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doi: 10.1227/NEU.0b013e31828bae28
Research-Human-Clinical Studies: Editor's Choice

Conservative Management of Bilateral Vestibular Schwannomas in Neurofibromatosis Type 2 Patients: Hearing and Tumor Growth Results

Peyre, Matthieu MD*,‡; Goutagny, Stéphane MD, PhD*,‡; Bah, Alpha MD*,‡; Bernardeschi, Daniele MD‡,§; Larroque, Béatrice MD, PhD; Sterkers, Olivier MD‡,§; Kalamarides, Michel MD, PhD*,‡

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Author Information

*AP-HP, Hôpital Beaujon, Department of Neurosurgery, Clichy, France;

Université Paris 7 - Denis Diderot, Paris, France;

§AP-HP, Hôpital Beaujon, Department of ENT Surgery, Clichy, France;

AP-HP, Hôpital Beaujon, Epidemiology, Biostatistics and Clinical Research Unit, Clichy, France

Correspondence: Michel Kalamarides, MD, PhD, Department of Neurosurgery, APHP, Hopital Beaujon, 100 bvd du general Leclerc, 92110 Clichy, France. E-mail: michel.kalamarides@bjn.aphp.fr

Received July 13, 2012

Accepted January 29, 2013

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BACKGROUND: As new treatment modalities develop for the management of vestibular schwannomas (VS) in patients with neurofibromatosis type 2, it remains crucial to ascertain the natural history of the disease.

OBJECTIVE: To determine the relationship between hearing and tumor growth in patients undergoing conservative VS management.

METHODS: Patients harboring bilateral VS with at least 1 year of radiological follow-up were selected. Conservative management was proposed based on the small tumor size and/or serviceable hearing at presentation. Tumor size was calculated by using the 2-component box model and reported as mean tumor diameter. Hearing was evaluated by using pure-tone average and the American Academy of Otololaryngologists and Head and Neck Surgery classification.

RESULTS: Forty-six patients harboring 92 VS were included. The mean clinical and radiological follow-up times were 6.0 and 4.2 years, respectively. The mean tumor diameter was 13 mm at presentation and 20 mm at the end of follow-up. Mean tumor growth rate was 1.8 mm/year. During follow-up, 17 patients (37%) underwent surgery for VS. Surgery-free rate for VS was 88% at 5 years. The number of patients with at least 1 serviceable ear was 39 (85%) at presentation and 34 (74%) at the end of follow-up, including 22 (66%) with binaural serviceable hearing maintained. There was no statistical correlation between tumor growth rate and preservation of serviceable hearing. Tumor growth rates and age at presentation were inversely correlated.

CONCLUSION: This study illustrates the high variability among neurofibromatosis type 2 patients regarding hearing status and VS growth rate and justifies the choice of initial conservative management in selected cases.

ABBREVIATIONS: AAO-HNS, American Academy of Otololaryngologists and Head and Neck Surgery classification

MTD, mean tumor diameter

NF2, neurofibromatosis type 2

PTA, pure-tone average

SDS, speech discrimination score

VS, vestibular schwannomas

Neurofibromatosis type 2 (NF2) is a rare autosomal-dominant disease with an incidence of 1 case in 33 000 live births, and a prevalence of 1/56 000.1,2 NF2 is characterized by the development of multiple benign nervous system tumors, including bilateral vestibular schwannomas (VS), which are the hallmark of the disease.3,4 Patients may also develop schwannomas of other cranial and spinal nerves, meningiomas, and ependymomas. Tumors associated with NF2 are caused by the inactivation of both alleles of the NF2 tumor-suppressor gene, located on chromosome 22.5,6

Until recently, surgery was the main treatment option for VS in NF2 patients. Other therapeutic alternatives have since been evaluated, including chemotherapy7 and radiosurgery.8-10 Alternatively, initial management may remain conservative, especially for small tumors with retained serviceable hearing. The natural history of bilateral VS in NF2 has already been thoroughly described in previous studies emphasizing their highly variable growth rates.11-16 Several studies have concluded that VS growth rates tend to decrease with increasing age.11,12 In this unique series, we decided to evaluate the results of initial conservative treatment in NF2 patients presenting with bilateral VS. The results were analyzed per ear and per patient with emphasis on the hearing results in relation to the growth pattern of tumors. Such data on VS natural history are fundamental to evaluating the efficacy of actual therapeutic options, including therapeutic clinical trials.

