NC subjects ( p < 0.05 and p < 0.05, respectively). All subject groups performed similarly on tasks assessing nonvisuospatial cognitive domains, such as auditory short-term and working memory, executive function, and attention. PROMs did not seem to correlate with performance on neuropsychological tasks. CONCLUSION: Patients with vestibular loss exhibit impairments in tasks requiring visuospatial representation but perform similarly to NC subjects in tasks of auditory working memory, executive function, or attention. Currently available questionnaires may be insufficient to screen patients for cognitive deficits.

Imbalance and dizziness caused by unilateral vestibular schwannomas correlate with vestibulo-ocular reflex precision and bias.

Imbalance and dizziness are disabling symptoms for many patients with vestibular schwannomas (VS) but symptom severity typically does not correlate with the vestibulo-ocular reflex (VOR) amplitude-based metrics used to assess peripheral vestibular damage. In this study, we tested the hypothesis that imbalance and dizziness in patients with VS relate to VOR metrics that are not based on response amplitude. Twenty-four patients with unilateral, sporadic VS tumors were studied, and objective (balance) and subjective (dizziness) vestibular dysfunction was quantified. The VOR was tested using two yaw-axis motion stimuli, low-frequency en-bloc sinusoidal, and high-frequency head-on-body impulsive rotations. Imbalance correlated with VOR precision (the inverse of the trial-to-trial variability) and with low-frequency VOR dynamics (quantified with the time constant), and these two metrics were also strongly correlated. Dizziness correlated with the VOR bias caused by an imbalance in static central vestibular tone, but not with dynamic VOR metrics. VOR accuracy (mean response amplitude relative to the ideal response) was not correlated with the severity of imbalance or dizziness or with measures of VOR precision or time constant. Imbalance in patients with VS, therefore, scales with VOR precision and time constant, both of which appear to reflect the central vestibular signal-to-noise ratio, but not with VOR slow-phase accuracy, which is based on the magnitude of the central vestibular signals. Dizziness was related to the presence of a static central tone imbalance but not to any VOR metrics, suggesting that abnormal perception in VS may be affected by factors that are not captured by yaw-axis VOR measurements.NEW & NOTEWORTHY The severity of symptoms associated with unilateral vestibular schwannomas (VS) is poorly correlated with standard yaw-axis vestibulo-ocular reflex (VOR) metrics that are based on response amplitude. In this study, we show that the balance and perceptual dysfunction experienced by patients with VS scales with VOR metrics that capture information about the central signal-to-noise ratio (balance) and central static tone (dizziness), but are not correlated with the VOR gain, which reflects central signal amplitude.

Subacute combined degeneration of the cord secondary to nitrous oxide misuse: No laughing matter.

Nitrous oxide (N2O) has several traditional uses as a surgical and dental anaesthetic, as well as in aerosol spray propellants. It is the combination of analgesic and euphoric qualities coupled with accessibility as an over-the-counter household item that lends N2O to recreational use. Despite increasing evidence that prolonged use of N2O both medically and as a drug of abuse can cause disabling neurological side-effects, it remains widely used. We present the case of an 18-year-old male who was diagnosed with subacute combined degeneration of the cord (SCDC) secondary to acute, heavy recreational use of N2O. The patient presented with progressive paraesthesia affecting his hands and feet associated with distal weakness. MRI of the cervical spine revealed symmetric bilateral high T2 signal within the dorsal columns extending from the level of C2 to T2 with the inverted 'V' sign on axial T 2-weighted slices indicative of SCDC. Although vitamin B12 levels were within normal range, marked elevation of methylmalonic acid and homocysteine support the diagnosis of B12 inactivation and functional B12 deficiency, which fully resolved with treatment.

Improved Speech Intelligibility in Subjects With Stable Sensorineural Hearing Loss Following Intratympanic Dosing of FX-322 in a Phase 1b Study.

