Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS.

Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole-genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG)exp] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG)11 short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1-negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type, and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.

Comparison of Incremental Vestibulo-ocular Reflex Adaptation Training Versus x1 Training in Patients With Chronic Peripheral Vestibular Hypofunction: A Two-Year Randomized Controlled Trial.

BACKGROUND AND PURPOSE: A crossover, double-blinded randomized controlled trial to investigate once-daily incremental vestibulo-ocular reflex (VOR) adaptation (IVA) training over 2 years in people with stable and chronic peripheral vestibular hypofunction. METHODS: Twenty-one patients with peripheral vestibular hypofunction were randomly assigned to intervention-then-control (n = 12) or control-then-intervention (n = 9) groups. The task consisted of either x1 (control) or IVA training, once daily every day for 15 minutes over 6-months, followed by a 6-month washout, then repeated for arm 2 of the crossover. Primary outcome: vestibulo-ocular reflex gain. Secondary outcomes: compensatory saccades, dynamic visual acuity, static balance, gait, and subjective symptoms. Multiple imputation was used for missing data. Between-group differences were analyzed using a linear mixed model with repeated measures. RESULTS: On average patients trained once daily 4 days per week. IVA training resulted in significantly larger VOR gain increase (active: 20.6% ± 12.08%, P = 0.006; passive: 30.6% ± 25.45%, P = 0.016) compared with x1 training (active: -2.4% ± 12.88%, P = 0.99; passive: -0.6% ± 15.31%, P = 0.68) (P < 0.001). The increased IVA gain did not significantly reduce with approximately 27% persisting over the washout period. x1 training resulted in greater reduction of compensatory saccade latency (P = 0.04) and increase in amplitude (P = 0.02) compared with IVA training. There was no difference between groups in gait and balance measures; however, only the IVA group had improved total Dizziness Handicap Inventory (P = 0.006). DISCUSSION AND CONCLUSIONS: Our results suggest IVA improves VOR gain and reduces perception of disability more than conventional x1 training. We suggest at least 4 weeks of once-daily 4 days-per-week IVA training should be part of a comprehensive vestibular rehabilitation program.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A356).

Once-Daily Incremental Vestibular-Ocular Reflex Adaptation Training in Patients With Chronic Peripheral Vestibular Hypofunction: A 1-Week Randomized Controlled Study.

BACKGROUND AND PURPOSE: This was a double-blinded randomized controlled study to investigate the effects of once-daily incremental vestibulo-ocular reflex (VOR) training over 1 week in people with chronic peripheral vestibular hypofunction. METHODS: A total of 24 patients with peripheral vestibular hypofunction were randomly assigned to intervention (n = 13) or control (n = 11) groups. Training consisted of either x1 (control) or incremental VOR adaptation exercises, delivered once daily for 15 minutes over 4 days in 1 week. Primary outcome: VOR gain with video-oculography. Secondary outcomes: Compensatory saccades measured using scleral search coils, dynamic visual acuity, static balance, gait, and subjective symptoms. Between-group differences were analyzed with a linear mixed-model with repeated measures. RESULTS: There was a difference in the VOR gain increase between groups (P < 0.05). The incremental training group gain increased during active (13.4% ± 16.3%) and passive (12.1% ± 19.9%) head impulse testing (P < 0.02), whereas it did not for the control group (P = 0.59). The control group had reduced compensatory saccade latency (P < 0.02). Both groups had similarly improved dynamic visual acuity scores (P < 0.05). Both groups had improved dynamic gait index scores (P < 0.002); however, only the incremental group had improved scores for the 2 walks involving head oscillations at approximately 2 Hz (horizontal: P < 0.05; vertical: P < 0.02), increased gait speed (P < 0.02), and step length (P < 0.01) during normal gait, and improved total Dizziness Handicap Inventory (P < 0.05). CONCLUSIONS: Our results suggest incremental VOR adaptation significantly improves gain, gait with head rotation, balance during gait, and symptoms in patients with chronic peripheral vestibular hypofunction more so than conventional x1 gaze-stabilizing exercises.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A336).

