D. Bradley Welling

Recent advances in molecular biology have led to a better understanding of the etiology of many cranial base tumors. The ultimate goal of understanding tumorigenesis cellular mechanisms is to develop new treatment options that improve patient outcomes. NF2-related schwannomatosis, formerly known as neurofibromatosis type 2 (NF2), is an inherited genetic disorder associated with bilateral vestibular schwannomas (VS). This chapter discusses the structure and function of the NF2 gene, associated signaling pathways, candidate genes involved in NF2 tumorigenesis, and phenotypic-genotypic correlations. Recent advances in treatment options, including pharmacological and gene therapeutic approaches, are also discussed.

The management of NF2-related schwannomatosis (SWN) (NF2) is one of the most complex subjects in neurotology. Patients are often debilitated by both the natural history of NF2 tumors and interventions. A variety of treatment options exist, and due to the complexity of clinical decision-making and need for multidisciplinary care, referrals to centers with expertise in this condition should be considered.

Purpose The UmboMic is a recently developed middle ear microphone that functions by detecting the sound-induced motion of the umbo [1]. To prepare for a live animal study of the in vivo performance of the UmboMic, we developed the surgical implantation and fixation system in cadaveric sheep ears. Methods Temporal bones from seven female sheep were prepared for implantation of the UmboMic system. Fixation hardware for sheep was designed to secure the UmboMic sensor in position so that the sensing tip contacted the umbo in the middle-ear cavity and the non-sensing tail end was secured to the surrounding mastoid bone. First, pre-surgical micro-CT scans of the temporal bones and open-source software were used to simulate surgical drilling, and to virtually plan and fit the UmboMic fixation system. Then, in physical sheep temporal bones, sound-induced umbo motion was measured with a laser Doppler vibrometer as a preliminary step. After surgical implantation of the UmboMic system, the position of the UmboMic sensor was evaluated with microscopic visualization and post-surgical micro-CT. Implanted UmboMic sensor function in response to acoustic frequency sweeps to the external ear canal was measured in two specimens. Results Measurements of sheep temporal bone anatomical dimensions with micro-CT showed that the facial recess featured a mean maximum height of 2.36 mm, length of 12.2 mm, and depth from outer opening surface of facial recess to the umbo of 11.1 mm. The amplitude of umbo motion prior to UmboMic implantation was consistent with that previously reported by [2], with a displacement of ~ 14 nm/Pa up to a frequency of 5.5 kHz, followed by a gradual drop-off. When bench tested and implanted in sheep temporal bones, the UmboMic sensitivity was as predicted from [1], ~ 1–2 fC/nm. Conclusion When implanted in sheep cadaveric ears, UmboMic performance was similar to previous measurements in fresh human cadaveric temporal bones. The method of simulating surgical drilling using micro-CT and simple open-source software is economical and broadly applicable in understanding the 3D biological anatomy and implantable device design and customization. The UmboMic implantation in cadaveric sheep ears was possible, and this study represents a step towards planned live animal studies.

The aim of this study was to investigate the pathology of hearing loss caused by cochleo-vestibular schwannoma. Surgical specimens have demonstrated that a tumor may displace normal nerve fibers of the cochlear nerve to one side (pushing pattern) or the neoplastic cells may invade the tumor and grow between normal nerve fibers (infiltrating pattern). The goal was to study the relationship of the tumor to the remaining fibers of the cochlear nerve. Nerve fibers within all 28 tumors showed positive anti-neurofilament (NF) labeling. Axons within tumors were sometimes turned orthogonal to their original plane. Onion bulb formations were observed in tumors giving rise to early Antoni B-like regions of degeneration. Positive anti-myelin protein zero (MPZ) labeling was demonstrated. No clear capsule was found between tumor and nerve. There was a comingling of tumor and nerve fibers either with the nerve of origin or with both the nerve of origin and surrounding internal auditory canal nerves. Iba1+ macrophages were prevalent within cochleovestibular schwannomas. Our results suggest that retro cochlear mechanisms of hearing loss go beyond compression of the eighth cranial nerve, involve both myelin and axon degeneration, and suggest an inflammatory component from the earliest stage of the disease.

This systematic review of 25 years of QOL outcomes in VS patients is broad in scope and a valuable contribution to both patients and treating teams alike. The point made by the author that standardized QOL measures and validated tools could aid in tr...

Rapidly progressing bilateral hearing loss may indicate intracranial metastatic malignancy. MRI and CT imaging can provide useful information on symptom etiology, and as with this coronal CT image of the sinuses and anterior skull base revealing a right ethmoid/cribriform mass (arrow), accessible areas for timely diagnostic biopsy may be identified.

Objectives: To determine if the chronic use of bevacizumab, prior to withholding for elective surgery in the preoperative period, increases the risk of hemorrhage during vestibular schwannoma (VS) resections. Methods: Retrospective reviews of estimated intraoperative blood loss volume during surgical resection of 50 bevacizumab‐treated and 56 bevacizumab‐untreated VS from patients with NF2 ‐related schwannomatosis ( NF2 ‐SWN). Two index cases are included. Additionally, masked histopathologic examination of tissues from bevacizumab‐treated and untreated VS was evaluated. Results: The mean blood loss during VS resection was statistically increased in patients with prior bevacizumab treatment (421 mL) compared to untreated patients (285 mL) ( p = 0.015). When accounting for both tumor size and the amount of tumor resected, blood loss per percent of tumor resected was also elevated in the bevacizumab treated group (15.78 mL/%resection) when compared to the untreated group (12.97 mL/%resection) ( p = 0.024). Intraoperative hemostasis using standard techniques was difficult, and some cases resulted in early termination of the surgical procedure prior to total resection. Eighteen percent of bevacizumab‐treated patients had gross total or near total tumor resection, while untreated tumors had 52% gross total or near total resections ( p ‐value = 0.001). The length of time on bevacizumab preoperatively correlated with intraoperative blood loss ( p = 0.049). The median time patients were treated with bevacizumab prior to surgery was 23.5 months and ranged from 3 to 121 months. The median time off bevacizumab prior to surgery was 11.5 months and ranged from 0.75 to 87 months. Histopathologic examination revealed no readily apparent difference in blood vessel density, integrity, or growth patterns. Conclusions: Bevacizumab treatment prior to excision of NF2 ‐SWN VS in this retrospective case series is associated with increased intraoperative hemorrhage. Bleeding was difficult to control using standard techniques, thus warranting preoperative surgical awareness. Underlying pathologic mechanisms are not yet understood and are under further investigation. Level of Evidence: 3.