Prevalence, Determinants, and Consequences of Vestibular Hypofunction. Results From the KORA-FF4 Survey.

Objective: Uni- or bilateral vestibular hypofunction (VH) impairs balance and mobility, and may specifically lead to injury from falls and to disability. The extent of this problem in the general population is still unknown and most likely to be underestimated. Objective of this study was to determine the prevalence, determinants, and consequences of VH in the general population. Methods: Data originates from the cross-sectional second follow-up (FF4) in 2013/14 of the KORA (Cooperative Health Research in the Region of Augsburg)-S4 study (1999-2001) from Southern Germany. This was a random sample of the target population consisting of all residents of the region aged 25-74 years in 1999. We included all participants who reported moderate or severe vertigo or dizziness during the last 12 months and a random sub-sample of participants representative for the general population without vertigo or dizziness during the last 12 months were tested. VH was assessed with the Video-Head Impulse Test (vHIT). Trained examiners applied high-acceleration, small-amplitude passive head rotations ("head impulses") to the left and right in the plane of the horizontal semicircular canals while participants fixated a target straight ahead. During head impulses, head movements were measured with inertial sensors, eye movements with video-oculography (EyeSeeCam vHIT). Results: A total of 2,279 participants were included (mean age 60.8 years, 51.6% female), 570 (25.0%) with moderate or severe vertigo or dizziness during the last 12 months. Of these, 450 were assessed with vHIT where 26 (5.8%) had unilateral VH, and 16 (3.6%) had bilateral VH. Likewise, 190 asymptomatic participants were tested. Of these 5 (2.6%) had unilateral VH, and 2 (1.1%) had bilateral VH. Prevalence of uni- or bilateral VH among tested symptomatic participants was 2.4% in those < 48 years, and 32.1% in individuals aged 79 and over. Age-adjusted prevalence was 6.7% (95% CI 4.8%; 8.6%). VH was associated with worse health, falls, hearing loss, hearing impairment, and ear pressure. Conclusion: VH may affect between 53 and 95 million adults in Europe and the US. While not all affected persons will experience the full spectrum of symptoms and consequences, adequate diagnostic and therapeutic measures should become standard of care to decrease the burden of disease.

Usability of the Video Head Impulse Test: Lessons From the Population-Based Prospective KORA Study.

Objective: The video head impulse test (vHIT) has become a common examination in the work-up for dizziness and vertigo. However, recent studies suggest a number of pitfalls, which seem to reduce vHIT usability. Within the framework of a population-based prospective study with naïve examiners, we investigated the relevance of previously described technical mistakes in vHIT testing, and the effect of experience and training. Methods: Data originates from the KORA (Cooperative Health Research in the Region of Augsburg) FF4 study, the second follow-up of the KORA S4 population-based health survey. 681 participants were selected in a case-control design. Three examiners without any prior experience were trained in video head impulse testing. VHIT quality was assessed weekly by an experienced neuro-otologist. Restrictive mistakes (insufficient technical quality restricting interpretation) were noted. Based on these results, examiners received further individual training. Results: Twenty-two of the 681 vHITs (3.2%) were not interpretable due to restrictive mistakes. Restrictive mistakes could be grouped into four categories: slippage, i.e., goggle movement relative to the head (63.6%), calibration problems (18.2%), noise (13.6%), and low velocity of the head impulse (4.6%). The overall rate of restrictive mistakes decreased significantly during the study (12% / examiner within the first 25 tested participants and 2.1% during the rest of the examinations, p < 0.0001). Conclusion: Few categories suffice to explain restrictive mistakes in vHIT testing. With slippage being most important, trainers should emphasize the importance of tight goggles. Experience and training seem to be effective in improving vHIT quality, leading to high usability.

Head-Movement-Emphasized Rehabilitation in Bilateral Vestibulopathy.

Objective: Although there is evidence that vestibular rehabilitation is useful for treating chronic bilateral vestibular hypofunction (BVH), the mechanisms for improvement, and the reasons why only some patients improve are still unclear. Clinical rehabilitation results and evidence fromeye-head control in vestibular deficiency suggest that headmovement is a crucial element of vestibular rehabilitation. In this study, we assess the effects of a specifically designed head-movement-based rehabilitation program on dynamic vision, and explore underlying mechanisms. Methods: Two adult patients (patients 1 and 2) with chronic BVH underwent two 4-week interventions: (1) head-movement-emphasized rehabilitation (HME) with exercises based on active head movements, and (2) eye-movement-only rehabilitation (EMO), a control intervention with sham exercises without head movement. In a double-blind crossover design, the patients were randomized to first undergo EMO (patient 1) and-after a 4-week washout-HME, and vice-versa (patient 2). Before each intervention and after a 4-week follow-up patients' dynamic vision, vestibulo-ocular reflex (VOR) gain, as well as re-fixation saccade behavior during passive headmotion were assessed with the head impulse testing device-functional test (HITD-FT). Results: HME, not EMO, markedly improved perception with dynamic vision during passive head motion (HITD-FT score) increasing from 0 to 60% (patient 1) and 75% (patient 2). There was a combination of enhanced VOR, as well as improved saccadic compensation. Conclusion: Head movement seems to be an important element of rehabilitation for BVH. It improves dynamic vision with a combined VOR and compensatory saccade enhancement.

