Cervical vestibular-evoked myogenic potential in vestibular schwannoma after gamma-knife surgery

Auris Nasus Larynx 42 (2015) 265–270

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Cervical vestibular-evoked myogenic potential in vestibular schwannoma after gamma-knife surgery Yi-Fang Lee a,d, Cheng-Chia Lee b,d, Mao-Che Wang a,d, Kang-Du Liu b,d, Hsiu-Mei Wu c,d, Wan-Yuo Guo c,d, An-Suey Shiao a,d, David Hung-Chi Pan b,d, Wen-Yuh Chung b,d, Sanford P.C. Hsu b,d,* a

Department of Otolaryngology, Taipei Veterans General Hospital, Taiwan Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taiwan c Department of Radiology, Taipei Veterans General Hospital, Taiwan d School of Medicine, National Yang-Ming University, Taipei, Taiwan b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 23 November 2014 Accepted 14 January 2015 Available online 7 February 2015

Objective: Gamma-knife radiosurgery (GKS) for vestibular schwannomas (VSs) has become popular during the last two decades, and a promising tumor control rate has been reported. Therefore, the evaluation and preservation of auditory-vestibular nerve function after GKS have become more and more important in these patients with long-term survival. We have traditionally used pure-tone audiometry (PTA) for evaluation of auditory nerve function, and the caloric test for superior vestibular nerve function. Vestibular-evoked myogenic potential (VEMP) has recently emerged from various neurophysiological examinations for assessment of the integrity of the inferior vestibular nerve function. This novel tool has been established to represent a sacculo-collic reflex. By using these three tools, the auditory-vestibular nerve function of VS patients can be evaluated and monitored before and after GKS. Methods: Fourteen patients with unilateral VS that underwent GKS were prospectively recruited. All of them received a battery of auditory-vestibular function tests including PTA, caloric, and cVEMP tests before and after GKS at each time point (1, 6, and 12 months). Our data also included the tumor volumes and their relationship with the PTA, caloric, and cVEMP test results. Results: The PTA, caloric, and cVEMP tests showed abnormal results before GKS in 85.7%, 78.6% and 78.6% of our VS patients, respectively. The PTA, caloric, and cVEMP results did not show strong correlations between each other. However, there was a tendency that when the tumor grew larger, the auditoryvestibular function deficits became more severe. The PTA and cVEMP test results remained stable during the 1-year follow-up after GKS. However, the caloric test showed transient deterioration at the 6th month follow-up, which then recovered by the 1-year follow-up. Conclusion: The combination of these three tests can help us diagnose VS and assess the change in auditory-vestibular nerve function during the post-GKS follow-up period. The results of these three tests were independent for smaller tumors, but all tests may show abnormal findings with larger tumors. Although the study is still ongoing, the preliminary data showed that GKS treatment would not affect the auditory-vestibular nerve function within a 1-year follow-up period. ß 2015 Elsevier Ireland Ltd. All rights reserved.

Keywords: Vestibular schwannoma Gamma-knife Radiosurgery Vestibular evoked myogenic potential Caloric test

1. Introduction Vestibular schwannomas (VSs) are histologically benign, slowgrowing tumors that arise from the eighth cranial nerve

* Corresponding author at: Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, 17F, No. 201, Shipai Road, Sec. 2, Beitou, Taipei 11217, Taiwan, ROC. Tel.: +886 2 28757718; fax: +886 2 28757702. E-mail address: [email protected] (Sanford P.C. Hsu). http://dx.doi.org/10.1016/j.anl.2015.01.004 0385-8146/ß 2015 Elsevier Ireland Ltd. All rights reserved.

complexes. Because of the greater awareness of VS, increasing availability of high-resolution neuroimaging, and improvement of electrophysiological techniques, there is an increasing incidence of VS diagnosed at the early stage. Although there is an ongoing debate about the ideal management of VS, stereotactic radiosurgical treatment has become more and more popular during the last two decades, and promising results have been reported [1–5]. In our series published in 2005 [5], the long-term (average 31 months) tumor control rate was 96.8%. Sixty percent of patients (n = 12/20) retained serviceable hearing. Only 1% of

