Fluorescein-Assisted Microsurgical Resection of Vestibular Schwannoma: A Prospective Feasibility Study.

OBJECTIVE: To evaluate the optimal dose and timing of administration of sodium fluorescein (SF) for selective fluorescence of sporadic vestibular schwannoma (VS) during microsurgery with the YELLOW 560-nm microscope filter (YE560) and to characterize the potential benefit of this fluorescence as determined by intraoperative surgeon assessment. STUDY DESIGN: Prospective cohort study. SETTING: Tertiary referral center. PATIENTS: Adult patients undergoing VS microsurgery. INTERVENTIONS: Intraoperative intravenous administration of SF and visualization with the YE560. MAIN OUTCOME MEASURES: Time to differential fluorescence, duration of fluorescence, correlation of fluorescence of VS with electrostimulation and white light microscopy visual assessment, and likelihood of surgeons to use SF with the YE560 in future cases. RESULTS: Novel use of SF and YE560 during microsurgery achieved selective fluorescence of VS with capabilities to differentiate nerve fascicles and tumor approximately 30 minutes after administration. Nuances of SF administration and timing are discussed. Seventy-five percent of surgeons observed an excellent correlation of selective fluorescence with white light microscopy. Representative images and cases are presented. CONCLUSIONS: SF and YE560 may be used in VS microsurgery to visually differentiate VS from surrounding nerves. Potential benefits include enhanced visualization of the tumor-nerve interface for tumor dissection and detection of any residual disease, such as in the fundus after hearing preservation microsurgery.

Computational repositioning and preclinical validation of mifepristone for human vestibular schwannoma.

The computational repositioning of existing drugs represents an appealing avenue for identifying effective compounds to treat diseases with no FDA-approved pharmacotherapies. Here we present the largest meta-analysis to date of differential gene expression in human vestibular schwannoma (VS), a debilitating intracranial tumor, and use these data to inform the first application of algorithm-based drug repositioning for this tumor class. We apply an open-source computational drug repositioning platform to gene expression data from 80 patient tumors and identify eight promising FDA-approved drugs with potential for repurposing in VS. Of these eight, mifepristone, a progesterone and glucocorticoid receptor antagonist, consistently and adversely affects the morphology, metabolic activity, and proliferation of primary human VS cells and HEI-193 human schwannoma cells. Mifepristone treatment reduces VS cell viability more significantly than cells derived from patient meningiomas, while healthy human Schwann cells remain unaffected. Our data recommend a Phase II clinical trial of mifepristone in VS.

Air-conducted and skull-tap cervical vestibular evoked myogenic potentials in determining nerve division involvement in vestibular schwannoma patients.

BACKGROUND: Air-conducted and skull-tap cervical vestibular evoked myogenic potentials (AC-cVEMP and Tap-cVEMP) have been shown to be very promising tools in clinical practice. They are noninvasive, easy to obtain and - importantly - they require little time and the cost of the instruments is low. OBJECTIVES: The aim of this study was to evaluate the usefulness of the combined use of ACand Tap-cVEMPs as a diagnostic tool for advanced assessment of vestibular schwannoma in determining tumor origin, and to investigate whether the results are helpful for a surgeon as an additional source of information about the tumor before surgery. MATERIAL AND METHODS: ACand Tap-cVEMPs were acquired (with EMG-based biofeedback) from the sternocleidomastoid muscles (SCM) of 30 vestibular schwannoma patients just before surgery. The results were compared to the surgical information about nerve bundle involvement in the tumor and the size of the tumor obtained from magnetic resonance imaging (MRI). RESULTS: On the tumor side, abnormal corrected amplitude asymmetry ratios were detected in 73.33% of the patients, abnormalities in P1-latencies in 70% of the patients, and both in 90% of the patients. The cervical vestibular evoked myogenic potential (cVEMP) results indicated the affected nerve division to be the inferior in 23.33% of the patients, the superior in 20% of the patients, and both in 46.67% of the patients. No cVEMP abnormalities were found in 10% of cases. The combined results of both ACand Tap-cVEMP were significantly compatible with the surgical information about the tumor origin. The number of abnormalities was significantly correlated with the tumor size. CONCLUSIONS: The information provided by the combined application of ACand Tap-cVEMPs might be useful for a surgeon in presurgical planning, providing more detailed information about the tumor and the affected nerve division in the internal auditory canal. It is not a diagnostic replacement for MRI in vestibular schwannoma patients; however, in our opinion, ACand Tap-cVEMPs may serve as additional sources of information about the tumor before the surgery.

