Pascal Senn

Differential Distribution of Stem Cells in the Auditory and Vestibular Organs of the Inner Ear

The adult mammalian cochlea lacks regenerative capacity, which is the main reason for the permanence of hearing loss. Vestibular organs, in contrast, replace a small number of lost hair cells. The reason for this difference is unknown. In this work we show isolation of sphere-forming stem cells from the early postnatal organ of Corti, vestibular sensory epithelia, the spiral ganglion, and the stria vascularis. Organ of Corti and vestibular sensory epithelial stem cells give rise to cells that express multiple hair cell markers and express functional ion channels reminiscent of nascent hair cells. Spiral ganglion stem cells display features of neural stem cells and can give rise to neurons and glial cell types. We found that the ability for sphere formation in the mouse cochlea decreases about 100-fold during the second and third postnatal weeks; this decrease is substantially faster than the reduction of stem cells in vestibular organs, which maintain their stem cell population also at older ages. Coincidentally, the relative expression of developmental and progenitor cell markers in the cochlea decreases during the first 3 postnatal weeks, which is in sharp contrast to the vestibular system, where expression of progenitor cell markers remains constant or even increases during this period. Our findings indicate that the lack of regenerative capacity in the adult mammalian cochlea is either a result of an early postnatal loss of stem cells or diminishment of stem cell features of maturing cochlear cells.

Minimum Audible Angle, Just Noticeable Interaural Differences and Speech Intelligibility with Bilateral Cochlear Implants Using Clinical Speech Processors

Sound localization and speech intelligibility were assessed in 5 patients implanted bilaterally with Medel C40+ or Medel C40 cochlear implant (CI) systems. The minimum audible angle (MAA) around the head in the horizontal plane was assessed in patients with bilateral CI using white noise bursts of 1000 ms duration presented from a loudspeaker mounted on a rotating boom and compared with the MAA of age-matched normal hearing controls. Spatial discrimination was found to be good in front and in the back of the head with near-normal MAA values (patients: 3–8°, controls: 1–4°). In contrast, poor performance on the sides was found (patients: 30 to over 45°, controls 7–10°). Bilateral CI significantly improved spatial discrimination in front for all patients, when compared with the use of either CI alone. Just noticeable differences (JNDs) in interaural intensity and time were assessed using white noise bursts (1000 ms duration; 50 ms linear ramp). In addition, interaural time JNDs were assessed using click trains (800 ms duration, 40 µs clicks, 50 Hz) and noise bursts in which either only the envelope or only the fine structure was shifted in time. In comparison with normal hearing controls, patients with bilateral CI showed near-normal interaural intensity JNDs but substantially poorer interaural time JNDs depending on the type of stimulus. In contrast to envelope onset/offset cues, interaural fine structure time differences were not perceived by the patients using CI systems employing the continuous interleaved sampling strategy without synchronization between their pulse stimulation times. Speech intelligibility in quiet and CCITT noise from the side (±90°) was assessed using the German HSM sentence test and was significantly better when using bilateral CI in comparison with either unilateral CI, mainly due to a head shadow effect. These favorable results are in agreement with the patients’ subjective experiences assessed with a questionnaire and support the use of bilateral CI.

Novel Slow- and Fast-Type Drug Release Round-Window Microimplants for Local Drug Application to the Cochlea: An Experimental Study in Guinea Pigs

Novel drug release microimplants (0.8 × 1.14 mm; custom-made by Leiras, now Schering OY, Finland) of slow- and fast-release types containing either 0.9 mg beclomethasone or no drug at all were placed unilaterally onto the round-window membrane (RWM) of 45 guinea pigs for a maximum duration of 28 days. The following parameters were tested on days 1, 14 and 28 after implantation: threshold levels of beclomethasone in the perilymph of the scala tympani, auditory brain stem responses (ABR thresholds and ABR threshold shifts), RWM morphology and hair cell loss (cytocochleograms). None of the animals in the non-implanted control group (n = 5) or placebo implant group (n = 15), but all animals in the slow-release-type implant group (n = 15) and fast-release-type implant group (n = 15) revealed the presence of beclomethasone on day 1 (34.9 and 64.3 pg/µl, respectively), day 14 (43.8 and 46.9 pg/µl, respectively) and day 28 after implantation (4.7 and 60.5 pg/µl, respectively). Histology of the RWMs appeared normal, and cytocochleograms revealed no inner hair cell loss and outer hair cell loss within normal ranges (from 0.5 ± 0.4 to 0.8 ± 0.2% per cochlea) in both ears in all experimental groups at any time during examination (days 1, 14 and 28). Initial values of ABR thresholds at 3, 6, 9 and 12 kHz did not differ significantly in any of the experimental groups. In non-implanted controls, no significant differences of ABR thresholds were observed in all frequencies tested in either ear on days 1, 14 and 28 compared to initial values, and ABR threshold shifts ranged from –3 ± 5 dB (min.) to +5 ± 7 dB (max.). On day 28 after implantation, there were no significant differences of ABR threshold shifts between this and the implant groups, except for 6 kHz of the slow-release device. Therefore, the placebo implants, the slow-release and the fast-release beclomethasone implants appear suitable for further experiments.