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patients (n = 2/195) experienced temporary facial palsy, and 1% (n = 2/195) developed a new trigeminal neuralgia. There was no treatment-related death. However, we had no ideal tool for monitoring vestibular nerve function, while these patients often had minor complaints like tinnitus, dizziness, or vertigo during long-term follow-up. Vestibular-evoked myogenic potential (VEMP) represents a relatively novel tool for investigation and diagnosis of many common central and vestibular disorders [6– 9]. Numerous experimental animal models [10–12] and clinical studies [13–16] have suggested that cervical VEMP (cVEMP) represents a vestibulo-collic reflex, with the afferent branch originating from the acoustic cells of the saccule and conducting signals through the inferior vestibular nerve. In this study, we report our preliminary data using the cVEMP along with conventional audiometry and the caloric test to evaluate the effect of GKS on the auditory-vestibular nerve function in VS patients. 2. Patients and methods 2.1. Patient population Fourteen patients with unilateral VS who underwent GKS between May 2008 and April 2010 were prospectively enrolled. Before GKS, all of the patients underwent a detailed history-taking, physical examination, neurological examination, otoscopic examination, brain MRI study, and a battery of tests including PTA, the caloric test with video-nystagmography (VNG) recordings, and the cVEMP test. Patients with neurofibromatosis were excluded from the present analysis. There were eight female and six male patients. The median age was 49 years (range 27–70 years). The median tumor volume was 3.1 mL (range 0.2–10.9 mL) as outlined (Table 1). Radiosurgery was performed using the Leksell Gamma Unit C (Elekta Instrument, Inc.). The dose planning of a representative case is shown in Fig. 1. The median marginal dose was 12.5 Gy (range 12–13 Gy) and the median maximum dose was 21.9 Gy (range 19– 24 Gy). The median mean tumor dose was 17.3 Gy (range 16–19 Gy). None of the identifiable portions of the facial nerve received more than 13 Gy and none of the trigeminal nerve received more than 15 Gy. The margin dose was lowered to 11 Gy in one patient whose tumor bulged into the brainstem. The mean number of isocenters was 11 (range 2–19 isocenters). 2.2. Pure-tone audiogram The hearing thresholds at the frequency of 250 through 8000 Hz were measured by an audiometer (GSI 61 Two Channel Clinical Table 1 Characteristics of 14 patients with unilateral VS treated with GKS. Parameter

Values

Median age in years (range) Female/male (case no.) Tumor location (right/left, case no.) Median tumor volume in mL (range) Pre-GKS status Symptoms (%) (case no.) Hearing impairment Tinnitus Dizziness Assessment of auditory-vestibular function (%) (case no.) Abnormala PTA Abnormal caloric test Abnormal cVEMP test

49 (27–70) 8/6 6/8 3.1 (0.2–10.9)

85.7% (12) 64.3% (9) 64.3% (9) 85.7% (12) 78.6% (11) 78.6% (11)

a The abnormal results of different auditory-vestibular functional examinations were defined as: PTA: >30 dB loss in any frequency hearing; Caloric test: asymmetric caloric response with canal paresis >25%; cVEMP asymmetry ratio (Var) = 100*[(Au Aa)/(Aa + Au)] > 0.25.

Fig. 1. Illustration of dose planning in VS: combination of multiple collimators to construct a best-fit curve.

