Recently, GKS has been regarded as a major therapeutic. Nervus intermedius dysfunction following Gamma Knife surgery for vestibular schwannoma

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1 J Neurosurg 118: , 2013 AANS, 2013 Nervus intermedius dysfunction following Gamma Knife surgery for vestibular schwannoma Clinical article Seong-Hyun Park, M.D., 1 Kyu-Yup Lee, M.D., 2 and Sung-Kyoo Hwang, M.D. 1 Departments of 1 Neurosurgery and 2 Otorhinolaryngology, Kyungpook National University Hospital, Daegu, Korea Object. The purpose of this study was to evaluate the function of the nervus intermedius, the nonmotor component of the facial nerve, following modern Gamma Knife surgery (GKS) for the treatment of vestibular schwannoma. Methods. Sixty-five consecutive patients at our center underwent GKS as a primary treatment option for vestibular schwannoma between 2005 and The authors interviewed patients with a functional questionnaire to evaluate the function of the nervus intermedius before and after radiosurgery from their subjective point of view. Data from 50 patients treated using GKS for a unilateral vestibular schwannoma were obtained. Results. Nine (18%) of 50 patients presented with at least one preradiosurgical disturbance of the nervus intermedius caused by the vestibular schwannoma itself, with dysfunctions of lacrimation, salivation, nasal secretion, and taste. Of the 41 patients without preradiosurgical disturbances, 9 (22%) experienced the onset of at least one new disturbance after GKS. Specifically for each dysfunction, of the 45 patients without a lacrimal disturbance before GKS, 5 (11.1%) had a new lacrimal disturbance after GKS. New onset of a salivary disturbance after GKS was reported in 3 (6.2%) of 48 patients. In 1 patient (2%), increased nasal secretion was noted 1 year after GKS. Five (10.6%) of 47 patients without a preradiosurgical taste disturbance experienced the symptom after GKS. No facial palsy developed in any patient before or after GKS. There was no significant correlation between postradiosurgical nervus intermedius dysfunction and tumor size, margin dose, or patient age. Conclusions. The authors demonstrated that 22% of patients undergoing modern GKS for vestibular schwannoma experience various disturbances of nonmotor components of the facial nerve as a result of the radiosurgery. Through this study, we can provide useful information about the likelihood of certain postradiosurgical symptoms for vestibular schwannoma. ( Key Words nervus intermedius facial nerve vestibular schwannoma Gamma Knife surgery stereotactic radiosurgery Recently, GKS has been regarded as a major therapeutic option for small- to medium-sized vestibular schwannomas, generally producing satisfactory clinical outcomes. Supporters of stereotactic radiosurgery have mainly focused their attention on the excellent rate of tumor control and the preservation of the hearing and motor components of the facial nerve. 1,9 11 However, previous studies of nonmotor dysfunction of the facial nerve following GKS have been limited. 12,13 Those studies focus on ocular disturbance and involve older GKS technology. Abbreviations used in this paper: CISS = constructive interference in steady state; CPA = cerebellopontine angle; GKS = Gamma Knife surgery. This is the first study to provide detailed results about a wide range of disturbances to nonmotor functions resulting from modern GKS, including lacrimal, salivary, nasal, and taste disturbances. The nervus intermedius, which is the sensory component of the facial nerve, exits the lateral brainstem between the motor root of the facial and vestibulocochlear nerves. It carries parasympathetic secretomotor (lacrimal, nasal, submandibular, and sublingual glands) and special sense (taste) fibers (Fig. 1). From the patient s perspective regarding health-related quality of life, interest in disturbances to the nonmotor component of the facial nerve is increasing. Modern GKS using a low peripheral dose usually does not cause a new facial motor disturbance; 566 J Neurosurg / Volume 118 / March 2013