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

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

Cognitive behavior therapy for chronic subjective dizziness: a randomized, controlled trial.

PURPOSE: The aim of this study was to evaluate the effects of a brief cognitive behavior therapy (CBT) intervention on the physical symptoms, illness-related disability, and psychologic distress of patients with chronic subjective dizziness. MATERIALS AND METHODS: Forty-one patients with chronic subjective dizziness referred by a neurootologic clinic were randomly assigned to immediate treatment or a wait-list control. Three weekly treatment sessions based on the CBT model of panic disorder, adapted for patients with dizziness, were administered by a clinical psychologist. Treatment included psychoeducation, behavioral experiments, exposure to feared stimuli, and attentional refocusing. Outcomes were measured on the Dizziness Handicap Inventory and the Depression, Anxiety and Stress Scales. Two further measures developed for this study; the Dizziness Symptoms Inventory and the Safety Behaviours Inventory were used to measure physical symptoms and safety behaviors. RESULTS: The intervention was associated with significant reductions in disability on the Dizziness Handicap Inventory, reduced dizziness and related physical symptoms on the Dizziness Symptoms Inventory, and reduced avoidance and safety behaviors as measured by the Safety Behaviours Inventory. Pre- to posteffect sizes ranged from 0.98 to 1.15. There was no change in psychologic outcomes measured on the Depression, Anxiety and Stress Scales. CONCLUSIONS: A 3-session psychologic intervention based on the CBT model can produce significant improvements in dizziness-related symptoms, disability, and functional impairment among patients with chronic subjective dizziness. This suggests that treatment of this condition may be reasonably simple and cost-effective for most of the patients.

A Prospective Study on the Vestibular Toxicity of Gentamicin in a Clinical Setting.

OBJECTIVE: Gentamicin is a widely used aminoglycoside with ototoxicity as a known adverse effect. Because of the difficulty in clinical recognition, the prevalence of gentamicin ototoxicity in practice is thought to be higher than reported. This study aimed to prospectively assess the effect of gentamicin on vestibular function and whether ototoxicity is underrecognized. STUDY DESIGN: Single-center, prospective, nonblinded trial. SETTING: Inpatient tertiary hospital setting followed by vestibular outpatient clinic review. PATIENTS: Forty-eight patients undergoing a urologic procedure were recruited, with 24 and 17 patients having one or two follow-up tests, respectively, after initial gentamicin administration. INTERVENTIONS: Single dose of gentamicin during a urologic procedure. MAIN OUTCOME MEASURES: Gains for the vestibuloocular reflex (VOR) were measured using the video head impulse test before receiving gentamicin and at two other timepoints after gentamicin. The gains in VOR were then compared with previous testing sessions to determine if there was a deterioration after gentamicin use. RESULTS: Before receiving gentamicin, the gains for horizontal VOR were measured for 48 patients. The gains were measured a second time for 24 patients at varying durations postgentamicin (1-56 d) and a third time for 17 patients (14-152 d) postgentamicin. The mean VOR gain for Timepoints 1, 2, and 3 were 0.72 ± 0.13, 0.75 ± 0.16, and 0.79 ± 0.18, respectively. Linear-mixed model with repeated-measure analysis revealed no significant difference in VOR gain between Timepoints 1 and 2 ( p = 0.19). CONCLUSION: There was no significant effect observed on mean VOR gain decrement after a single dose of gentamicin.

Murine typhus returns to New South Wales: a case of isolated meningoencephalitis with raised intracranial pressure.

Murine typhus (MT) occurs worldwide, but, in Australia, is only regularly diagnosed in south-west Western Australia. Meningoencephalitis is an uncommon complication of MT, often accompanied by rash or systemic involvement. We report a case of MT presenting exclusively with meningoencephalitis, raised intracranial pressure, papilloedema and bilateral 6th cranial nerve palsies. MT should be considered in patients with "aseptic" meningitis or meningoencephalitis, even in the absence of other typical features of a typhus-like illness.