Audiometer, USA). We defined an abnormal PTA finding as a mean hearing threshold >30 dB at 500, 1 k, 2 kHz test frequencies. Audiographic configurations were classified into six groups based on the modified Sheehy’s classification [17]. Low-frequency loss meant that hearing loss was worse in the low frequencies (250 and 500 Hz) than in the middle (1 and 2 kHz) and high frequencies (4 and 8 kHz), and presented as a rising curve. Mid-frequency loss was defined as hearing loss that was worse in the middle frequencies than in the high and low frequencies, and presented as a U-shaped curve. High-frequency loss meant that hearing loss was worse in the high frequencies than in the middle and low frequencies, and presented as a sloping curve. Global frequency loss indicated hearing loss in all frequencies, and presented as a flat configuration. Total deafness referred to scale out in all frequencies. 2.3. Caloric test The bithermal caloric test was performed with a VNG recorder (ICS CHARTR Air Caloric Stimulator NCA-200, Schaumburg, IL, 60173, USA). We used 24.1 8C cold air blown into each patient’s ear canal for 60 s with a constant flow of 8 L/min (left side first followed by the right side); then used 50.1 8C hot air, repeating the same procedures mentioned above. Canal paresis was defined as a >25% difference between maximum slow-phase velocity measurements for each ear, compared with the sum of the slow-phase velocities from each ear. If cold or hot air failed to elicit a caloric response, the subject underwent the above procedures again to confirm the caloric areflexia. 2.4. Acquisitions of cVEMP The subjects were placed in a supine position with head elevation. Electromyographic activity of the sternocleidomastoid muscles (SCMs) was recorded using surface electrodes from the upper half of the ipsilateral sternocleidomastoid muscle with the reference electrodes on the lateral ends of the upper sternum and the ground electrodes on the forehead. The sound stimuli (500 Hz short tone burst, 95 dBnHL, 1 ms rise/fall, 1 ms plateau) were conducted to the ears monaurally at 5 Hz with an insertion-type earphone. The electromyographic signals were amplified (gain = / 5000) and collected with a bandpass filter (30–2000 Hz) by a digital system (model Navigator Pro Loader Ver. 3.00, Bio-Logic System Corp., Mundelein, IL, USA). The analysis time was 53.3 ms. Responses of 64 stimuli were averaged for one trial, and two trials were acquired for one complete test. The cVEMP asymmetry ratio (Var) was calculated as 100*[(Au Aa)/(Aa + Au)] (Au represented the amplitude of p13–n23 on the unaffected side, and Aa represented the p13–n23 amplitude on the affected side). The Var was expressed in percentages. The Var of the healthy controls was 15  10% (mean  SD) at our laboratory. Abnormality in Var was

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Fig. 2. cVEMP study of a patient with right VS. (a) Left panel: normal left ear. (b) Right panel: abnormal right ear showed low amplitude and prolonged latency.

Fig. 3. Correlation between three auditory-vestibular functional tests.

defined as a >25% difference between the affected side and the unaffected side (Fig. 2). 2.5. Follow-up protocol After GKS, all patients underwent MR imaging studies at 6month intervals. Estimation of each tumor volume was established by MR calculation. Our method was to measure the tumor’s area on every slice. The sum of the areas was multiplied by the thickness of the MR image (3 mm) thus rendering the total tumor volume [5,12]. The clinical assessments, including neurological evaluation and auditory-vestibular function tests (PTA, caloric test, and cVEMP), were conducted periodically at the 1st, 6th, and 12th month, and then every year after GKS. 2.6. Statistical analysis Frequency distributions and summary statistics were calculated for all variables. The definitions of abnormal findings on different auditory-vestibular functional examinations are described in Table 1. Correlations between each two of the test groups were calculated by Spearman correlation test. The results of PTA, caloric, and cVEMP tests before and after GKS were compared by paired T-test. A p-value less than 0.05 indicated statistical significance. The software used for statistical analysis was SPSS for Windows Release 17.0.1 (SPSS Inc., Chicago, IL, USA). 3. Results The pre-treatment auditory-vestibular symptoms of our 14 patients with unilateral VS consisted of hearing loss in 12 patients (85.7%), tinnitus in 9 (64.3%), and dizziness in