2 Radiosurgery for vestibular schwannoma facial nerve outcome scale. 5 Classification by size was based on the Koos grading system from Grade I to IV as follows: Grade I, small intracanalicular tumor; Grade II, small tumor with protrusion into the CPA cistern; Grade III, tumor occupying the CPA cistern with no brainstem displacement; and Grade IV, large tumor with brainstem and cranial nerve displacement. 8 According to the Koos classification, 5 vestibular schwannomas were Grade I, 17 were Grade II, 25 were Grade III, and 3 were Grade IV. The mean follow-up period after radiosurgery was 50.1 months (range months), and a minimum of 2 years of follow-up was done. Fig. 1. Schematic diagram showing the motor and sensory (nervus intermedius) roots of the facial nerve. CN = cranial nerve. however, bothersome complaints related to disturbances to the sensory component of the facial nerve need to be acknowledged, as such complications may affect the patient s quality of life. In this study, we evaluated the dysfunction of the nervus intermedius following GKS for vestibular schwannoma to give better advice about postradiosurgical complications to patients who undergo radiosurgery with minimal morbidity. Methods Patient Population Sixty-five consecutive patients underwent GKS for vestibular schwannoma at our center between 2005 and Ten patients, including those with neurofibromatosis Type 2, were excluded because only unilateral tumors with no previous resection were included in this study. As a result, 55 patients with a unilateral vestibular schwannoma treated by GKS were enrolled in this study. Data were obtained from 50 (90.9%) of these 55 patients because 5 patients were lost to follow-up or did not respond appropriately to our interview. The 50 patients included 19 male and 31 female patients with a mean age of 58.9 years (range years). Twenty-three patients had a left-sided vestibular schwannoma and 27 had a right-sided lesion. Before and after radiosurgery, clinical otoneurological and radiological examinations were performed. We evaluated patients using a functional questionnaire proposed by Stripf and colleagues 12 before GKS and 1 and 2 years after GKS to evaluate the function of nervus intermedius from the patient s point of view. The functional questionnaire was translated into Korean by an otorhinolaryngologist (K.Y.L.) at our hospital. It comprised 4 parts assessing lacrimation, salivation, nasal secretion, and taste. Each part of the questionnaire was divided into pre- and postradiosurgical occurrences, with each section containing questions related to the presence of symptoms, their character, and the time of onset and duration. Each disturbance after GKS was classified into the following 4 categories: 1) deterioration; 2) no change; 3) improvement compared with the preradiosurgical status; and 4) normal function. Facial nerve motor function was assessed before and after GKS by using the House-Brackmann J Neurosurg / Volume 118 / March 2013 Radiosurgical Technique Stereotactic radiosurgery was performed using the Gamma Knife (model C, Elekta AB). For the 3D reconstructions and treatment planning, we used combinations of CT scanning with 1.25-mm axial cuts, T1-, T2-, and enhanced T1-weighted MRI studies with 2-mm axial slices, and CISS images with 0.5-mm slices. The CISS imaging helped identify the facial and vestibulocochlear nerves in the CPA cistern; it provided a good contrast between the CSF and the nerves, with a focus on T2-weighted sequences. The MR images were transferred to a workstation for postprocessing and analysis. The Leksell GammaPlan system (Elekta) was used to plan the GKS for all patients. To deliver a highly conformal dose to the tumor, multiple small isocenters were used. The mean number of isocenters was 10.1 (range 2-27). The volume of the tumor ranged from 0.05 to 4.8 cm 3 (mean 1.61 cm 3 ). The margin dose was either 12 or 13 Gy (median 12 Gy, mean 12.4 Gy). The choice of the margin dosage for a small- or mediumsized tumor was mostly determined by the Gardner and Robertson hearing classification; 2 12 Gy were used for serviceable hearing and 13 Gy were used for nonserviceable hearing. In all patients, the 50% isodose line was used for the margin. The maximal radiation doses varied between 24 and 26 Gy (median 24 Gy, mean 24.8 Gy). Statistical Analysis All analyses were performed using SPSS 18.0 for Windows (IBM Corp.). A descriptive analysis was performed on epidemiological and tumor-related factors and on dysfunction of the intermediate nerve after GKS. To evaluate the data, we used the chi-square test. Probability values < 0.05 were accepted as the threshold for statistical significance. Results Eighteen (36%) of 50 patients presented with at least one disturbance of the nervus intermedius following GKS, with dysfunctions of lacrimation, salivation, nasal secretion, and taste. Nine of the 50 patients had preradiosurgical symptoms. Of the 41 patients without preradiosurgical disturbances, 9 (22%) experienced at least one new disturbance after GKS. Overall, 1 disturbance was reported in 13 (72.2%) of 18 patients, 2 in 4 patients (22.2%), and 3 in 1 patient (5.6%). Of the 24 disturbances in 18 patients, the most common deficit was a lacrimal disturbance (10 cases [41.7%]). 567

