Alexander A. Tarnutzer

Does my dizzy patient have a stroke? A systematic review of bedside diagnosis in acute vestibular syndrome

Dizziness is the third most common major medical symptom reported in general medical clinics[1][1] and accounts for about 3%–5% of visits across care settings.[2][2] In the United States, this translates to 10 million ambulatory visits per year because of dizziness,[3][3] with roughly 25% of these

Gravity Dependence of Subjective Visual Vertical Variability

The brain integrates sensory input from the otolith organs, the semicircular canals, and the somatosensory and visual systems to determine self-orientation relative to gravity. Only the otoliths directly sense the gravito-inertial force vector and therefore provide the major input for perceiving static head-roll relative to gravity, as measured by the subjective visual vertical (SVV). Intraindividual SVV variability increases with head roll, which suggests that the effectiveness of the otolith signal is roll-angle dependent. We asked whether SVV variability reflects the spatial distribution of the otolithic sensors and the otolith-derived acceleration estimate. Subjects were placed in different roll orientations (0-360 degrees, 15 degrees steps) and asked to align an arrow with perceived vertical. Variability was minimal in upright, increased with head-roll peaking around 120-135 degrees, and decreased to intermediate values at 180 degrees. Otolith-dependent variability was modeled by taking into consideration the nonuniform distribution of the otolith afferents and their nonlinear firing rate. The otolith-derived estimate was combined with an internal bias shifting the estimated gravity-vector toward the body-longitudinal. Assuming an efficient otolith estimator at all roll angles, peak variability of the model matched our data; however, modeled variability in upside-down and upright positions was very similar, which is at odds with our findings. By decreasing the effectiveness of the otolith estimator with increasing roll, simulated variability matched our experimental findings better. We suggest that modulations of SVV precision in the roll plane are related to the properties of the otolith sensors and to central computational mechanisms that are not optimally tuned for roll-angles distant from upright.

Roll-dependent modulation of the subjective visual vertical: contributions of head- and trunk-based signals.

Precision and accuracy of the subjective visual vertical (SVV) modulate in the roll plane. At large roll angles, systematic SVV errors are biased toward the subjects body-longitudinal axis and SVV precision is decreased. To explain this, SVV models typically implement a bias signal, or a prior, in a head-fixed reference frame and assume the sensory input to be optimally tuned along the head-longitudinal axis. We tested the pattern of SVV adjustments both in terms of accuracy and precision in experiments in which the head and the trunk reference frames were not aligned. Twelve subjects were placed on a turntable with the head rolled about 28 degrees counterclockwise relative to the trunk by lateral tilt of the neck to dissociate the orientation of head- and trunk-fixed sensors relative to gravity. Subjects were brought to various positions (roll of head- or trunk-longitudinal axis relative to gravity: 0 degrees , +/-75 degrees ) and aligned an arrow with perceived vertical. Both accuracy and precision of the SVV were significantly (P < 0.05) better when the head-longitudinal axis was aligned with gravity. Comparing absolute SVV errors for clockwise and counterclockwise roll tilts, statistical analysis yielded no significant differences (P > 0.05) when referenced relative to head upright, but differed significantly (P < 0.001) when referenced relative to trunk upright. These findings indicate that the bias signal, which drives the SVV toward the subjects body-longitudinal axis, operates in a head-fixed reference frame. Further analysis of SVV precision supports the hypothesis that head-based graviceptive signals provide the predominant input for internal estimates of visual vertical.

Ataxia telangiectasia: a "disease model" to understand the cerebellar control of vestibular reflexes.

Experimental animal models have suggested that the modulation of the amplitude and direction of vestibular reflexes are important functions of the vestibulocerebellum and contribute to the control of gaze and balance. These critical vestibular functions have been infrequently quantified in human cerebellar disease. In 13 subjects with ataxia telangiectasia (A-T), a disease associated with profound cerebellar cortical degeneration, we found abnormalities of several key vestibular reflexes. The vestibuloocular reflex (VOR) was measured by eye movement responses to changes in head rotation. The vestibulocollic reflex (VCR) was assessed with cervical vestibular-evoked myogenic potentials (cVEMPs), in which auditory clicks led to electromyographic activity of the sternocleidomastoid muscle. The VOR gain (eye velocity/head velocity) was increased in all subjects with A-T. An increase of the VCR, paralleling that of the VOR, was indirectly suggested by an increase in cVEMP amplitude. In A-T subjects, alignment of the axis of eye rotation was not with that of head rotation. Subjects with A-T thus manifested VOR cross-coupling, abnormal eye movements directed along axes orthogonal to that of head rotation. Degeneration of the Purkinje neurons in the vestibulocerebellum probably underlie these deficits. This study offers insights into how the vestibulocerebellum functions in healthy humans. It may also be of value to the design of treatment trials as a surrogate biomarker of cerebellar function that does not require controlling for motivation or occult changes in motor strategy on the part of experimental subjects.