9 (64.3%) (Table 1). The percentages of abnormal findings on different audio-vestibular examinations varied and are listed in Table 1. Among these patients, 12 patients (85.7%) had abnormal PTA, 11 (78.6%) had abnormal caloric response, and 11 (78.6%) had abnormal cVEMP response (Table 1). The relationship between the PTA, caloric, and cVEMP test results was analyzed (as Fig. 3). Except the positive correlation between PTA and cVEMP studies, there was no significant correlation between them. We summarized the correlations between tumor volume and auditory-vestibular functional parameters as follows. First, we found that the PTA configuration consisted of normal hearing in 2 patients (14.3%), low-frequency loss (rising type) in 0 (0%), midfrequency loss (U-shaped) in 1 (7.1%), high-frequency loss (sloping type) in 8 (57.1%), and global frequency loss (flat type) in 3 (21.4%). The most common presentation of the VS patients was highfrequency hearing loss. Besides, there was a trend toward a correlation between tumor volume and severity of hearing loss, but there was no statistical significance (Table 2.1). Table 2.1 PTA correlated with tumor volume. Audiographic configurationa

n

Mean tumor volume (mL)*

Normal hearing (normal type) Low-frequency loss (rising type) Mid-frequency loss (U-shaped) High-frequency loss (sloping type) Global frequency loss (flat type) Total deafness

2 0 1 8 3 0

2.3 – 1.6 3.1 4.4 –

a

Based on the modified Sheehy’s classification. No statistical significance between normal hearing and global frequency loss group with regard to tumor size (p > 0.05). *

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268 Table 2.2 Caloric test and cVEMP correlated to tumor volume.

Table 3 Pre- and post-GKS changes in PTA, caloric test, and cVEMP.

Caloric test

cVEMP

N

Mean tumor volume (mL)*

Normal Normal Abnormal Abnormal

Normal Abnormal Normal Abnormal

1 1 1 11

1.2 0.8 2.2 2.8

*

Statistical significance between both normal and both abnormal test results group with regard to tumor size (p < 0.05).

Second, in order to analyze the relationship between tumor size and vestibular function, we further divided our patients into four groups, based on the caloric and cVEMP test results. The patient with normal responses in both tests had a tumor size of 1.2 cc, while those patients with abnormal results in both tests had a mean tumor size of 2.8 cc. The correlation between tumor size and the severity of vestibular dysfunction was statistically significant (p-value <0.05) (Table 2.2). The comparison of the PTA, caloric, and cVEMP test results between the pre-GKS and post-GKS period was also analyzed. At the first month after GKS, there were no significant differences between pre- and post-GKS status in the PTA, caloric, and cVEMP studies. At 6 months after GKS, however, the caloric test showed results that were worse than the pre-GKS status, but the other two tests still showed no significant difference compared with the pre-GKS status. Finally, at 1 year after GKS, there was no significant change in any of the three tests (Table 3). Fig. 4 shows the changes in these functional tests and tumor volumes of all patients after GKS. 4. Discussion The PTA and caloric test have been used for a long time to evaluate the cochleo-vestibular deficits associated with VS. The PTA test and the caloric response mainly reflect functions of the cochlear nerve and the superior vestibular nerve, respectively Cervical VEMP, however, is now established to represent the sacculo-collic reflex and has been used for assessment of the

Pre/post-GKS PTA Paired difference meana Difference SDb Significancec Caloric test Paired difference mean Difference SD Significance cVEMP Paired difference mean Difference SD Significance

1 month

6 months

12 months

0.9 6.3 0.618

7.9 17.9 0.124

7.3 13.8 0.070

2.6 23.3 0.679

22.1 31.7 0.022

15.9 36.9 0.132

13.5 40.5 0.235

4.9 37.0 0.628

8.1 20.1 0.158

a Paired difference mean: the mean difference of PTA, caloric, and cVEMP test results between pre-GKS and post-GKS status (at 1, 6, and 12 months, separately). b Difference SD: the standard deviation of paired difference. c Significance of PTA, caloric and cVEMP test results between pre-GKS and postGKS status at 1, 6, and 12 months (statistical significance was defined as p < 0.05).