Ailanthone Promotes Human Vestibular Schwannoma Cell Apoptosis and Autophagy by Downregulation of miR-21.

Ailanthone (AIL) is a quassinoid isolated from the traditional Chinese medicinal herb Ailanthus altissima. The antitumor activities of AIL have been reported in several cancers. The purpose of the present study was to explore the effect of AIL on vestibular schwannomas (VSs). Various concentrations of AIL (0-1 µM) were used to treat human primary VS cells, and then cell viability, proliferation, apoptosis, and autophagy were assessed. Expression of miR-21 in VS cells was altered by miRNA transfection. The functional actions of AIL on miR-21 dysregulated cells were also assessed. AIL significantly reduced the viability of VS cells, and the IC50 value was 0.48 ± 0.023 µM. In response to 0.6 µM AIL, BrdU+ cell rate and cyclin D1 expression were reduced, apoptotic cell rate was increased, caspase 3 and caspase 9 were cleaved, Beclin-1 and LC3-II were accumulated, and p62 was downregulated. miR-21 was lowly expressed in AIL-treated cells, and AIL-induced apoptosis and autophagy were attenuated by miR-21 overexpression. In addition, AIL downregulated Ras and Raf and deactivated MEK, ERK, mTOR, and p70S6K, while the downregulation and deactivation induced by AIL were reversed by miR-21 overexpression. To conclude, AIL inhibited VS cell proliferation and induced apoptosis and autophagy. The antitumor activities of AIL in VS cells were realized possibly via downregulation of miR-21 and blocking the Ras/Raf/MEK/ERK and mTOR pathways.

Sulforaphane, a natural component of broccoli, inhibits vestibular schwannoma growth in vitro and in vivo.

Vestibular schwannoma (VS) is an intracranial tumor that causes significant morbidity, including hearing loss, tinnitus, dizziness, and possibly even death from brainstem compression. However, FDA-approved pharmacologic treatments for VS do not exist. Sulforaphane (SFN) is a naturally occurring isothiocyanate found in cruciferous vegetables, such as broccoli, with potent chemoprotective effects in several cell types. Our objective was to determine whether SFN is effective against VS in vitro and in vivo. Human primary VS cells, HEI-193 schwannoma cells, and SC4 Nf2-/- Schwann cells were used to investigate the inhibitory effects of SFN in vitro. Cell proliferation was assessed by bromodeoxyuridine (BrdU) incorporation, and cell viability and metabolic activity was calculated by MTT assay. Apoptosis was measured by flow cytometry, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and Western blot for cleaved caspases. A mouse model with a murine schwannoma allograft was also used to examine the antitumor activity of SFN. SFN exhibited significant antiproliferative activity in schwannoma cells in vitro, via the inhibition of HDAC activity and the activation of ERK. SFN treatment induced apoptosis and cell cycle arrest at the G2/M phase. SFN also significantly inhibited schwannoma growth in vivo. Our preclinical studies motivate a future prospective clinical study of SFN for the treatment of VS.

Electrical vestibular stimulation after vestibular deafferentation and in vestibular schwannoma.