Human Vestibulo-Ocular Reflex Adaptation Reduces when Training Demand Variability Increases.

One component of vestibular rehabilitation in patients with vestibulo-ocular reflex (VOR) hypofunction is gaze-stabilizing exercises that seek to increase (adapt) the VOR response. These prescribed home-based exercises are performed by the patient and thus their use/training is inherently variable. We sought to determine whether this variability affected VOR adaptation in ten healthy controls (× 2 training only) and ten patients with unilateral vestibular hypofunction (× 1 and × 2 training). During × 1 training, patients actively (self-generated, predictable) move their head sinusoidally while viewing a stationary fixation target; for × 2 training, they moved their outstretched hand anti-phase with their head rotation while attempting to view a handheld target. We defined the latter as manual × 2 training because the subject manually controls the target. In this study, head rotation frequency during training incrementally increased 0.5-2 Hz over 20 min. Active and passive (imposed, unpredictable) sinusoidal (1.3-Hz rotations) and head impulse VOR gains were measured before and after training. We show that for controls, manual × 2 training resulted in significant sinusoidal and impulse VOR adaptation of ~ 6 % and ~ 3 %, respectively, though this was ~two-thirds lower than increases after computer-controlled × 2 training (non-variable) reported in a prior study. In contrast, for patients, there was an increase in impulse but not sinusoidal VOR response after a single session of manual × 2 training. Patients had more than double the variability in VOR demand during manual × 2 training compared to controls, which could explain why adaptation was not significant in patients. Our data suggest that the clinical × 1 gaze-stabilizing exercise is a weak stimulus for VOR adaptation.

Ocular motor fixation deficits in Friedreich ataxia.

Friedreich ataxia (FRDA) is the most common genetic cause of ataxia with a prevalence of approximately 1 in 29,000. Ocular motor abnormalities are common in FRDA and include fixation instability, saccadic dysmetria, and vestibular dysfunction. It has not yet been determined whether aspects of spatial attention, which are closely coupled to eye movements, are similarly compromised in FRDA. This study examined attentional engagement and disengagement of eye movements in FRDA using a gap overlap task. Thirteen individuals with genetically confirmed FRDA and 12 age-matched unaffected controls participated in the experiment. The gap overlap paradigm was used to examine the effect of early (gap condition), simultaneous (null condition), or late (overlap condition) removal of a central fixation on saccadic latency to a peripheral target stimulus. Although the FRDA group showed a larger gap effect (i.e., difference in saccadic latencies between the overlap and gap condition), these participants demonstrated a greater difference in latencies in the overlap relative to the null condition, suggestive of deficits within the disengagement process of attentional orienting. We propose a role for the cerebellum in these deficits in the disengagement of spatial attention based on evidence of cerebellar connectivity with regions involved in exogenous shifts of attention. The significant correlations between saccadic latency and disease severity as measured by the Friedreich Ataxia Rating Scale further support the proposal that saccadic latency might be useful as a surrogate marker of disease severity and progression in future clinical trials in FRDA.

Vestibular, saccadic and fixation abnormalities in genetically confirmed Friedreich ataxia.

Friedreich ataxia (FRDA), the commonest of the inherited ataxias, is a multisystem neurodegenerative condition that affects ocular motor function. We assessed eye movement abnormalities in 20 individuals with genetically confirmed FRDA and compared these results to clinical measures. All subjects were assessed with infrared oculography. Fifteen individuals underwent a full protocol of eye movement recordings. Ten subjects were analysed using two-dimensional scleral coil equipment and five using three-dimensional scleral coil recording equipment. We also recorded visual quality of life, Sloan low contrast letter acuity and Friedreich Ataxia Rating Scale scores to compare to the visual measures. Whilst saccadic velocity was essentially normal, saccadic latency was prolonged. The latency correlated with clinical measures of disease severity, including the scores for the Friedreich Ataxia Rating Scale and the Sloan low contrast letter acuity tests. Fixation abnormalities consisting of square wave jerks and ocular flutter were common, and included rare examples of vertical square wave jerks. Vestibular abnormalities were also evident in the group, with markedly reduced vestibulo-ocular reflex gain and prolonged latency. The range of eye movement abnormalities suggest that neurological dysfunction in FRDA includes brainstem, cortical and vestibular pathways. Severe vestibulopathy with essentially normal saccadic velocity are hallmarks of FRDA and differentiate it from a number of the dominant spinocerebellar ataxias. The correlation of saccadic latency with FARS score raises the possibility of its use as a biomarker for FRDA clinical trials.