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Patient Population

Patients harboring bilateral VS with at least 1 year of radiological follow-up were selected from our NF2 database from 1991 to 2011. The local institutional review board approved this retrospective chart review. All patients or their parents provided informed consent. Patients were excluded from the study if they underwent surgery during the first year after initial presentation (n = 33) or if radiological data were incomplete over the period of clinical management (n = 38). Patients who underwent surgery for either VS during the follow-up period were excluded from the final analysis, since resection of 1 VS could influence contralateral tumor growth.17 The initial decision to perform conservative management was made either by the surgeon, in the case of bilateral small VS or in the case of medium tumors with bilateral serviceable hearing, or by the patient when surgery was refused.

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Hearing Evaluation

Hearing was measured at presentation and throughout follow-up by pure-tone average (PTA) and speech discrimination score (SDS), defined as the percentage of words recognized at maximum comfortable loudness. PTA was calculated as an average of pure-tone thresholds by air conduction at the following 4 frequencies: 500, 1000, 2000, and 3000 Hz.18 Hearing was then classified by using the American Academy of Otololaryngologists and Head and Neck Surgery classification (AAO-HNS)18 (class A, PTA 0-30 dB and SDS >70%; class B, PTA >30 dB and <50 dB and SDS > 50%; class C, PTA >50 dB and SDS >50%; Class D, PTA at any level and SDS <50%). Classes A and B were qualified as serviceable hearing. Binaural hearing was defined as bilateral serviceable hearing (A/A, A/B, or B/B) and monaural hearing as unilateral serviceable hearing (A/C or D and B/C or D).

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Tumor Measurements

Because some initial magnetic resonance imaging (MRI) scans were only available as printed images, tumor volumes were measured manually by 1 investigator (M.P.) using the 3-diameters technique (V = D1 × D2 × D3/2) and the 2-component box model, where the intra- and extrameatal portions of the tumor are analyzed separately.13 Tumor volumes of both components were then converted into a mean tumor diameter (MTD = [2 × V]1/3), and the intra- and extrameatal MTDs were summed. Because VS growth patterns are highly variable, a linear-fit model has been suggested to estimate VS growth.13,17 To estimate the slope of the growth curve of the MTD over time for each tumor, we performed linear regressions of the MTD of each patient over time, using the MTD at presentation and at last follow-up. Tumor growth rate was calculated by using the following formula: (final volume − initial volume)/follow-up interval.

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Mutation Analysis

Detection of NF2 gene mutation was performed by direct sequencing (BigDye Terminator chemistry on ABI3110XL, Applied Biosystems) and gene dosage (MultiplexLigation-dependent Probe Amplification, MRC Holland) of the 17 NF2 coding exons.

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Statistical Analysis

The median duration of follow-up without deterioration of hearing or without surgery was calculated by using the Kaplan-Meier technique. The covariates studied included sex, age at diagnosis of NF2, global tumor burden (including the number of intracranial meningiomas, intracranial schwannomas, and spinal tumors), and type of constitutional NF2 mutation. The 2-tailed Fisher exact test, Pearson correlation coefficient, and linear regression were used for tests of association. The Mann-Whitney U test was used to test between-group differences in growing parameters. Probability values lower than .05 (P < .05) were considered to be statistically significant.

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Patient Characteristics

Nineteen (41%) of the 46 patients were female. The mean age at diagnosis of NF2 was 25.5 years (median, 19.6 years; range, 7-94 years). The mean length of clinical follow-up was 6.0 years (median, 4.9 years; range, 1.2-17.6 years), and the mean length of radiological follow-up was 4.2 years (median, 3.7 years; range, 1.2-11.6 years). At the end of the study, conservative treatment was continued for 24 patients (52%), whereas 17 (37%) patients underwent surgery during the course of the study. Among the 17 patients who underwent surgery for a growing VS, 7 had a second surgery for the contralateral tumor following our study period. Conservative management was stopped in 1 patient to introduce chemotherapy because of tumor growth with deteriorating hearing in the only hearing ear. Two patients were lost to follow-up, and 2 patients died before any VS treatment. The rate of surgery-free VS survival was 74% for the entire series (68/92). The actuarial rate of surgery-free survival was 81% at 5 years (Figure 1A). Actuarial rates of surgery-free VS were 100%, 93%, and 88% at 1, 2, and 5 years, respectively (Figure 1B).