BACKGROUND: Vestibular reflexes, evoked by human electrical (galvanic) vestibular stimulation (EVS), are utilized to assess vestibular function and investigate its pathways. Our study aimed to investigate the electrically-evoked vestibulo-ocular reflex (eVOR) output after bilateral and unilateral vestibular deafferentations to determine the characteristics for interpreting unilateral lesions such as vestibular schwannomas. METHODS: EVOR was recorded with dual-search coils as binocular three-dimensional eye movements evoked by bipolar 100 ms-step at EVS intensities of [0.9, 2.5, 5.0, 7.5, 10.0] mA and unipolar 100 ms-step at 5 mA EVS intensity. Five bilateral vestibular deafferented (BVD), 12 unilateral vestibular deafferented (UVD), four unilateral vestibular schwannoma (UVS) patients and 17 healthy subjects were tested with bipolar EVS, and five UVDs with unipolar EVS. RESULTS: After BVD, bipolar EVS elicited no eVOR. After UVD, bipolar EVS of one functioning ear elicited bidirectional, excitatory eVOR to cathodal EVS with 9 ms latency and inhibitory eVOR to anodal EVS, opposite in direction, at half the amplitude with 12 ms latency, exhibiting an excitatory-inhibitory asymmetry. The eVOR patterns from UVS were consistent with responses from UVD confirming the vestibular loss on the lesion side. Unexpectedly, unipolar EVS of the UVD ear, instead of absent response, evoked one-third the bipolar eVOR while unipolar EVS of the functioning ear evoked half the bipolar response. CONCLUSIONS: The bidirectional eVOR evoked by bipolar EVS from UVD with an excitatory-inhibitory asymmetry and the 3 ms latency difference between normal and lesion side may be useful for detecting vestibular lesions such as UVS. We suggest that current spread could account for the small eVOR to 5 mA unipolar EVS of the UVD ear.

Growth inhibitory and anti-tumour activities of OSU-03012, a novel PDK-1 inhibitor, on vestibular schwannoma and malignant schwannoma cells.

BACKGROUND: Vestibular schwannomas (VS) frequently express high levels of activated AKT. Small-molecule inhibitors of AKT signalling may have therapeutic potential in suppressing the growth of benign VS and malignant schwannomas. METHOD: Primary VS and Schwann cells, human malignant schwannoma HMS-97 cells and mouse Nf2(-/-) Schwann cells and schwannoma cells were prepared to investigate the growth inhibitory and anti-tumour activities of OSU-03012, a celecoxib-derived small-molecule inhibitor of phosphoinositide-dependent kinase-1. Cell proliferation assays, apoptosis, Western blot, in vivo xenograft analysis using SCID mice and immunohistochemistry were performed. RESULTS: OSU-03012 inhibited cell proliferation more effectively in both VS and HMS-97 cells than in normal human Schwann cells. The IC5) of OSU-03012 at 48h was approximately 3.1 microM for VS cells and 2.6 microM for HMS-97 cells, compared with the IC(50) of greater than 12 microM for human Schwann cells. Similarly, mouse Nf2(-/-) schwannoma and Nf2(-/-) Schwann cells were more sensitive to growth inhibition by OSU-03012 than wild-type mouse Schwann cells and mouse schwannoma cells established from transgenic mice carrying the NF2 promoter-driven SV40 T-antigen gene. Like VS cells, malignant schwannoma HMS-97 cells expressed high levels of activated AKT. OSU-03012 induced apoptosis in both VS and HMS-97 cells and caused a marked reduction of AKT phosphorylation at both the Ser-308 and Thr-473 sites in a dose-dependent manner. In vivo xenograft analysis showed that OSU-03012 was well tolerated and inhibited the growth of HMS-97 schwannoma xenografts by 55% after 9 weeks of oral treatment. The anti-tumour activity correlated with reduced AKT phosphorylation. CONCLUSION: OSU-03012 is a potential chemotherapeutic agent for VS and malignant schwannomas.

Effects of ErbB2 signaling on the response of vestibular schwannoma cells to gamma-irradiation.