Improved Oculomotor Physiology and Behavior After Unilateral Incremental Adaptation Training in a Person With Chronic Vestibular Hypofunction: A Case Report.

BACKGROUND AND PURPOSE: Traditional vestibular rehabilitation therapies are effective in reducing vestibular hypofunction symptoms, but changes to the vestibulo-ocular reflex (VOR) are minimal. This controlled case report describes an increase in VOR after 6 months of incremental VOR adaptation (IVA) training in a person with chronic unilateral vestibular hypofunction. CASE DESCRIPTION: The participant was a 58-year-old female with a confirmed (Neurologist P.D.C.) left vestibular lesion stable for 2 years prior to entering a clinical trial examining the effects of daily IVA training. She was evaluated monthly for self-reported symptoms (dizziness handicap inventory), VOR function (video head impulse test), and VOR behavior (Dynamic Visual Acuity test). Intervention consisted of 6 months of 15 minutes per day unassisted training using the IVA training regime with a device developed in our laboratory. The take-home device enables the VOR response to gradually normalize on the ipsilesional side via visual-vestibular mismatch training. The intervention was followed by a 6-month wash-out and 3-month control period. The control condition used the same training device set to function like standard VOR training indistinguishable to the participant. OUTCOMES: After the intervention, ipsilesional VOR function improved substantially. The VOR adapted both via a 52% increase in slow-phase response and via 43% earlier onset compensatory saccades for passive head movements. In addition, the participant reported fewer symptoms and increased participation in sports and daily activities. DISCUSSION: Here, a participant with chronic vestibular hypofunction showing improved oculomotor performance atypical for traditional vestibular rehabilitation therapies, subsequent to using the newly developed IVA technique, is presented. It is the first time to our knowledge an improvement of this magnitude has been demonstrated as well as sustained over an extended period of time.

Delayed vestibular evoked responses to the eyes and neck in a patient with an isolated brainstem lesion.

OBJECTIVE: Two recently described tests of the vestibular system, vestibular evoked myogenic potentials (VEMPs) and ocular vestibular evoked myogenic potentials (OVEMPs), test the descending and ascending vestibular brainstem pathways, respectively. We describe a case of a patient in whom these investigations localised the lesion and suggested its nature. METHODS: VEMPs (to clicks and short duration galvanic stimulation) and OVEMPs (to clicks) were recorded. RESULTS: Click- and galvanic-evoked VEMPs were delayed on the left side (by approximately 5-6 ms), and click-evoked OVEMPs were similarly delayed (by approximately 4 ms) following left-sided stimulation. Repeat testing 21 months later showed partial resolution. CONCLUSIONS: The observed delays in evoked potentials suggested a demyelinating lesion. Furthermore, the similarity in delayed responses to neck and extraocular muscles was suggestive of a lesion at the root entry zone of the vestibulocochlear nerve. SIGNIFICANCE: VEMPs and OVEMPS may thus provide information about the location and nature of lesions affecting central vestibular pathways.

Vergence-mediated changes in Listing's plane do not occur in an eye with superior oblique palsy.