integrity of the inferior vestibular nerve [6,7,16,18,19]. It is a technique based on the residual acoustic sensitivity of the sacculus, which during the course of its evolution functioned as a hearing organ. It is frequently used for assessment of dizzy patients with various central or peripheral vestibular disorders [6], and provides electrophysiological evidence about the competence of the vestibular-collic pathway. Although cVEMP is an oligosynaptic reflex, involving the saccular macula, inferior vestibular nerve, lateral vestibular nucleus, medial vestibulospinal tract, accessory nucleus, and motor neurons of the sternocleidomastoid muscles, it is suitable for evaluation of the neurophysiological presentation of patients with a cerebellopontine angle tumor, especially VS. By combining these three neurophysiological tests (PTA, caloric test, and cVEMP), the overall auditory-vestibular function will be clearer. In the present study, the abnormal rates of our patients on the PTA, caloric test, and cVEMP study (Var) were 85.7%, 78.6%, and 78.6%, respectively (Table 1). Without a doubt, the PTA is the most appropriate and convenient tool for evaluation of hearing loss associated with VS. Although there was no significant correlation between tumor

Fig. 4. Comparison of pre- and post-GKS changes in PTA, caloric test, and cVEMP study results, and tumor volume.

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size and hearing level at each frequency, there seemed to be a trend toward larger tumors causing more severe hearing dysfunction (Table 2.1). Since mid- and high-frequency nerve fibers lie on the outer surface, and low-frequency nerve fibers are found at the central core of the cochlear nerve [22], the compression neuropathy or nerve conduction block of the cochlear nerve leads to mid- or high-frequency hearing loss. In addition, the positive correlation between the PTA and cVEMP in the current study (Fig. 3) reflects the closer anatomical relationship between the cochlear nerve and inferior vestibular nerve in a cross-section of the human internal auditory canal [23,24]. Therefore, VSs originating from the inferior vestibular nerve tend to be deeper and affect cochlear function more easily [25]. In vestibular functional studies, the caloric test was used to evaluate the vestibulo-ocular reflex [18,26], which travels through the upper brainstem, while the cVEMP study helped to evaluate the vestibulo-collic reflex, which travels via the lower brainstem. VS patients may have either abnormal caloric or cVEMP findings based on the tumor size, origin and extension. That is, if the tumor originates from the inferior vestibular nerve and interrupts the descending pathway from the brainstem to the lower cranial nerves (IX, X, XI), it may show abnormal findings on the cVEMP study only. On the other hand, if the VS originates from the superior vestibular nerve (SVN) and extends into the upper brainstem, the sacculo-collic reflex may be spared and lead to a normal cVEMP finding. When the VS grows too large or has wide extension (to both the upper and lower brainstem), both reflex pathways may be affected and show abnormalities on caloric and cVEMP testing [27]. For example, we found one of our patients suffering from persistent dizziness had normal caloric test but abnormal cVEMP response (Table 2.2). This finding supports the role of the cVEMP study as an adjuvant neurophysiological test for evaluation of audio-vestibular function and should be used in combination with the PTA and caloric test [20,21]. Instead of the traditional caloric test, oVEMP is another novel tool for evaluation of SVN function [28,29]. Like the caloric test evaluates the rotational vestibulo-ocular reflex, the oVEMP test assesses the translational vestibulo-ocular reflex. Both tests travel along the SVN to the extraocular muscles and have been proved to be significantly correlated with each other for cases with VS. However, the caloric test is still the gold standard method for evaluation of vestibular function. In addition, abnormal caloric responses were proved to be correlated with tumor size already [21,26]. Based on the above findings in literature review, we chose to do one test only (caloric test) due to time cost and for better compliance of the patients during follow-up period. From the perspective of anatomy, VS may selectively influence cochlear, superior or inferior vestibular nerve functions, depending on the size and origin of the tumor [16,26,30–32]. Dysfunction of the vestibular nerve due to VS could be caused by either compression of the functioning nerve, or impairment of the blood supply to the nerve, as mentioned before [18]. The schwannoma, as a myelin sheath tumor, would not impair the function of the nerves that it covered until it was large enough to cause a mass effect. Therefore, there is the possibility of discord between the nerves of origin and their function in each scenario, which may weaken the role of cVEMP in the diagnosis of VS. Although current evidence is not adequate to differentiate the tumor origin of VS clearly, the cVEMP study is still a good complementary functional examination for small and moderatesized VS, especially in the post-treatment vestibular function follow-up. Several reports demonstrated that cVEMP and caloric testing could be of assistance in deciding on treatment strategy, and in post-treatment functional follow-up [18,27,29,33]. Chen et al. used caloric and cVEMP tests to evaluate vestibular nerve function pre- and postoperatively for patients with VS. In that