OBJECTIVE: For vestibular schwannomas (VSs) that require treatment, options are limited to microsurgery or irradiation (IR). Development of alternative therapies that augment or replace microsurgery or IR would benefit patients not suitable for current therapies. This study explored the ability of ErbB2 inhibitors to modulate the effects of IR on VS cells. STUDY DESIGN: Prospective study using primary cultures derived from human VSs. METHODS: Primary cultures of VS cells were derived from acutely resected tumors. Cultures received single escalating doses (15-40 Gy) of gamma-irradiation from a Cs gamma-irradiation source. Cell proliferation was determined by BrdU uptake and apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Trastuzumab (Herceptin) and PD158780 were independently used to inhibit ErbB2 signaling while neuregulin-1beta (NRG-1) was used to activate ErbB2. RESULTS: IR induces VS cell cycle arrest and apoptosis in doses greater than 20 Gy, demonstrating that VS cells are relatively radioresistant. This radioresistance likely arises from their low proliferative capacity as a sublethal dose of IR (10 Gy) strongly induces deoxyribonucleic acid (DNA) damage evidenced by histone H2AX phosphorylation. Inhibition of ErbB2, which decreases VS cell proliferation, protects VS cells from radiation-induced apoptosis, while NRG-1, an ErbB2 ligand and VS cell mitogen, increases radiation-induced VS cell apoptosis. CONCLUSIONS: Compared with many neoplastic conditions, VS cells are relatively radioresistant. The radio-protective effect of ErbB2 inhibitors implies that the sensitivity of VS cells to IR depends on their proliferative capacity. These results hold important implications for current and future treatment strategies.

Incidence of dysarthria in children with cerebellar tumors: a prospective study.

The present study investigated dysarthric symptoms in children with cerebellar tumors. Ten children with cerebellar tumors and 10 orthopedic control children were tested prior and one week after surgery. Clinical dysarthric symptoms were quantified in spontaneous speech. Syllable durations were analyzed in syllable repetition and sentence production tasks. Localization of the cerebellar lesions were defined after manual transfer from individual 2D-MR images onto 3D images of a spatially normalized healthy brain. Cerebellar children showed few and mild clinical signs of dysarthria. No difference was present in the sentence production task compared to controls. In five cerebellar children, syllables were prolonged in the syllable repetition task after surgery. Syllable duration normalized in an additional four-week session in all but one case. The MR-analysis showed that superior paravermal cerebellar areas likely involved in dysarthria in adults (paravermal lobules HVI, Crus I) were not significantly affected. In children, speech impairments appear to be rare after cerebellar surgery because tumors most commonly affect posterior-inferior and medial parts of the cerebellum while critical cerebellar regions are likely spared. The results suggest a similar localization of speech functions in the cerebellum in children and adults.

Preservation of tap vestibular evoked myogenic potentials despite resection of the inferior vestibular nerve.

Sound and skull-tap induced vestibular evoked myogenic potentials (VEMP) were studied in a 43-year-old man following inferior vestibular neurectomy. Surgery was performed because of a small acoustic neuroma. Postoperative caloric testing suggested sparing of superior vestibular nerve function on the operated side. In response to sound stimulation there were no VEMP on the operated side, irrespective of whether sounds were presented by air- or bone-conduction. This suggests sound-induced VEMP to be critically dependent on inferior vestibular nerve function and this is in agreement with present knowledge. However, VEMP were obtained in response to forehead skull taps, i.e. positive-negative VEMP not only on the healthy side but also on the operated side. This suggests remnant vestibular function on the operated side of importance for forehead skull tap VEMP, because with complete unilateral vestibular loss there are no (positive-negative) VEMP on the lesioned side. Thus, forehead skull-tap VEMP depend, at least partly, on the superior vestibular nerve function.

Otoacoustic emissions recorded at high rates in patients with confirmed acoustic neuromas.