3 S. H. Park, K. Y. Lee, and S. K. Hwang Dysfunction of the Parasympathetic Fiber: Lacrimation, Salivation, and Nasal Secretion A lacrimal disturbance before GKS was reported in 5 (10%) of 50 patients and in 10 patients (20%) after GKS (Fig. 2), which was a statistically significant increase (p < 0.001). Of the 5 patients with a preradiosurgical lacrimal disturbance, 4 (80%) had no change in their condition after GKS and 1 (20%) improved; no patient s condition deteriorated or normalized. Five (11.1%) of 45 patients had a new lacrimal dysfunction after GKS. New onset of a lacrimal disturbance occurred on average 16 months after GKS (range 8-36 months). A postradiosurgical lacrimal disturbance improved in 1 patient 2 years after onset. Two patients presented with dry eye before GKS and 3 with increased tearing. Dry eyes were reported in 5 (10%) of 50 patients after GKS, and increased tearing was reported in 5 patients (10%). A crocodile tears syndrome was observed in 1 patient after GKS. Over the course of tracking 10 patients with lacrimal disturbance after GKS, the condition remained constant in 9 patients (90%), and 1 patient (10%) showed improvement. No increase or decrease in tearing was related to facial palsy, because no impairment of the motor component of the facial nerve occurred in any patient before or after GKS. Salivary disturbances after GKS were reported in 5 (10%) of 50 patients. In all 5 patients, reduced salivation was reported. Two patients had preradiosurgical symptoms, while 3 (6.2%) of 48 patients had an onset of a salivary disturbance within 12 months after GKS (range 6-12 months). In 1 patient (2%), increased nasal secretion was reported 1 year after GKS. Dysfunction of the Special Sensory Fiber: Taste The patients with a taste disturbance before and after GKS were all female. A taste disturbance was experienced by 3 patients (6%) prior to GKS and by 8 (16%) after GKS, which was a statistically significant increase (p < 0.001). Of the 3 patients with a preradiosurgical taste disturbance, 1 experienced deterioration after GKS (33.3%), 1 had no change (33.3%), and 1 improved (33.3%); in no case was there a return to normal function. Five (10.6%) of 47 patients without a preradiosurgical taste disturbance experienced the symptom after GKS (mean onset 18.6 months after GKS, range 1-48 months). Of the 8 patients Fig. 2. Bar graph showing the nervus intermedius disturbance regarding lacrimation, taste, salivation, and nasal secretion after GKS. with a taste disturbance after GKS, deterioration from its onset was experienced by 2 patients (25%), there was no change in 3 patients (37.5%), and there was improvement in 2 patients (25%); in 1 patient there was a return to normal function (12.5%). Dysfunction of the Motor Fiber Facial palsy did not develop in any patient before or after GKS. As expected, modern GKS using a low margin dose did not cause a dysfunction of the motor component of the facial nerve. Relationship of Symptoms With Tumor Size, Radiation Dose, and Age Three (60%) of 5 patients at Koos Grade I experienced nervus intermedius dysfunction after GKS. A postradiosurgical disturbance occurred in 4 (23.5%) of 17 patients with Koos Grade II tumors. Nine (36%) of 25 patients with Koos Grade III tumors suffered a deficit following GKS. Two of (66.7%) 3 patients with Koos Grade IV tumors experienced symptoms. No correlation between tumor size and disturbances in the nervus intermedius after GKS was found (p = 0.305) (Table 1). Of the 29 patients who underwent GKS with a 12- Gy margin dose, a nervus intermedius disturbance occurred in 12 (41.4%). A neurological deficit developed in 6 (28.6%) of 21 patients following GKS at 13 Gy. No correlation between margin dosage and disturbances to the nervus intermedius after GKS was found (p = 0.352). Six (33.3%) of 18 older patients ( 65 years) presented with a postradiosurgical disturbance, whereas 12 (37.5%) of 32 younger patients (< 65 years) presented with a new disturbance. No correlation between age and disturbance to the nervus intermedius was observed (p = 0.768). Discussion Treatment of vestibular schwannomas includes microsurgery, radiosurgery, and conservative treatment with serial monitoring, and the treatment strategy is determined by therapeutic indication, surgeon s experience, and medical environment. 