PURPOSE: As a normal subject looks from far to near, Listing's plane rotates temporally in each eye. Since Listing's plane relates to the control of torsional eye position, mostly by the oblique eye muscles, the current study was conducted to test the hypothesis that a patient with isolated superior oblique palsy would have a problem controlling Listing's plane. METHOD: Using the three-dimensional scleral search coil technique, binocular Listing's plane was measured in four patients with congenital and in four patients with acquired unilateral superior oblique palsy during far- (94 cm) and near- (15 cm) viewing. The results were compared to previously published Listing's plane data collected under exactly the same conditions from 10 normal subjects. RESULTS: In patients with unilateral superior oblique palsy, either congenital or acquired, Listing's plane in the normal eye rotated temporally on near-viewing, as in normal subjects, while in the paretic eye it failed to do so. In patients with acquired superior oblique palsy, Listing's plane was already rotated temporally during far-viewing and failed to rotate any farther on near-viewing, whereas in patients with congenital superior oblique palsy Listing's plane in the paretic eye was oriented normally during far-viewing and failed to rotate any farther on near-viewing. CONCLUSIONS: These results suggest that the superior oblique muscle, at least in part, is responsible for the temporal rotation of Listing's plane that occurs in normal subjects on convergence.

Changes in the three-dimensional angular vestibulo-ocular reflex following intratympanic gentamicin for Ménière's disease.

The 3-dimensional angular vestibulo-ocular reflexes (AVOR) elicited by rapid rotary head thrusts were studied in 17 subjects with unilateral Ménière's disease before and 2-10 weeks after treatment with intratympanic gentamicin and in 13 subjects after surgical unilateral vestibular destruction (SUVD). Each head thrust was in the horizontal plane or in either diagonal plane of the vertical semicircular canals, so that each head thrust effectively stimulated only one pair of canals. The AVOR gains (eye velocity/head velocity during the 30 ms before peak head velocity) for the head thrusts exciting each individual canal were averaged and taken as a measure of the function of that canal. Prior to intratympanic gentamicin, gains for head thrusts that excited canals on the affected side were 0.91 +/- 0.20 (horizontal canal, HC), 0.78 +/- 0.20 (anterior canal, AC), and 0.83 +/- 0.10 (posterior canal, PC). The asymmetries between these gain values and those for head thrusts that excited the contralateral canals were <2%. In contrast, caloric asymmetries averaged 40% +/- 32%. Intratympanic gentamicin resulted in decreased gains attributable to each canal on the treated side: 0.40 +/- 0.12 (HC), 0.35 +/- 0.14 (AC), 0.31 +/- 0.14 (PC) (p <0.01). However, the gains attributable to contralateral canals dropped only slightly, resulting in marked asymmetries between gains for excitation of ipsilateral canals versus their contralateral mates: HC: 34% +/- 12%, AC: 24% +/- 25%, and PC: 42% +/- 13%. There was no difference in the AVOR gain for excitation of the ipsilateral HC after gentamicin in patients who received a single intratympanic injection (0.39 +/- 0.11, n = 12) in comparison to those who received 2-3 injections (0.42 +/- 0.15, n = 5, p = 0.7). Gain decreases attributed to the gentamicin-treated HC and AC were not as severe as those observed after SUVD. This finding suggests that intratympanic gentamicin causes a partial vestibular lesion that may involve preservation of spontaneous discharge and/or rotational sensitivity of afferents.

Comparison of head thrust test with head autorotation test reveals that the vestibulo-ocular reflex is enhanced during voluntary head movements.