Otoacoustic emission testing was carried out on 39 patients with confirmed acoustic neuromas, and satisfactory emissions were recorded from the neuroma ear of 59% of them. A comparison of the patients with and without emissions showed no significant differences in low-frequency or high-frequency hearing loss, optimum speech discrimination score, or canal paresis in the affected ear between the two groups. Emissions were recorded at stimulus rates up to 5,000 clicks/s by using the maximum length sequence (MLS) technique. The decrease in the emission amplitude with increase in click rate (rate suppression) was significantly less than the amount that would be expected from normal subjects for several of the neuroma patients. However, one patient showed normal suppression despite having a large neuroma and no measurable hearing. This would suggest that efferent suppression may not be the only mechanism involved.

Usefulness of auditory brainstem responses at high stimulus rates in the diagnosis of acoustic neuroma.

The effects of the stimulus rate on the auditory brainstem responses (ABRs) of acoustic neuroma (AN) patients were studied. Ninety-decibel click stimuli at a normal hearing level were delivered at stimulus rates of 9.5, 20, 40 and 90 Hz, and ABRs were recorded of 40 AN patients (40 ears) at each stimulus rate. Subjects with normal hearing (42 ears) and patients with sensorineural hearing loss (30 ears) were also studied to obtain normative data. The following two parameters were examined: the interpeak latency difference between wave I and wave V (IPL I-V) at each stimulus rate, and the increase in IPL I-V (delta IPL I-V) when the stimulus rate was increased from 9.5 Hz. AN patients showed significantly larger values for both parameters at all stimulus rates compared to those of the control groups. Among 6 AN patients with normal ABRs at 9.5 Hz, 5 showed abnormal IPL I-V or abnormal delta IPL I-V at 90 Hz, when the upper normal limits of both parameters were defined as the mean plus 2 SD of the group with normal hearing. These results suggest that recording ABR at high stimulus rates provides valuable information for detecting AN patients with normal ABRs.

Direct cochlear nerve action potentials as an aid to hearing preservation in middle fossa acoustic neuroma resection.

A new application of auditory evoked potentials using direct cochlear nerve action potentials (CNAPs) for monitoring middle fossa acoustic neuroma resection with attempted hearing preservation is described. Twenty patients have been studied to date. With this technique, a monitoring electrode is secured between the floor of the internal auditory canal and the dura adjacent to the cochlear nerve in an extradural location. Standard auditory evoked potential techniques with click stimuli and microelectrical recording allow observation of nearfield waveforms in seconds versus several minutes required for farfield potentials recorded from the scalp. Advantages of this technique over auditory brainstem response monitoring may include nearly real time measurement of potentials, improved surgeon learning curve and possibly higher rates of hearing preservation, and applicability to all patients undergoing hearing-preservation surgery independent of presence or absence of ABR tracing. Immediate changes in amplitude and latency of waveforms appear to compare with reversible and irreversible intraoperative auditory system damage, thereby guiding surgical maneuvers.

Effects of contralateral white noise stimulation on transitory evoked otoacoustic emissions in patients with acoustic neuroma.

Transitory evoked otoacoustic emissions are normal phenomena observed in most persons with hearing levels greater than 35 dB. Further, masking of the contralateral ear produces amplitude reductions in the transitory evoked otoacoustic emissions. We have undertaken a study of transitory evoked otoacoustic emissions in 20 patients with acoustic neuroma. All patients were assessed for transitory evoked otoacoustic emissions bilaterally, with and without contralateral masking with white band noise at 40, 50, and 60 dB. We found that transitory evoked otoacoustic emissions were present in 30% of ears with tumor and that the presence of transitory evoked otoacoustic emissions is associated with improved preoperative hearing levels, but that tumor size is not associated with the presence or absence of transitory evoked otoacoustic emissions. The amplitude of transitory evoked otoacoustic emissions from ears with tumor, when present, is decreased when compared with normal ears of normal patients. Further, with contralateral masking little of the amplitude reduction observed in normal patients is observed in the ears with acoustic neuroma. However, with masking of the contralateral ear, the ear without tumor demonstrated significantly greater amplitude reductions than normal ears from normal patients (p = 0.0006). Pertinent anatomy and possible explanations for these findings are discussed.

Determinants and impact of headache after acoustic neuroma surgery.