Figure 1
Figure 1
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Intracranial meningiomas were found in 60% (55/92) of patients, other intracranial schwannomas were found in 50% (46/92) of patients, and spinal ependymomas were found in 10% (9/92). The global tumor burden varied between 2 and 40 tumors (mean, 7 tumors; median, 6 tumors). The VS growth rates did not correlate significantly with either the number of intracranial meningiomas, schwannomas, or spinal ependymomas, or with total tumor burden.

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VS Growth

At presentation, 56% of VS were intracanalicular (52/92). The mean MTD at presentation was 17 mm (median, 16 mm; range, 1-50 mm). Among the 92 VS, 6% (6/92) exhibited shrinkage, 8% (7/92) were stable, with no growth over the course of the study, and 86% (79/92) grew. Among those 79 growing tumors, 31% had a growth rate of less than 1 mm/year, 44% grew between 1 and 3 mm/year, and 25% grew greater than 3 mm/year (Figure 2). The overall mean VS growth rate was 1.8 mm/year (median, 1.4 mm/year; range, 0-8 mm/year). Among the 79 growing tumors, the mean VS growth rate was 2.1 mm/year (median, 1.6 mm/year). There was an inverse correlation between age at diagnosis and tumor growth rate following a logarithmic fit (r2 = 0.32) (Figure 3B). In support of this finding, our data demonstrated that tumor growth rate was statistically higher in patients younger than 20 years at diagnosis of NF2 in comparison with those diagnosed at 20 years or older (2.6 mm/year vs 0.9 mm/year, Mann-Whitney U test, P < .001). There was a statistical correlation between left-sided and right-sided VS growth rates, but with a weak r2 (r2 = 0.33, P < .001) (Figure 3A). There was no correlation between initial MTD (ie, size) and tumor growth rate (r2 = 0.002, P = .64).

Figure 2
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Figure 3
Figure 3
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Mutation analysis was performed in 37 of the 46 patients (80.4%), and a constitutional NF2 mutation was identified in 20 of the 37 patients (54%). Seventeen truncating mutations were identified, and the growth rate of VS in corresponding patients was not different from that of patients with nontruncating mutations (t test, P > .05).

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Hearing Results

In this unique series, we were able to evaluate the hearing outcome for each patient and each individual VS. At presentation, 85% of patients (39/46) had serviceable hearing with at least 1 serviceable ear, and 72% (33/46) had binaural serviceable hearing, whereas 13% (6/46) had monaural serviceable hearing, and 15% (7/46) had unserviceable hearing. At the end of the study, 74% of the patients (34/46) still had serviceable hearing, and 66% of those with initial binaural serviceable hearing (22/33) had retained binaural serviceable hearing, whereas 26% (12/46) had monaural serviceable hearing and 26% (12/46) had unserviceable hearing. Despite a high rate of serviceable hearing preservation at the end of follow-up (74%), only 66% of evaluable patients (22/33) preserved binaural serviceable hearing. The PTA data for the whole cohort are presented in Table 1.