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study, cVEMP was used to disclose the residual function of the inferior vestibular nerve [27]. Chen also suggested that VEMP could be used to formulate the best surgical approach before VS surgery, and to define the nature of the VS (compressing or infiltrating the nerve) after surgery. Furthermore, the VEMP study had been a method to comprehensively define the outcomes of radiation treatment in several reports [29]. Therefore, the authors believed that the cVEMP study is a useful tool for evaluating post-SRS vestibular nerve function. Although radiosurgery has been used widely to treat small to moderate-sized VS in recent decades [1–5,34–36], very few studies have investigated vestibular nerve function after radiosurgery in a prospective manner. Based on the knowledge of cVEMP discussed above, we began to document the results of PTA, caloric, and cVEMP tests in our VS patients who underwent GKS. Except the caloric test was significantly deteriorated at 6 months after GKS, there was no significant change in any of the test results compared with the pre-GKS status during 1-year follow-up. These results suggest that GKS may impair vestibular nerve function temporarily in the early post GKS period due to nerve compression by tumor swelling caused by the radiation effect, but recovery could be expected about 1 year later. Although there was no statistical significance in the correlation between tumor volume and vestibular deterioration, these neurophysiological results appear to be compatible with the time course of tumor swelling after GKS (Fig. 4). As a means to attain certainty, however, we look forward to collecting longer follow-up data to establish the relationship between tumor volume changes and neurophysiological changes. Differentiating the origin of the VS and explaining the patients’ annoying presentations like tinnitus or dizziness is sometimes difficult when they have cerebellopontine angle tumors, especially when a tumor comes from a superior or an inferior vestibular nerve, or when a meningioma mimics VS. The recent development of the cVEMP study, accompanied with the PTA and caloric test, appears to overcome part of these difficulties when the patients undergo non-surgical approaches such as GKS [19,21,29,33]. The test takes a short time (usually less than 30 min) and incurs less medical expense. The fee for a VEMP study in our institute is only 80 US dollars, which is much less than a routine MR imaging study (1000 US dollars). Hence, adding a VEMP examination as a routine survey when a VS patient undergoes radiosurgery would be practical, for both diagnosis and follow-up [29]. 5. Study limitation This is an ongoing prospective study with several limitations. First, the study involves only a small number of patients treated at our hospital who followed up regularly after GKS; therefore, there may be some selection bias existing, since enrolled patients usually have better compliance and pre-GKS neurological performance. Second, the follow-up period is still short for observation of postGKS changes in cochlea-vestibular nerve function. This prospective project will continue to collect longer follow-up data and enrolling more patients. 6. Conclusion GKS for treatment of VS has been proved during the last two decades to have a good tumor control rate. After GKS, auditoryvestibular nerve function becomes an important issue and may influence the patient’s quality of life. In our study, using cVEMP along with conventional PTA and caloric tests, we found that the auditory-vestibular nerve function was not significantly deteriorated at the first year follow-up after GKS. The study is still ongoing, and we hope to draw further definite conclusions after a longer follow-up period.

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