Headache after acoustic neuroma surgery is known to occur clinically, but has not been studied systematically until recently. In the present study, 155 patients were surveyed regarding their experience of headache and associated symptoms following resection of an acoustic neuroma: 73 percent (n = 98) of patients undergoing suboccipital resection of an acoustic neuroma and 53 percent (n = 8) of patients undergoing translabyrinthine resection of acoustic neuroma complained of headache following surgery. The average pain intensity was greater for the suboccipital approach. Only 9 percent (n = 14) reported troublesome or frequent headaches preoperatively. Headache was described most often as tension type, with episodic acute exacerbations mimicking migraine. Clinical observations suggest that most patients are treated successfully with various combinations of reassurance, tricyclic antidepressants, nonsteroidal anti-inflammatory medications, trigger-point injections, adjunctive stress management techniques (relaxation), and physical therapy. The impact of recurrent headache on work and recreational function is notable. Several possible pathophysiological and biopsychosocial models are proposed to account for the prevalent headache problem. Although spontaneous resolution usually occurs over time, additional study is needed to determine the natural history of postoperative headache once it occurs.

Contralateral suppression of transiently evoked otoacoustic emissions and neuro-otology.

Transiently evoked otoacoustic emissions can be suppressed with simultaneous contralateral sound stimulation. This is considered to be effected via the efferent pathway from the superior olivary complex (SOC) to the contralateral cochlea. This study examined this effect in patients with extrinsic and intrinsic lesions of the brainstem which may affect the efferent pathway either within the vestibular nerve which carries the efferent bundle to the cochlea or within the brainstem at the level of the SOC. Suppression is reduced or absent in these patients and the site and size of the lesion determines whether the suppression is affected unilaterally or bilaterally. Lesions affecting the auditory afferent pathway without significant alteration in hearing appear to affect the efferent pathway too.

Intensity perception. XIV. Intensity discrimination in listeners with sensorineural hearing loss.

Intensity discrimination of pulsed tones (also called level discrimination) was measured as a function of level in 13 listeners with sensorineural hearing impairment of primarily cochlear origin, one listener with a vestibular schwannoma, and six listeners with normal hearing. Measurements were also made in normal ears presented with masking noise spectrally shaped to produce audiograms similar to those of the cochlearly impaired listeners. For unilateral impairments, tests were made at the same frequency in the normal and impaired ears. For bilateral-sloping impairments, tests were made at different frequencies in the same ear. The normal listeners showed results similar to other data in the literature. The listener with a vestibular schwannoma showed greatly reduced intensity resolution, except at a few levels. For listeners with recruiting sensorineural impairments, the results are discussed according to the configuration of the impairment and are compared across configurations at equal SPL, equal SL, and equal loudness level. Listeners with increasing hearing losses at frequencies above the test frequency generally showed impaired resolution, especially at high levels, and less deviation from Weber's law than normal listeners. Listeners with decreasing hearing loss at frequencies above the test frequency showed nearly normal intensity-resolution functions. Whereas these trends are generally present, there are also large differences among individuals. Results obtained from normal listeners who were tested in the presence of masking noise indicate that elevated thresholds and reduced dynamic range account for some, but not all, of the effects of recruiting sensorineural impairment on intensity resolution.

[Simultaneous occurrence of an acoustic neurinoma and a glomus tympanicum tumor in a patient. An unusual constellation and problematic surgical task]. / Gleichzeitiges Vorkommen eines Akustikusneurinoms und eines Glomus-tympanicum-Tumors bei einem Patienten. Eine ungewöhnliche Konstellation und problematische chirurgische Aufgabe.

We present the case of a 65-year-old woman who was found to have a concurrent ipsilateral acoustic neuroma and glomus tympanicum tumor. Both tumors were removed in one operation. The acoustic neuroma was removed via the translabyrinthine approach because of preoperative deafness while the glomus tumor was found only during the operation to remove the neuroma. A preoperative biopsy was not associated with significant bleeding while microscopic examination of the biopsy tissue indicated only chronic infection.