OBJECTIVES: To compare 2 clinical tests of vestibular function, the head autorotation test (HART) and the head thrust test (HTT), and to determine why they give disparate results in patients with known unilateral vestibular deficiency (UVD) due to labyrinthectomy. METHODS: We used scleral coils to measure the horizontal (yaw) vestibulo-ocular reflex (VOR) in 5 healthy human subjects and in 11 patients who underwent labyrinthectomy. We used 2 paradigms. Using HART, subjects visually fixated a target during self-generated, swept-frequency, sinusoidal, horizontal head rotations. Using HTT, patients fixated the target during horizontal head thrusts delivered randomly in direction and time. RESULTS: In subjects without UVD, eye movements were almost perfectly compensatory for both paradigms. In subjects with UVD, VOR gain for ipsilesional head thrusts was low for both paradigms, but significantly (P<.001) higher (less abnormal) for HART (0.60 +/- 0.13) than for HTT (0.14 +/- 0.13). Contralesional gain was reduced for both, to 0.64 +/- 0.20 for HART and to 0.57 +/- 0.17 for HTT. Because ipsilesional and contralesional gains were not statistically different for HART (P =.69), comparison of VOR gains for half-cycle responses to the HART stimulus could not reliably identify the side of the known lesion. In contrast, HTT consistently identified the side of the lesion for all subjects with UVD. To investigate whether preprogramming contributes to the boost in VOR as measured by HART, we compared the gain and response delay of eye movements during actively self-generated and passively received head thrusts. For subjects without UVD, response delays were shorter for active (6 +/- 1 milliseconds) than for passive (12 +/- 1 milliseconds) HTT. For ipsilesional rotations of subjects with UVD, active HTT yielded a significantly higher gain (0.44 +/- 0.20) (P<.001) and a shorter delay (15 +/- 6 milliseconds) (P<.001) than did passive HTT (0.14 +/- 0.13 and 37 +/- 15 milliseconds, respectively). Contralesional test results revealed a similar performance boost for active head movements. Data are given as mean +/- SD. CONCLUSION: When comparison of half-cycle gains is used to identify the lesion side, self-generated predictable head movement paradigms, such as HART and active HTT, are less accurate than passive HTT in the characterization of UVD, in part because preprogramming can augment the VOR during voluntary head movements.

Dehiscence of bone overlying the superior canal as a cause of apparent conductive hearing loss.

OBJECTIVE: To identify patients with superior semicircular canal dehiscence and apparent conductive hearing loss and to define the cause of the air-bone gap. STUDY DESIGN: Prospective study of patients with superior canal dehiscence. SETTING Tertiary referral center. PATIENTS: Vestibular and/or auditory findings indicative of canal dehiscence and demonstration of superior canal dehiscence on computed tomography of the temporal bone. INTERVENTION: Vestibular-evoked myogenic potentials, three-dimensional eye movement recordings, and surgical resurfacing of the superior canal. OUTCOME MEASURE: Association of superior canal dehiscence with an air-bone gap on audiometry. RESULTS: Four patients with dehiscence of bone overlying the superior canal were found to have air-bone gaps in the affected ears that were greatest at lower frequencies and averaged 24 +/- 7 dB over the frequency range of 250 to 4,000 Hz. Three of these patients had undergone stapedectomy before the identification of superior canal dehiscence. The air-bone gap was unchanged postoperatively. Each patient had an intact vestibular-evoked myogenic potential (VEMP) response from the affected ear, a finding that would not have been expected based on a middle ear cause of conductive hearing loss. One patient underwent resurfacing of the superior canal through a middle fossa approach. Postoperatively, his vestibular symptoms were relieved, and his air conduction thresholds were improved by 20 dB. CONCLUSIONS: Superior canal dehiscence can result in apparent conductive hearing loss. The third mobile window created by the dehiscent superior canal results in dissipation of acoustic energy and is a cause of inner ear conductive hearing loss.

The 2D modified head impulse test: a 2D technique for measuring function in all six semi-circular canals.

The head impulse test can be used to measure peripheral vestibular function of all six semicircular canals. Traditionally, vertical canal function is measured by rotating the head from a starting neutral position (forward facing) about a diagonal plane that bisects the sagittal and coronal planes. These types of head rotations elicit eye movements with large vertical and torsional (about the line of sight) angular velocity components. Three-dimensional (3D: horizontal, vertical and torsional) eye measurement techniques are needed to measure these velocity components. We wanted to determine whether 2D measurements coupled to a modified head impulse test are sufficient to measure function of all six canals. In this study we measured individual canal function in patients (n=5) with peripheral unilateral hypofunction and control subjects (n=4) using the traditional head impulse test and the 'gold standard' 3D (dual-coil) scleral search coil technique. We compared these results with those from our 2D modified head impulse test using the 2D coil technique (single-coil). We show that both techniques detect similar levels of asymmetrical function in patients and are equally accurate in isolating canals with hypofunction. We conclude that 2D eye measurement techniques, such as video pupil-tracking, can be used to test all six canals.