16 Facial palsy is still of concern following resection of vestibular schwannoma, because it is a critical complication for the patient. Despite great advances in microsurgery, the rate of facial motor nerve damage is significantly higher with microsurgery than with GKS. 13 Due to the development of modern imaging, which has made a smaller peripheral dose (10 14 Gy) possible, the amount of facial palsy resulting from GKS, as reported by numerous authors, is close to zero. 1,7,11 The progress in contemporary GKS causes a shift in perspective to other aspects of the postsurgical quality of life. 3 In recent years, a few studies have suggested that more attention should be focused on the nonmotor components of facial nerve injury, because, along with deafness and facial weakness, dysfunction of the nervus intermedius following GKS meaningfully affects quality of life. 11,13 Whereas one study provided results primarily for ocular disturbance following archeo -GKS, 13 our study provides a wide range of results for nonmotor dysfunc- 568 J Neurosurg / Volume 118 / March 2013

4 Radiosurgery for vestibular schwannoma TABLE 1: Dysfunction of nervus intermedius according to the tumor size and dose to the margin Postradiosurgical Disturbances* Factor Lacrimation Taste Salivation Nasal Secretion p Value Koos grade I II III IV margin dose (Gy) * There were 24 disturbances in 18 patients. tion of the nervus intermedius following modern GKS, including disturbances to lacrimation, salivation, nasal secretion, and taste. Dysfunction of the Nervus Intermedius There are more studies about the dysfunction of nonmotor components of the facial nerve after microsurgery than after GKS. Stripf et al. 12 reported that, postoperatively, 70 patients (45%) experienced crocodile tears and 62 (40%) had dry eyes. Disturbances in taste were noted in 52 patients (33%) after surgery. Increased nasal secretion was noted postoperatively in 68 patients (44%). These complications seem to correlate with an anatomical feature of the nervus intermedius between the brainstem and the porus acousticus. This nerve has no perineurium and is sheathed only by a thin arachnoid membrane. 6 A normal nervus intermedius contains 20% unmyelinated fibers. 15 Therefore, the nonmotor component of the nerve fiber is more vulnerable to mechanical damage than the thicker motor portion of the facial nerve. In fact, Watanabe et al. 14 reported that a postoperative taste disturbance was commonly experienced even in patients whose postoperative facial motor function was only at House- Brackmann Grade I. Tamura et al. 13 demonstrated that radiosurgery can induce nervus intermedius injury in a small percentage of patients (14%). However, these patients were treated 11 years ago with what the authors considered archeo-gks technology when compared with today s radiosurgical instruments, which allow for better imaging and, in many cases, lower margin doses. In their study, the margin dose ranged from 8 to 16 Gy (median 12 Gy). In our study, the margin dose ranged from 12 to 13 Gy (median 12 Gy). We found that 9 (22%) of 41 patients experienced a new onset of a postradiosurgical nervus intermedius dysfunction. No increase in tumor growth after radiosurgery was found in these 9 patients. Even though the nervus intermedius is anatomically less protected from radiation than the motor component, a radiosurgical technique using a low margin dose and a highly conformal dosage plan decreased the incidence of postradiosurgical dysfunction of both the nonmotor and motor fibers of the facial nerve, when compared with microsurgery. In the present study, 11.1% of 45 patients without a J Neurosurg / Volume 118 / March 2013 preradiosurgical lacrimal disturbance had a new lacrimal symptom after GKS (mean onset of 16 months). In the study by Tamura and colleagues, 13 14% of patients complained of lacrimal disturbance after GKS. Régis et al. 11 reported that 27% of patients who underwent GKS experienced a lacrimal disturbance. However, the risk of the lacrimal disturbance is much higher in patients treated by microsurgery due to a high incidence of facial palsy. The study by Tamura et al. 13 reported a taste disturbance in 8.1% patients after archeo-gks and in 45.5% of patients after microsurgery. Watanabe et al. 14 reported that a taste disturbance occurred postoperatively in 28.6% of patients with no preoperative taste disturbance. In our experience with modern GKS, a postradiosurgical onset of a taste disturbance occurred in 10.6% of patients (mean onset of 18.6 months). Our results show that a delayed onset of a nervus intermedius dysfunction occurred in many cases, and we advocate a careful and long follow-up period. Compared with lacrimal and taste disturbances, nasal and salivary disturbances were rare after GKS in our study. A review of the literature turned up no study reporting these symptoms because patients may recover through a quick adaptation and not experience much discomfort. Our study demonstrated that the nervus intermedius can be damaged by radiosurgery, even though the incidence is low. With microsurgery, the danger of injury to the facial nerve increases with tumor size, with the incidence of facial neuropathy ranging from 0% to 6% for small tumors and from 8% to 24% for moderately sized tumors. 