Gaze fixation deficits and their implication in ataxia–telangiectasia

Background and aim: Ataxia–telangiectasia (A-T) is an autosomal recessive disorder characterised by progressive neurological deficits, including prominent ocular motor dysfunction. Unstable fixation often leads to difficulty reading and blurred vision. Here we characterise the disturbance of visual fixation in A-T. Methods: Eye movements were recorded from 13 A-T patients (with dual search coils in five patients and video oculography in seven) during attempted fixation. Results: Two abnormalities—nystagmus and saccadic intrusions—were common. Horizontal, vertical and torsional nystagmus was present in straight ahead (spontaneous nystagmus) and eccentric gaze (gaze evoked nystagmus). In eight patients the horizontal nystagmus changed directions—periodic alternating nystagmus (PAN). Two types of saccadic intrusions were seen—micro-saccadic oscillations (SO) and square wave saccadic intrusions (SWSI). SO were small amplitude (0.1–0.9°) and high frequency (14–33 Hz) back to back horizontal saccades. SWSI ranged between 1° and 18° (median 3°) with an intersaccadic interval ranging between 50 and 800 ms (median 300 ms). The potential impact of abnormal gaze stabilisation on vision was quantified. Discussion: Degeneration of cerebellar Purkinje neurons disinhibit the caudal fastigial oculomotor region (FOR) and vestibular nuclei (VN). Disinhibition of VN can cause nystagmus, including PAN, while disinhibition of FOR can affect saccade generating mechanisms, leading to SWSI and SO.

Perception of self motion during and after passive rotation of the body around an earth-vertical axis.

We investigated the perception of self-rotation using constant-velocity chair rotations. Subjects signalled self motion during three independent tasks (1) by pushing a button when rotation was first sensed, when velocity reached a peak, when velocity began to decrease, and when velocity reached zero, (2) by rotating a disc to match the perceived motion of the body, or (3) by changing the static position of the dial such that a bigger change in its position correlated with a larger perceived velocity. All three tasks gave a consistent quantitative measure of perceived angular velocity. We found a delay in the time at which peak velocity of self-rotation was perceived (2-5 s) relative to the beginning or to the end of chair rotation. In addition the decay of the perception of self-rotation was preceded by a sensed constant-velocity interval or plateau (9-14 s). This delay in the rise of self-motion perception, and the plateau for the maximum perceived velocity, contrasts with the rapid rise and the immediate decay of the angular vestibuloocular reflex (aVOR). This difference suggests that the sensory signal from the semicircular canals undergoes additional neural processing, beyond the contribution of the velocity-storage mechanism of the aVOR, to compute the percept of self-motion.

Persistent effects of playing football and associated (subconcussive) head trauma on brain structure and function: a systematic review of the literature.

Aim/objective There is ongoing controversy about persistent neurological deficits in active and former football (soccer) players. We reviewed the literature for associations between football activities (including heading/head injuries) and decline in brain structure/function. Design Systematic literature review. Data sources MEDLINE, Embase, PsycINFO, CINAHL, Cochrane-CRCT, SportDiscus, Cochrane-DSR=4 (accessed 2 August 2016). Eligibility criteria for selecting studies Original studies reporting on football-related persistent effects on brain structure/function. Results from neurocognitive testing, neuroimaging and EEG were compared with controls and/or correlated with heading frequency and/or head injuries. Methodological quality was rated for risk-of-bias, including appropriateness of controls, correction for multiple statistical testing and assessment of heading frequency and head injuries. Results 30 studies with 1691 players were included. Those 57% (8/14) of case–control studies reporting persistent neurocognitive impairment had higher odds for inappropriate control of type 1 errors (OR=17.35 (95% CI (10.61 to 28.36)) and for inappropriate selection of controls (OR=1.72 (1.22 to 2.43)) than studies observing no impairment. Studies reporting a correlation between heading frequency and neurocognitive deficits (6/17) had lower quality of heading assessment (OR=14.20 (9.01 to 22.39)) than studies reporting no such correlation. In 7 of 13 studies (54%), the number of head injuries correlated with the degree of neurocognitive impairment. Abnormalities on neuroimaging (6/8 studies) were associated with subclinical neurocognitive deficits in 3 of 4 studies. Summary/conclusions Various methodological shortcomings limit the evidence for persistent effects of football play on brain structure/function. Sources of bias include low-quality assessment of heading frequency, inappropriate control for type 1 errors and inappropriate selection of controls. Combining neuroimaging techniques with neurocognitive testing in prospective studies seems most promising to further clarify on the impact of football on the brain.

