Hearing Loss is more Strongly Associated with Protein Accumulation in the Labyrinth than with Vestibular Schwannoma Growth in Small Tumors: A Prospective Natural History Study of Neurofibromatosis Type 2

Background: Neurofibromatosis type 2 (NF2) patients with vestibular schwannomas (VS) develop sensorineural hearing loss. In a cross-sectional study of patients with NF2 we recently demonstrated that hearing impairment is strongly associated with pathologic perilymph protein accumulation, as demonstrated by abnormal FLAIR (fluid-attenuated inversion recovery) signal in the labyrinth. Predictive biomarkers of hearing loss are needed to determine the indications for and evaluate the effectiveness of various forms of hearing preservation surgery (e.g., middle fossa decompression).

Objective: To determine whether tumor growth or abnormal FLAIR signal can serve as a predictive biomarker for the development of hearing loss in patients with small VS (≤ 500 mm3) NF2.

Methods: One hundred and sixty-eight subjects were enrolled in a prospective, longitudinal study between 2008 and 2013. Subjects underwent yearly clinical, radiologic, and audiologic follow-up. Tumor growth was defined as an increase in volume of greater than 20%. Worsening of 4-frequency pure tone average (4PTA, 0.5,1,2,4 kHz) > 10 dB (dB) was considered significant new hearing loss during the study period. Hearing loss was defined as 4PTA greater than 20 dB at baseline.

Results: Fifty ears in 30 patients (mean age 28.4 years; range 8 to 68 years) harbored untreated VS ≤ 500 mm3 at study enrollment. Mean initial volume was 145.4 mm3 (range 1 to 476 mm3). Most tumors (38; 76%) were entirely intracanalicular. Nineteen ears had hearing loss at baseline. Twenty-nine ears had intralabrynthine FLAIR hyperintensity at baseline. Hearing loss at baseline was significantly correlated with total tumor volume (p = 0.006), internal auditory canal (IAC, p = 0.01) and posterior fossa (p = 0.02) component volume, and FLAIR hyperintensity (p < 0.001). However, by multivariate analysis, only FLAIR hyperintensity significantly correlated with hearing loss (p = 0.02).

Mean follow-up was 4.7 years (range 1.4 to 9.1 years). Forty-one VS grew and 22 ears experienced progressive hearing loss during the study period, while 11 ears acquired new intralabrynthine FLAIR hyperintensity. Among 49 ears with evaluable hearing, progressive hearing loss did not correlate with tumor growth, including IAC component growth. Conversely, progressive hearing loss did correlate with appearance of intralabrynthine FLAIR hyperintensity (p = 0.02). Tumor growth did not correlate with acquisition of FLAIR hyperintensity. All ears without intralabrynthine FLAIR hyperintensity retained normal hearing throughout the study.

Conclusion: Intralabyrinthine FLAIR hyperintensity, but not tumor growth, is related to hearing loss among small VS in NF2. This finding suggests a pathophysiology related to protein accumulation that may be due to either cochlear aperture obstruction or tumor-associated protein deposition. The current study is the first to define the natural history of small VS in NF2. These data provide a comparison for existing and future studies on management strategies for such patients, including middle fossa decompression and biologic therapy.