Isolation of Sphere-Forming Stem Cells from the Mouse Inner Ear

The mammalian inner ear has very limited ability to regenerate lost sensory hair cells. This deficiency becomes apparent when hair cell loss leads to hearing loss as a result of either ototoxic insult or the aging process. Coincidently, with this inability to regenerate lost hair cells, the adult cochlea does not appear to harbor cells with a proliferative capacity that could serve as progenitor cells for lost cells. In contrast, adult mammalian vestibular sensory epithelia display a limited ability for hair cell regeneration, and sphere-forming cells with stem cell features can be isolated from the adult murine vestibular system. The neonatal inner ear, however, does harbor sphere-forming stem cells residing in cochlear and vestibular tissues. Here, we provide protocols to isolate sphere-forming stem cells from neonatal vestibular and cochlear sensory epithelia as well as from the spiral ganglion. We further describe procedures for sphere propagation, cell differentiation, and characterization of inner ear cell types derived from spheres. Sphere-forming stem cells from the mouse inner ear are an important tool for the development of cellular replacement strategies of damaged inner ears and are a bona fide progenitor cell source for transplantation studies.

Patients with mild traumatic brain injury: Immediate and long-term outcome compared to intra-cranial injuries on CT scan

Background: Mild traumatic brain injury (MTBI) defined as Glasgow Coma Scale (GCS) 14 or 15 has shown contradictory short- and long-term outcomes. The objective of this study was to correlate intra-cranial injuries (ICI) on CT scan to neurocognitive tests at admission and to complaints after 1 year. Methods: Two hundred and five patients with MTBI underwent a CT scan and were examined with neurocognitive tests. After 1 year complaints were assessed by phone interviews. Results: The neurocognitive tests in 51% of the patients showed significant deficits; there was no difference for patients with GCS 14–15, nor was there a difference between patients with ICI to patients without. After 1 year patients with ICI had significantly more complaints than patients without ICI, the most frequent complaint was headache and memory deficits. Conclusions: No correlation was found between GCS or ICI and the neurocognitive tests upon admission. After 1 year, patients with ICI have significantly more complaints than patients without ICI. No cost savings resulted by doing immediate CT scan on all.

LIF promotes neurogenesis and maintains neural precursors in cell populations derived from spiral ganglion stem cells

BackgroundStem cells with the ability to form clonal floating colonies (spheres) were recently isolated from the neonatal murine spiral ganglion. To further examine the features of inner ear-derived neural stem cells and their derivatives, we investigated the effects of leukemia inhibitory factor (LIF), a neurokine that has been shown to promote self-renewal of other neural stem cells and to affect neural and glial cell differentiation.ResultsLIF-treatment led to a dose-dependent increase of the number of neurons and glial cells in cultures of sphere-derived cells. Based on the detection of developmental and progenitor cell markers that are maintained in LIF-treated cultures and the increase of cycling nestin-positive progenitors, we propose that LIF maintains a pool of neural progenitor cells. We further provide evidence that LIF increases the number of nestin-positive progenitor cells directly in a cell cycle-independent fashion, which we interpret as an acceleration of neurogenesis in sphere-derived progenitors. This effect is further enhanced by an anti-apoptotic action of LIF. Finally, LIF and the neurotrophins BDNF and NT3 additively promote survival of stem cell-derived neurons.ConclusionOur results implicate LIF as a powerful tool to control neural differentiation and maintenance of stem cell-derived murine spiral ganglion neuron precursors. This finding could be relevant in cell replacement studies with animal models featuring spiral ganglion neuron degeneration. The additive effect of the combination of LIF and BDNF/NT3 on stem cell-derived neuronal survival is similar to their effect on primary spiral ganglion neurons, which puts forward spiral ganglion-derived neurospheres as an in vitro model system to study aspects of auditory neuron development.