Table 1
Table 1
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To determine the factors influencing hearing outcome, we considered each ear independently. We observed no correlation between the decline in hearing (ie, increase in PTA) over time and the age at diagnosis (r2 = 0.01; P = .47). According to the AAO-HNS classification at initial evaluation, 71% of ears (65/92) were class A, 8% (7/92) class B, 4% (4/92) class C, and 17% (16/92) class D. At the end of follow-up, 49% (45 ears) were classified as class A, 12% (11 ears) as class B, 12% as class C, and 27% (25 ears) as class D (Figure 4A). Among the 92 VS, 20 VS (22%) presented with initial unserviceable hearing. Tumor growth rates were similar between the 20 VS with unserviceable hearing at presentation and the 72 VS with initial serviceable hearing (1.7 ± 0.05 mm/year vs 1.8 ± 0.02 mm/year, P = .32), but initial MTD was statistically larger in VS with unserviceable hearing at presentation (19 mm vs 11 mm; P = .003). Among the 72 VS with initial serviceable hearing, 58 ears remained serviceable, and 14 became unserviceable (Figure 4B). The tumor growth rate was not statistically different in patients who sustained serviceable hearing compared with patients who lost serviceable hearing (1.7 ± 0.02 mm/year vs 2.2 ± 0.03 mm/year, P = .09). Also, initial MTDs were not statistically different between those 2 groups (P = .19). Although their initial MTDs were not different, tumor growth rate tended to be lower in patients who kept serviceable hearing compared with patients whose hearing became unserviceable (1.7 ± 0.02 mm/year vs 2.2 ± 0.03 mm/year, P = .09). Consequently, the tumor growth rates of bilateral VS in NF2 are unpredictable based on initial MTDs and hearing.

Figure 4
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Functional Outcome of Conservative Management

Of the 39 patients and corresponding 72 VS with serviceable hearing at presentation, the actuarial rates of hearing preservation during the course of the study are depicted in Figure 5. Two patients presented with impaired facial function at diagnosis (2 had House-Brackmann grade IV facial palsy), and 2 patients developed a facial palsy during conservative management (2 developed grade IV facial palsy) without clear evidence of associated VIIth nerve schwannoma.

Figure 5
Figure 5
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In this study, we offer the first comprehensive evaluation of hearing outcome in relation to tumor growth parameters following conservative management of bilateral VS in NF2 patients. The study was restricted to the conservative management period of follow-up, and subjects were excluded from further analysis at first VS surgery because surgery of VS could influence the growth of the contralateral tumor.17,19 The results of the present study tend to agree in several respects with those of previously published works on natural history of unilateral (after resection of the first VS) and bilateral VS in NF2.11-14 VS growth rates were found to be highly variable but tended to decrease with increasing patient age, in a logarithmic rather than a linear fashion, thus reflecting clinical observations of a more active NF2 disease in young patients. The mean VS growth rate reported here (1.8 mm/year) was lower than in previously reported studies on NF2-related VS (Harris,15a 10 mm/year, Dirks et al,15b 8.4 mm/year). As in previous studies, the growth rates of left- and right-sided VS from the same patient were correlated, although the r2 value tended to be lower than in previously published series. We believe that this small correlation does not validate the use of contralateral VS as internal controls for studies of unilateral radiosurgery effects on tumor growth, as previously done.20 In a recent study by Dirks et al15b on long-term follow-up of VS in NF2 patients, the authors suggest that all VS grow over time. In our study, we found that 14% (13/92) displayed shrinkage or no growth but with a shorter follow-up in the current study (4.2 vs 9.5 years). Similarly, others have shown that VS may spontaneously decrease in size over time.19 As Dirks et al15b demonstrate, the existence of saltatory growth patterns for 46.7% of VS, they suggest that previous studies may have incorrectly classified tumors as nongrowing while they were actually quiescent over the course of the study. However, this observation relies on a small number of tumors (18 tumors in 12 patients), a nonvolumetric analysis of growth, and a subset of patients with a high tumor burden (11 tumors per patient). A definitive investigation of growth rates and saltatory growth patterns would require a large, long-term prospective natural history study based on 3-D volumetric MRI.

To our knowledge, our study is the first to report comprehensive hearing results per ear and per patient by using both PTA and speech discrimination score over a mean 4-year period of follow-up. A previous work by Fisher et al21 focused on 1-year evaluations and used only PTA evaluation of hearing. The authors concluded that a significant worsening in hearing occurred over a 1-year period without significant statistical association with concomitant tumor growth. Here, we observe a high rate of serviceable hearing preservation at the end of follow-up (74%) but with only 66% of patients (22/33) conserving binaural serviceable hearing. We confirm that hearing progression in NF2 patients with bilateral VS is not statistically correlated with tumor growth rate. However, this result only applies to a subset of small NF2-related VS tumors undergoing observation in this study. Because the mean MTD was statistically higher in tumors with unserviceable hearing at presentation, and considering that our study only focuses on a subset of patients, the relationship between tumor size/growth and hearing remains to be fully elucidated in future investigations. Therefore, based on this series, we suspect that therapeutic trials focused on VS volume as a primary end point will not be able to evaluate a potential effect on improvement of hearing. An ongoing trial (bevacizumab for symptomatic VS in NF2: NCT01207687) includes patients with progressive hearing loss with hearing response as primary outcome measures and radiological response as a secondary measure. In contrast, 2 active trials with everolimus (NCT01490476 and NCT01419639) are evaluating whether the drug has an effect on the VS growth as a primary objective and assess the effect on hearing function as a secondary objective, when applicable. However, the number of subjects may be inadequate to draw statistical conclusions on hearing effects, particularly if hearing and tumor responses do not correlate.