OBJECTIVES: There are no approved pharmacologic therapies for chronic sensorineural hearing loss (SNHL). The combination of CHIR99021+valproic acid (CV, FX-322) has been shown to regenerate mammalian cochlear hair cells ex vivo. The objectives were to characterize the cochlear pharmacokinetic profile of CV in guinea pigs, then measure FX-322 in human perilymph samples, and finally assess safety and audiometric effects of FX-322 in humans with chronic SNHL. STUDY DESIGNS: Middle ear residence, cochlear distribution, and elimination profiles of FX-322 were assessed in guinea pigs. Human perilymph sampling following intratympanic FX-322 dosing was performed in an open-label study in cochlear implant subjects. Unilateral intratympanic FX-322 was assessed in a Phase 1b prospective, randomized, double-blinded, placebo-controlled clinical trial. SETTING: Three private otolaryngology practices in the US. PATIENTS: Individuals diagnosed with mild to moderately severe chronic SNHL (≤70 dB standard pure-tone average) in one or both ears that was stable for ≥6 months, medical histories consistent with noise-induced or idiopathic sudden SNHL, and no significant vestibular symptoms. INTERVENTIONS: Intratympanic FX-322. MAIN OUTCOME MEASURES: Pharmacokinetics of FX-322 in perilymph and safety and audiometric effects. RESULTS: After intratympanic delivery in guinea pigs and humans, FX-322 levels in the cochlear extended high-frequency region were observed and projected to be pharmacologically active in humans. A single dose of FX-322 in SNHL subjects was well tolerated with mild, transient treatment-related adverse events (n = 15 FX-322 vs 8 placebo). Of the six patients treated with FX-322 who had baseline word recognition in quiet scores below 90%, four showed clinically meaningful improvements (absolute word recognition improved 18-42%, exceeding the 95% confidence interval determined by previously published criteria). No significant changes in placebo-injected ears were observed. At the group level, FX-322 subjects outperformed placebo group in word recognition in quiet when averaged across all time points, with a mean improvement from baseline of 18.9% (p = 0.029). For words in noise, the treated group showed a mean 1.3 dB signal-to-noise ratio improvement (p = 0.012) relative to their baseline scores while placebo-treated subjects did not (-0.21 dB, p = 0.71). CONCLUSIONS: Delivery of FX-322 to the extended high-frequency region of the cochlea is well tolerated and enhances speech recognition performance in multiple subjects with stable chronic hearing loss.

Effects of vestibular neurectomy and neural compensation on head movements in patients undergoing vestibular schwannoma resection.

The vestibular system is vital for maintaining balance and stabilizing gaze and vestibular damage causes impaired postural and gaze control. Here we examined the effects of vestibular loss and subsequent compensation on head motion kinematics during voluntary behavior. Head movements were measured in vestibular schwannoma patients before, and then 6 weeks and 6 months after surgical tumor removal, requiring sectioning of the involved vestibular nerve (vestibular neurectomy). Head movements were recorded in six dimensions using a small head-mounted sensor while patients performed the Functional Gait Assessment (FGA). Kinematic measures differed between patients (at all three time points) and normal subjects on several challenging FGA tasks, indicating that vestibular damage (caused by the tumor or neurectomy) alters head movements in a manner that is not normalized by central compensation. Kinematics measured at different time points relative to vestibular neurectomy differed substantially between pre-operative and 6-week post-operative states but changed little between 6-week and > 6-month post-operative states, demonstrating that compensation affecting head kinematics is relatively rapid. Our results indicate that quantifying head kinematics during self-generated gait tasks provides valuable information about vestibular damage and compensation, suggesting that early changes in patient head motion strategy may be maladaptive for long-term vestibular compensation.

Self-motion perception is sensitized in vestibular migraine: pathophysiologic and clinical implications.

Vestibular migraine (VM) is the most common cause of spontaneous vertigo but remains poorly understood. We investigated the hypothesis that central vestibular pathways are sensitized in VM by measuring self-motion perceptual thresholds in patients and control subjects and by characterizing the vestibulo-ocular reflex (VOR) and vestibular and headache symptom severity. VM patients were abnormally sensitive to roll tilt, which co-modulates semicircular canal and otolith organ activity, but not to motions that activate the canals or otolith organs in isolation, implying sensitization of canal-otolith integration. When tilt thresholds were considered together with vestibular symptom severity or VOR dynamics, VM patients segregated into two clusters. Thresholds in one cluster correlated positively with symptoms and with the VOR time constant; thresholds in the second cluster were uniformly low and independent of symptoms and the time constant. The VM threshold abnormality showed a frequency-dependence that paralleled the brain stem velocity storage mechanism. These results support a pathogenic model where vestibular symptoms emanate from the vestibular nuclei, which are sensitized by migraine-related brainstem regions and simultaneously suppressed by inhibitory feedback from the cerebellar nodulus and uvula, the site of canal-otolith integration. This conceptual framework elucidates VM pathophysiology and could potentially facilitate its diagnosis and treatment.

The influence of target distance on perceptual self-motion thresholds and the vestibulo-ocular reflex during interaural translation.