Tinnitus before and 6 Months after Cochlear Implantation

In this prospective multicenter study, tinnitus loudness and tinnitus-related distress were investigated in 174 cochlear implant (CI) candidates who underwent CI surgery at a Swiss cochlear implant center. All subjects participated in two session, one preoperatively and one 6 months after device activation. In both sessions, tinnitus loudness was assessed using a visual analogue scale and tinnitus distress using a standardized tinnitus questionnaire. The data were compared with unaided pre- and postoperative pure tone thresholds, and postoperative speech reception scores. 71.8% of the subjects reported tinnitus preoperatively. Six months after CI surgery 20.0% of these reported abolition of their tinnitus, 51.2% a subjective improvement, 21.6% no change and 7.2% a deterioration. Of the 49 (28.2%) subjects with no tinnitus preoperatively, 5 developed tinnitus 6 months after CI. These 5 had poorer speech understanding after CI surgery with their device than the group who remained tinnitus free. We found no correlation between tinnitus improvement, age, duration of tinnitus, or change in unaided hearing thresholds between the two sessions.

Low-dose temporal bone CT in infants and young children: effective dose and image quality.

If your institution is like ours, you must perform many temporal bone CT studies in children and worry about radiation exposure. These authors compared techniques using 80 kV/90–100 mAs (low dose) and 140kV/170 mAs (high dose) for temporal bone CT studies in children aged 5 years. Neuroradiologists and otologists evaluated 23 structures in those studies. Low-dose CT was given lower scores but these differences were only significant when otologists evaluated the studies. Thus, the image quality of low-dose CT was perceived as insufficient by our clinical colleagues. BACKGROUND AND PURPOSE: The temporal bone is ideal for low-dose CT because of its intrinsic high contrast. The aim of this study was to retrospectively evaluate image quality and radiation doses of a new low-dose versus a standard high-dose pediatric temporal bone CT protocol and to review dosimetric data from the literature. MATERIALS AND METHODS: Image quality and radiation doses were compared for 38 low-dose (80 kV/90–110 mAs) and 16 high-dose (140 kV/170 mAs) temporal bone CT scans of infants to 5-year-old children. The CT visualization quality of 23 middle and inner ear structures was subjectively graded by 3 neuroradiologists and 3 otologists by using a 5-point scale with scores 1–2 indicating insufficient and scores 3–5 indicating sufficient image quality. Effective doses of local and literature-derived protocols were calculated from dosimetric data by using NRPB-SR250 software. RESULTS: Insufficient image-quality scores were more frequent in low-dose scans versus high-dose scans, but the difference was only statistically significant for otologists (6.0% versus 3.4%, P = .004) and not for neuroradiologists (1.2% versus 0.7%, P = .84). Image quality was critical for small structures (such as the stapes or lamella at the internal auditory canal fundus). Effective doses were 0.25–0.3 mSv for low-dose scans, 1.4–1.8 mSv for high-dose scans, and 0.9–2.6 mSv for literature-derived protocols. CONCLUSIONS: The image quality of the new low-dose protocol remains diagnostic for assessing middle and inner ear anatomy despite a 3- to 8-fold dose reduction over previous and literature-derived protocols. However, image quality of small structures is critical and may be perceived as insufficient.

Severe complications after intrathecal methotrexate (MTX) for treatment of primary central nervous system lymphoma (PCNSL).

Primary central nervous system lymphoma (PCNSL) is a rare and highly malignant tumor with increasing incidence. Survival has improved with the use of nonsurgical treatment modalities, of which methotrexate (MTX)-based intrathecal chemotherapy has been an important option. Here, we describe devastating complications in three patients with diffuse large B-cell lymphomas. After intrathecal MTX therapy two patients died secondary to fulminant brain edema. A third patient developed severe dementia, gait disturbance and urinary incontinence due to leukencephalopathy. Since bulky disease was present in all three patients, CSF flow may have been impaired. This might have exposed adjacent tissue to prolonged toxic drug concentrations. Regarding the severe complications seen in these patients, it is useful to consider high-dose intravenous MTX treatment only in periventricular PCNSL.

The Pre- and Post-Somatic Segments of the Human Type I Spiral Ganglion Neurons - Structural and Functional Considerations Related to Cochlear Implantation

Highlights • Pre- and post-somatic segments of type I spiral ganglion neurons (SGNs) are unmyelinated in man.• Following hair cell loss and retrograde nerve degeneration SGNs survive as “mono-polar” cells in human deafness.• Non-myelinated Schwann cells may consolidate the neural cell bodies and protect SGNs from further degeneration.• Human SGNs can persist as electrically excitable mono-polar cells even after long-time deafness.• Robust survival of human SGNs is a prerequisite for cochlear implant function.