Most importantly, our study exemplifies what should be the cornerstone of investigating VS natural history in NF2 and should serve as a baseline for future studies on the effectiveness of nonablative treatments such as radiosurgery.8-10 We demonstrate here that conservative management alone may achieve a higher rate of serviceable hearing preservation than reported in most published radiosurgery series. We advocate that radiosurgery should not be compared with microsurgery but, rather, with conservative management and chemotherapy whose goal is more functional than oncologic. The management strategies are, in fact, not strictly comparable, because most radiosurgical series contain patients with previous microsurgical treatment, which may influence tumor growth rate17 and, therefore, tumor control rate. Thus, patients with and without previous microsurgical excision should be analyzed separately. Finally, radiological stability should be defined as a stable or decreased growth rate after radiosurgery, and future works should include linear regressions of pre- and postradiosurgical treatment VS growth rates to allow a more refined evaluation of its effect (Table 2). This study might also serve as a guideline to evaluate and report the results of early proactive management of bilateral VS in NF2, which applies to small tumors with serviceable preoperative hearing. In a series published by Brackmann et al22 on early proactive management of such tumors, 72.5% of patients presented with a tumor size of less than 1 cm and 92.5% had a preoperative AAO-HNS class A or B hearing.

Table 2
Table 2
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The results presented in this retrospective study are informative for clinical management of NF2, but it should be kept in mind that patients with a more aggressive NF2 phenotype (ie, Wishart) would have been excluded because of the need for surgery less than 1 year after initial diagnosis. This might introduce a source of bias toward the less aggressive NF2 phenotype (ie, Gardner) in this study, but it is largely counterbalanced by the number of patients included.

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This study offers a clear and comprehensive analysis on the results of conservative management of bilateral VS in NF2 patients and demonstrates that conservative management should remain a viable option at presentation in selected cases. Although performed in a selected group of patients, this investigation adds additional information regarding the natural history of VS in NF2 patients and confirms previously published data: (1) VS growth rates in NF2 patients are unpredictable; (2) 1 tumor in a single patient cannot be used as a control against the other; (3) growth rates and hearing outcome do not correlate; and (4) the significant majority of patients retain serviceable hearing; therefore, conservative management may be considered a favorable option for many patients. This study could serve as a baseline for future studies on the efficacy of nonablative treatments such as radiosurgery and chemotherapy. It confirms the great variations in tumor growth and hearing outcomes among tumors and the need for refined classifications of patient groups.

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The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.

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We would like to thank Dr Joni K. Doherty, MD, PhD, for editorial assistance.

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The authors describe the natural history of NF2-associated acoustic neuromas with approximately 5-year average follow-up in terms of tumor growth rate and hearing preservation. Forty-six patients are included. This is a substantially longer follow-up than previous reports (in the otologic literature), which had looked at change between 2 MRIs up to 2 years apart. As such, this is important information that will prove especially invaluable as perhaps the best baseline against which any new interventions will be measured. The authors do, however, note 1 major limitation to the data. That is, that this is a select group of patients from which those with more severe forms of the disease have been excluded. This is not the group of NF2 patients as a whole, for whom the phenotype of the disease can be much more aggressive. I would point out 1 other major limitation that is inherent to this article and, indeed, to any article4 discussing a life-long disease process. Five years, or so, is quite a long follow-up for any neurosurgical manuscript brought to review. I would posit, however, that it is not very long when a disease process such as NF2 is considered. The authors demonstrate that, within this (sub)group of patients, most patients preserve some degree of hearing and most tumors grow slowly. Most patients can avoid intervention, at least initially. In reality, the horizon for most of these patients, at least those with more mild forms of NF2, is much longer, perhaps decades. If a very conservative posture is adopted, with tumors growing slowly and hearing worsening gradually all along, we are faced with the potential for many patients to face eventual treatment with little or no hope of a good facial nerve or hearing outcome. My experience has been that dealing with a patient who regrets not having acted earlier is often more upsetting than not achieving the hoped-for results when intervention is more proactive. Of course, if we do see the development of a nonablative treatment that holds tumors at bay indefinitely with little or no toxicity, then any wait will be worth it.