ED misdiagnosis of cerebrovascular events in the era of modern neuroimaging: A meta-analysis

Objective: With the emergency department (ED) being a high-risk site for diagnostic errors, we sought to estimate ED diagnostic accuracy for identifying acute cerebrovascular events. Methods: MEDLINE and Embase were searched for studies (1995–2016) reporting ED diagnostic accuracy for ischemic stroke, TIA, or subarachnoid hemorrhage (SAH). Two independent reviewers determined inclusion. We identified 1,693 unique citations, examined 214 full articles, and analyzed 23 studies. Studies were rated on risk of bias (QUADAS-2). Diagnostic data were extracted. We prospectively defined clinical presentation subgroups to compare odds of misdiagnosis. Results: Included studies reported on 15,721 patients. Studies were at low risk of bias. Overall sensitivity (91.3% [95% confidence interval (CI) 90.7–92.0]) and specificity (92.7% [91.7–93.7]) for a cerebrovascular etiology was high, but there was significant variation based on clinical presentation. Misdiagnosis was more frequent among subgroups with milder (SAH with normal vs abnormal mental state; false-negative rate 23.8% vs 4.2%, odds ratio [OR] 7.03 [4.80–10.31]), nonspecific (dizziness vs motor findings; false-negative rate 39.4% vs 4.4%, OR 14.22 [9.76–20.74]), or transient (TIA vs ischemic stroke; false discovery rate 59.7% vs 11.7%, OR 11.21 [6.66–18.89]) symptoms. Conclusions: Roughly 9% of cerebrovascular events are missed at initial ED presentation. Risk of misdiagnosis is much greater when presenting neurologic complaints are mild, nonspecific, or transient (range 24%–60%). This difference suggests that many misdiagnoses relate to symptom-specific factors. Future research should emphasize studying causes and designing error-reduction strategies in symptom-specific subgroups at greatest risk of misdiagnosis.

Disease-specific sparing of the anterior semicircular canals in bilateral vestibulopathy

OBJECTIVE Bilateral vestibular loss (BVL) is often diagnosed with great delay and an underlying cause is only identified in 50-80%. We measured horizontal and vertical semicircular canal function using the video-head-impulse test (vHIT) and hypothesized that specific vHIT-patterns may be linked to certain etiologies. METHODS We retrospectively analyzed 109 BVL-patients linked to aminoglycoside vestibulotoxicity (n=16), Menières disease (n=10), infectious inner-ear disorders (n=11), sensorineural hearing-loss (n=11), cerebellar-ataxia-neuropathy-vestibular-areflexia-syndrome (CANVAS, n=5), other causes (n=19) as well as those with unknown origin (n=47). Vestibulo-ocular reflex gains and cumulative saccade amplitudes were measured with vHIT, and the functional integrity of all semicircular canals was rated. RESULTS Overall, anterior canal hypofunction (n=86/218) was identified significantly (p<0.001) less often than horizontal (n=186/218) and posterior (n=194/218) hypofunction. Preserved anterior canal function was associated with aminoglycoside vestibulotoxicity, Menières disease and BVL of unknown origin, while no such sparing was found for inner-ear infections, CANVAS and sensorineural hearing loss. CONCLUSIONS Semicircular canal function in BVL shows disease-specific dissociations, potentially related to reduced vulnerability or superior recovery of the anterior canals. SIGNIFICANCE In patients with suspected BVL we recommend quantifying vHIT gains and saccade amplitudes for all semicircular canals as the pattern of canal hypofunction may help identifying the underlying disorder.

Temporal constancy of perceived direction of gravity assessed by visual line adjustments

Here we investigated how well internal estimates of direction of gravity are preserved over time and if the subjective visual vertical (SVV) and horizontal (SVH) can be used inter-changeably. Fourteen human subjects repetitively aligned a luminous line to SVV, SVH or subjective visual oblique (± 45°) over 5 min in otherwise complete darkness and also in dim light. Both accuracy (i.e., the degree of veracity as reflected by the median adjustment error) and precision (i.e., the degree of reproducability as reflected by the trial-to-trial variability) of adjustments along the principle axes were significantly higher than along the oblique axes. Orthogonality was only preserved in a minority of subjects. Adjustments were significantly different between SVV vs. SVH (7/14 subjects) and between ±45° vs. -45° (12/14) in darkness and in 6/14 and 14/14 subjects, respectively, in dim light. In darkness, significant drifts over 5min were observed in a majority of trials (33/56). Both accuracy and precision were higher if more time was taken to make the adjustment. These results introduce important caveats when interpreting studies related to graviception. The test re-test reliability of SVV and SVH can be influenced by drift of the internal estimate of gravity. Based on spectral density analysis we found a noise pattern consistent with 1/fβ noise, indicating that at least part of the trial-to-trial dynamics observed in our experiments is due to the dependence of the serial adjustments over time. Furthermore, using results from the SVV and SVH inter-changeably may be misleading as many subjects do not show orthogonality. The poor fidelity of perceived ± 45° indicates that the brain has limited ability to estimate oblique angles.