Cerebellar ataxia with bilateral vestibulopathy: description of a syndrome and its characteristic clinical sign.

We report four patients with the syndrome of cerebellar ataxia with bilateral vestibulopathy (CABV) and, using search coil oculography, we validate its characteristic clinical sign, namely impairment of the visually enhanced vestibulo-ocular reflex (VVOR) or doll's head reflex. In our four patients, CABV began in the sixth decade of life; they are still ambulant and self-caring 8-20 years after onset. The cause of CABV in our four patients is unknown. None has a family history of cerebellar or vestibular disease; spinocerebellar ataxia (SCA) 1, 2, 3, 6, 7 and Friedreich's ataxia were excluded by genetic testing. Three of the four have a sensory peripheral neuropathy but none has extrapyramidal or significant autonomic problems, and none has gluten sensitivity. We measured eye rotations in response to head-on-trunk head rotations and in response to head-and-trunk (en bloc) rotations. Horizontal smooth pursuit (SP), vestibulo-ocular reflex (VOR) and VVOR gains were measured in response to head rotations at 0.1, 0.3, 0.6 and 1.0 Hz. The optokinetic reflex (OKR) was tested by measuring optokinetic nystagmus slow phase velocity during constant 50 degrees /s rotation of the subject in light. The results showed that CABV patients had impairment of all three compensatory eye movement reflexes, the VOR, the OKR and SP. During VVOR testing, as the frequency of head rotation increased from 0.1 to 1.0 Hz, eye velocity failed to match head velocity, gaze velocity increased, and gaze position errors developed, which were corrected with bursts of saccades, the basis of the clinical sign of an impaired VVOR.

Vergence-mediated changes in the axis of eye rotation during the human vestibulo-ocular reflex can occur independent of eye position.

The aim of this study was to determine whether vergence-mediated changes in the axis of eye rotation in the human vestibulo-ocular reflex (VOR) would obey Listing's Law (normally associated with saccadic eye movements) independent of the initial eye position. We devised a paradigm for disassociating the saccadic velocity axis from eye position by presenting near and far targets that were centered with respect to one eye. We measured binocular 3-dimensional eye movements using search coils in ten normal subjects and 3-dimensional linear head acceleration using Optotrak in seven normal subjects. The stimuli consisted of passive, unpredictable, pitch head rotations with peak acceleration of approximately 2000 degrees /s(2 )and amplitude of approximately 20 degrees. During the pitch head rotation, each subject fixated straight ahead with one eye, whereas the other eye was adducted 4 degrees during far viewing (94 cm) and 25 degrees during near viewing (15 cm). Our data showed expected compensatory pitch rotations in both eyes, and a vergence-mediated horizontal rotation only in the adducting eye. In addition, during near viewing we observed torsional eye rotations not only in the adducting eye but also in the eye looking straight ahead. In the straight-ahead eye, the change in torsional eye velocity between near and far viewing, which began approximately 40 ms after the start of head rotation, was 10+/-6 degrees /s (mean +/- SD). This change in torsional eye velocity resulted in a 2.4+/-1.5 degrees axis tilt toward Listing's plane in that eye. In the adducting eye, the change in torsional eye velocity between near and far viewing was 16+/-6 degrees /s (mean +/- SD) and resulted in a 4.1+/-1.4 degrees axis tilt. The torsional eye velocities were conjugate and both eyes partially obeyed Listing's Law. The axis of eye rotation tilted in the direction of the line of sight by approximately one-third of the angle between the line of sight and a line orthogonal to Listing's plane. This tilt was higher than predicted by the one-quarter rule. The translational acceleration component of the pitch head rotation measured 0.5 g and may have contributed to the increased torsional component observed during near viewing. Our data show that vergence-mediated eye movements obey a VOR/Listing's Law compromise strategy independent of the initial eye position.