Preventing opioid-induced nausea and vomiting: Rest your head and close your eyes?

Although opioid-induced nausea and vomiting (OINV) is common and debilitating, its mechanism is still unclear. Recently, we suggested that opioids affect semicircular canal function and that this leads to a mismatch between canal input and other sensory information during head motion, which triggers OINV. Here, we assess if visual input is relevant for this mismatch. In a randomized-controlled crossover study 14 healthy men (26.9±3.4 years, mean±SD) were tested twice, once blindfolded and once with eyes open, with at least one-day washout. The opioid remifentanil was administered intravenously (0.15 µg/kg/min) for 60 minutes. After a thirty-minutes resting period, subjects' head and trunk were passively moved. Nausea was rated before remifentanil start (T0), before the movement intervention (T30) and after 60 minutes (T60) of administration. At rest (T0, T30), median nausea ratings were zero whether subjects were blindfolded or not. Movement triggered nausea independently of visual input (nausea rating 1.5/3.0 (median/interquartile range) in the blindfolded, 2.5/6 in the eyes-open condition, χ2(1) = 1.3, p = 0.25). As movement exacerbates OINV independently of visual input, a clash between visual and semicircular canal information is not the relevant trigger for OINV. To prevent OINV, emphasis should be put on head-rest, eye-closure is less important.

Covert anti-compensatory quick eye movements during head impulses.

BACKGROUND: Catch-up saccades during passive head movements, which compensate for a deficient vestibulo-ocular reflex (VOR), are a well-known phenomenon. These quick eye movements are directed toward the target in the opposite direction of the head movement. Recently, quick eye movements in the direction of the head movement (covert anti-compensatory quick eye movements, CAQEM) were observed in older individuals. Here, we characterize these quick eye movements, their pathophysiology, and clinical relevance during head impulse testing (HIT). METHODS: Video head impulse test data from 266 patients of a tertiary vertigo center were retrospectively analyzed. Forty-three of these patients had been diagnosed with vestibular migraine, and 35 with Menière's disease. RESULTS: CAQEM occurred in 38% of the patients. The mean CAQEM occurrence rate (per HIT trial) was 11±10% (mean±SD). Latency was 83±30 ms. CAQEM followed the saccade main sequence characteristics and were compensated by catch-up saccades in the opposite direction. Compensatory saccades did not lead to more false pathological clinical head impulse test assessments (specificity with CAQEM: 87%, and without: 85%). CAQEM on one side were associated with a lower VOR gain on the contralateral side (p<0.004) and helped distinguish Menière's disease from vestibular migraine (p = 0.01). CONCLUSION: CAQEM are a common phenomenon, most likely caused by a saccadic/quick phase mechanism due to gain asymmetries. They could help differentiate two of the most common causes of recurrent vertigo: vestibular migraine and Menière's disease.

Telomere length in mantle cell lymphoma.

Telomere shortening is of pathogenic and prognostic importance in cancers. In the present study, we analyzed telomere length in 73 mantle cell lymphoma (MCL), 55 chronic lymphocytic leukemia (CLL), and 20 normal B-cell samples using quantitative PCR (Q-PCR) to study its association with disease characteristics and outcome. Telomere length was found to be highly variable in MCL (range, 2.2-13.8 kb; median, 4.3 kb). Telomere dysfunction in MCL was evident from comparison with normal B cells (median, 7.5 kb), but had no significant association with any biologic or clinical feature. This was in contrast to CLL, in which a significant correlation of short telomeres with poor prognostic subgroups was confirmed. There was a trend toward an increased number of genomic aberrations with shortening of telomeres in MCL. No difference in survival was observed between the groups with short and long telomeres, indicating that, as opposed to CLL, telomere length is not of prognostic relevance in MCL.

Treatment resistance in chronic lymphocytic leukemia: the role of the p53 pathway.

The importance of studying p53 pathway defects in chronic lymphocytic leukemia (CLL) has been promoted by the demonstration of the fundamentally different clinical course of patients with 17p deletion. The observation of resistance to chemotherapy and mutation of the remaining TP53 allele explain the clinical presentation of CLL with 17p deletion. Here we review recent evidence that cases with TP53 mutation in the absence of the deletion of 17p have a similar clinical and biological course as cases carrying the deletion 17p. In addition, other principal components of the DNA damage pathway reportedly are de-regulated by mutation (ATM), deletion (ATM) or potentially more complex down-regulation (miR-34a) in CLL. Nonetheless, challenges remain because we can only explain resistance in a proportion of the cases that are resistant to first line treatment. This is of particular practical interest because our armamentarium of drugs in clinical use that acts independent of the DNA damage pathway is growing, for example antibody-based treatment (alemtuzumab), immuno-modulating drugs (lenalidomide), CDK inhibitors (flavopiridol) and steroids.