An elegant and influential mathematical model of eye movements is the geometric compensation required for visual fixation location in the translational vestibulo-ocular reflex (VOR). Compensatory eye velocity scales with the inverse of fixation distance during head translation because larger angular eye movements are required to minimize retinal slip during head translation when targets are closer. This model has been extensively verified in experiments. Since the VOR and vestibular perception have shared anatomic pathways, we asked whether the same scaling may affect motion perception. Since perception does not require the linear-to-angular transformation required for the translational VOR, we hypothesized that perception would not scale with target distance. Subjects were tested with a motion direction-recognition threshold task in which they reported their perception of small translations of their body. Thresholds were measured in three conditions: (1) with a near target (0.20m) that extinguished just before each motion; (2) with a far target (0.47m); 3) with no target. The subject was always in darkness during motion. Thresholds were 0.59, 0.61 and 0.61cm/s, respectively. Translational VOR sensitivity (eye angular velocity divided by head translation velocity) was also measured and modulated with target distance. The scaling ratio of responses for the near vs. far target was 0.97 for perceptual thresholds, which was significantly different from the compensatory ratio (2.35; P<0.001) and the translational VOR scaling ratio (1.59; P=0.007) but not from no compensation (1.00; P=0.93). Thus, we conclude that despite shared anatomy for the VOR and perception, the brain processes signals according to the geometric functional constraints of each task.

Lesson of the month 2: Contusion confusion.

This lesson of the month highlights that certain radiology terminology may be used to report bleeding on head computerised tomography (CT) reports. On-call junior doctors should not be expected to interpret CT head images, so often their decisions will be based on the written report. The wording used can change the clinical decision and therefore the treatment given by a junior doctor. Clinical teams and junior doctors should be educated on terminology in relation to bleeding on CT head reports.

Consideration for routine outpatient pediatric cochlear implantation: A retrospective chart review of immediate post-operative complications.

INTRODUCTION: Cochlear implantation is well accepted as the treatment of choice for prelingual deafness in children [1]. However, the safety of routinely performing this procedure on an outpatient basis is debated. We aim to assess immediate postoperative complications that would affect a surgeon's decision to perform pediatric cochlear implantation on an outpatient basis. METHODS: A retrospective chart review was conducted which included all children 17 years old or younger who underwent cochlear implantation from 2004 to 2014 in a private neurotology practice. The immediate postoperative complication rates and types of complications were then examined. RESULTS: A total of 579 cochlear implants were placed in children ages 1-17 years old from 2004 to 2014. The most common complications were nausea/vomiting and dizziness/imbalance. The odds ratio of developing complications in the group ages 1-3 years old versus all other age patients was found to be statistically insignificant (OR 0.90, 95% CI 0.61 to 1.32, p = 0.58). The odds ratio of developing a complication after bilateral implantation compared to unilateral implantation was statistically significant (OR 1.96, 95% CI 1.18 to 3.28, p = 0.01). There was no difference in complication rates when comparing lateral wall and perimodiolar insertions. A total of 6 of 579 (1%) cochlear implants resulted in a complication requiring unplanned medical attention. CONCLUSIONS: Overall, this series offers a decade of experience in pediatric cochlear implantation that shows a low incidence of the need for unplanned medical attention in the immediate postoperative period. The most common complication seen is Post-operative nausea and vomiting (PONV) that appears to be amenable to outpatient management even in the youngest populations. This supports providers routinely performing pediatric cochlear implantation on an outpatient basis.

Vaccine strategies: Optimising outcomes.

Successful immunisation programmes generally result from high vaccine effectiveness and adequate uptake of vaccines. In the development of new vaccination strategies, the structure and strength of the local healthcare system is a key consideration. In high income countries, existing infrastructures are usually used, while in less developed countries, the capacity for introducing new vaccines may need to be strengthened, particularly for vaccines administered beyond early childhood, such as the measles or human papillomavirus (HPV) vaccine. Reliable immunisation service funding is another important factor and low income countries often need external supplementary sources of finance. Many regions also obtain support in generating an evidence base for vaccination via initiatives created by organisations including World Health Organization (WHO), the Pan American Health Organization (PAHO), the Agence de Médecine Préventive and the Sabin Vaccine Institute. Strong monitoring and surveillance mechanisms are also required. An example is the efficient and low-cost approaches for measuring the impact of the hepatitis B control initiative and evaluating achievement of goals that have been established in the WHO Western Pacific region. A review of implementation strategies reveals differing degrees of success. For example, in the Americas, PAHO advanced a measles-mumps-rubella vaccine strategy, targeting different population groups in mass, catch-up and follow-up vaccination campaigns. This has had much success but coverage data from some parts of the region suggest that children are still not receiving all appropriate vaccines, highlighting problems with local service infrastructures. Stark differences in coverage levels are also observed among high income countries, as is the case with HPV vaccine implementation in the USA versus the UK and Australia, reflecting differences in delivery settings. Experience and research have shown which vaccine strategies work well and the factors that encourage success, which often include strong support from government and healthcare organisations, as well as tailored, culturally-appropriate local approaches to optimise outcomes.

Matrix metalloproteinases: new directions toward inhibition in the fight against cancers.