Marc S. Schwartz

Los Angeles, California

I read with great interest, this article, Conservative Management of Bilateral Vestibular Schwannomas in Neurofibromatosis Type 2 Patients: Hearing and Tumor Growth Results. Without question, it is critically important to consider the natural history of vestibular schwannomas (VS) in NF2 both in regard to growth and hearing function when contemplating an intervention. The authors followed 46 patients with 92 VS for a mean of 6.0 years clinically and radiographically for a mean of 4.2 years. The mean tumor diameter at presentation was 17 mm. The authors consider surgery the main treatment option for these patients. This cohort of patients reveals several important points worth emphasizing. First of all, there is certainly a spectrum of disease presentation in NF2, with some patients having only bilateral VS, and others presenting with almost innumerable intracranial and intraspinal schwannomas, meningiomas, and ependymomas. The authors controlled for this and found that the VS growth rate was the same regardless of the overall background tumor burden, indicating that the number of tumors may not predict the aggressiveness of disease. In this group of 92 tumors, 79 showed growth during the observation period with a mean growth rate of 2.1 mm/year, not very different from the 1.9 mm/year and 1.2 mm/year rate shown in the sporadic VS population by 2 large meta-analysis articles including more than 1300 patients published in 2005.1,2 The authors did find an inverse relationship between age at diagnosis and tumor growth rate, with younger patients having more tumor growth. It is hard to explain why left-sided tumors would grow more than right-sided tumors. Surprisingly, patients in this series with a truncating mutation in the gene responsible for NF2 did not have more aggressive disease, which is contrary to what most other centers have found.3 Presenting tumor size was not associated with future growth, which is also somewhat surprising. The most important finding in this article, I feel, is that 74% of untreated patients still had serviceable hearing at a mean clinical follow-up of 6 years. Tumor growth rate was no different in the group that kept hearing compared with the group that lost class A or B hearing. This analysis lends support and reinforces our feelings about the management of VS in NF2 patients. First, it is extremely rare that treatment for VS has to be undertaken after first meeting a patient with NF2. There is almost always time to follow these patients to obtain a sense of their tumor growth patterns and subsequent clinical course. Second, these patients need both clinical (audiometric) and radiographic follow-up at regular intervals. We typically see them with MR imaging and audiology every 6 months for the first year and then yearly thereafter if everything remains stable. One cannot rely on the hearing getting worse alone, for instance, as a marker for a growing tumor, as this article so well demonstrates. Finally, the decision making for intervention always centers on preserving or rehabilitating neurological function, including hearing. Auditory brainstem implants have been the mainstay for hearing rehabilitation in NF2 patients, but cochlear implants can also be very effective in restoring useful hearing following microsurgery if the cochlear nerve is preserved, following stereotactic radiosurgery, or even when hearing is lost but there is no growth seen in the VS over a long period of time and a continued wait and rescan policy is used.4,5

Michael J. Link

Rochester, Minnesota

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1. What percentage of vestibular schwannomas will grow in known NF2 patients in 5 years?

a. 30-45%

b. 45-60%

c. 60-75%

d. 75-90%

2. Merlin, is the protein believed to be absent in NF2. What is the primary oncogenetic function of Merlin?

a. Growth factor

b. Tumor suppressor

c. Cell cycle control

d. None of the above

3. What are the factors that can affect vestibular schwannoma tumor growth rate in NF2 patients?

a. Gender

b. Age at diagnosis

c. Initial main tumor diameter

d. Truncating mutation


Intracranial tumor; Natural history; Neurofibromatosis type 2; Tumor growth; Vestibular schwannoma

Copyright © by the Congress of Neurological Surgeons


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