Matrix metalloproteinases are zinc-dependent enzymes whose main function is to cleave the components of the extracellular matrix. Their overexpression is evident in all cancers but to date there is no satisfactory way to inhibit their actions. Here, we look at their types, their structures, their functions and the developing understanding we have of them in the search for ways to drug them and inhibit their actions selectively. We investigate their subtle but exploitable differences in order that we can develop drugs to target them and even to target specific substrates and functions that they carry out. To date there are no new matrix metalloproteinase inhibitors developed to treat cancer, but we are progressing in our understanding of them, which is leading us ever closer to our goal.

Opioid Tapering in Fibromyalgia Patients: Experience from an Interdisciplinary Pain Rehabilitation Program.

OBJECTIVE: Despite current guideline recommendations against the use of opioids for the treatment of fibromyalgia pain, opioid use is reported in approximately 30% of the patient population. There is a lack of information describing the process and results of tapering of chronic opioids. The purpose of this study is to describe opioid tapering and withdrawal symptoms in fibromyalgia patients on opioids. DESIGN, SETTING, AND SUBJECTS: This retrospective research study included a baseline analysis of 159 patients consecutively admitted to the Mayo Clinic Pain Rehabilitation Center from 2006 through 2012 with a pain diagnosis of fibromyalgia completing a 3-week outpatient interdisciplinary pain rehabilitation program. Opioid tapering analysis included 55 (35%) patients using daily opioids. METHODS: Opioid tapering was individualized to each patient based on interdisciplinary pain rehabilitation team determination. Opioid withdrawal symptoms were assessed daily, utilizing the Clinical Opioid Withdrawal Scale. RESULTS: Patients taking daily opioids had a morphine equivalent mean dose of 99 mg/day. Patients on < 100 mg/day were tapered off over a mean of 10 days compared with patients on > 200 mg/day over a mean of 28 days (P < 0.001). Differences in peak withdrawal symptoms were not statistically significant based on the mean equivalent dose (P = 22). Patients taking opioids for <2 years did not differ in length of tapering (P =0.63) or peak COWS score (P =0.80) compared with >2 years duration. Patients had significant improvements in pain-related measures including numeric pain scores, depression catastrophizing, health perception, interference with life, and perceived life control at program completion. CONCLUSION: Fibromyalgia patients on higher doses of opioids were tapered off over a longer period of time but no differences in withdrawal symptoms were seen based on opioid dose. Duration of opioid use did not affect the time to complete opioid taper or withdrawal symptoms. Despite opioid tapering, pain-related measures improved at the completion of the rehabilitation program.

Assessment of family history of substance abuse for preventive interventions with patients experiencing chronic pain: A quality improvement project.

This quality improvement project demonstrates that RN Care Managers, in a chronic pain programme, can assess for a family history of substance abuse in 5-10 min. Information informs treatment based on specific high risk criteria. Benefits include heightened awareness of the genetic and environmental risks associated with a family history of substance abuse, an opportunity to participate in motivational interventions to prevent or minimize consequences of substance use disorders, and likely substantial overall health-care cost savings.

Characterisation of microcontaminants in Darwin Harbour, a tropical estuary of northern Australia undergoing rapid development.

The detection of microcontaminants in aquatic environments raises concerns about their potential to exert ecotoxicological effects and impact human health. In contrast to freshwater habitats, little information is available on environmental concentrations in urban estuarine and marine environments. This study investigated an extensive range of organic and inorganic microcontaminants in the Darwin Harbour catchment, a tropical estuary in northern Australia undergoing rapid urbanisation and industrial development. We sampled wastewater effluent and surface water from seven sites in Darwin Harbour for pharmaceuticals and personal care products, alkylphenols, hormones, pesticides, herbicides and metals. In vitro bioassays were used to estimate the (anti)estrogenic and (anti)androgenic activities of samples. Seventy-nine of 229 organic microcontaminants analysed were detected at concentrations ranging from 0.01 to 20 µg/L, with acesulfame, paracetamol, cholesterol, caffeine, DEET and iopromide detected at the highest concentrations in wastewater effluent (20 µg/L, 17 µg/L, 11 µg/L, 11 µg/L, 10 µg/L and 7.6 µg/L, respectively). Levels of estrogenic activity ranged from estradiol equivalency quotients (EEQs) of <0.10 to 6.29±0.16 ng/L while levels of androgenic activity ranged from dihydrotestosterone equivalency quotients (DHTEQs) of <3.50 to 138.23±3.71 ng/L. Environmental concentrations of organic microcontaminants were comparable to ranges reported from aquatic environments worldwide with sewage effluent discharges representing the dominant source of entry into Darwin Harbour. The measured concentration range of DEET was higher than ranges reported in previous studies.