4,10 We tried to identify factors related to the dysfunction of the nervus intermedius, but there was no observed relationship between the presence of postradiosurgical disturbances and tumor size, radiation dosage, and age. We should continue to find ways to reduce the morbidity and sequelae of the nervus intermedius, because these abnormalities are functionally very important yet underestimated in the course of evaluating GKS for vestibular schwannoma. There are some limitations to this study. This was a retrospective single-center study with a small number of patients and a relatively short follow-up period. Even though we evaluated data with a minimum of 2 years of follow-up, a longer follow-up is necessary to assess any 569

5 S. H. Park, K. Y. Lee, and S. K. Hwang delayed dysfunction of the nervus intermedius. We could not compare these results statistically with those who underwent microsurgery because we had a small number of patients treated by microsurgery and there was too great a difference in tumor size between the groups. Selection biases and methodological problems could be solved in prospective comparative studies that are randomized. Also, because we depend on subjective, self-evaluated answers to a functional questionnaire, it is not easy to interpret and objectively evaluate the data. Conclusions Postradiosurgical dysfunction of the nervus intermedius has not received attention from previous studies because these symptoms are not as impressive as hearing loss and facial palsy. In the present study, we demonstrated that 36% of patients with vestibular schwannoma following modern GKS experienced various disturbances of nonmotor components of the facial nerve, as a result of either preradiosurgical or postradiosurgical factors. Additionally, we concluded that 22% of patients without preradiosurgical disturbances had an onset of a dysfunction as a result of the radiosurgery. The incidence of postradiosurgical dysfunction of the nervus intermedius following modern GKS was surprising, considering the advances in imaging techniques and lower margin doses. We should recognize that the parasympathetic and special sensory nerve fibers have less protection from radiation than the motor fiber and that a patient s quality of life suffers as well from these dysfunctions following even modern GKS. Through this study, we can provide useful information to counsel patients about the likelihood of postradiosurgical symptoms following modern GKS for vestibular schwannoma. Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Author contributions to the study and manuscript preparation include the following. Conception and design: Park, Lee. Acquisition of data: Lee. Analysis and interpretation of data: Park. Drafting the article: Park. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Park. Statistical analysis: Park. Administrative/technical/material support: Hwang. Study supervision: Hwang. Acknowledgment The authors thank Wade Martin for his critical review of this manuscript. References 1. Flickinger JC, Kondziolka D, Niranjan A, Lunsford LD: Results of acoustic neuroma radiosurgery: an analysis of 5 years experience using current methods. 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J Korean Neurosurg Soc 42: , Koos WT, Day JD, Matula C, Levy DI: Neurotopographic considerations in the microsurgical treatment of small acoustic neurinomas. J Neurosurg 88: , Paek SH, Chung HT, Jeong SS, Park CK, Kim CY, Kim JE, et al: Hearing preservation after gamma knife stereotactic radiosurgery of vestibular schwannoma. Cancer 104: , Pollock BE, Lunsford LD, Norén G: Vestibular schwannoma management in the next century: a radiosurgical perspective. Neurosurgery 43: , Régis J, Pellet W, Delsanti C, Dufour H, Roche PH, Thomassin JM, et al: Functional outcome after gamma knife surgery or microsurgery for vestibular schwannomas. J Neurosurg 97: , Stripf T, Braun K, Gouveris H, Stripf EA, Mann WJ, Amedee RG: Influence of different approaches to the cerebellopontine angle on the function of the intermediate nerve. J Neurosurg 107: , Tamura M, Murata N, Hayashi M, Roche PH, Régis J: Facial nerve function insufficiency after radiosurgery versus microsurgery. Prog Neurol Surg 21: , Watanabe K, Saito N, Taniguchi M, Kirino T, Sasaki T: Analysis of taste disturbance before and after surgery in patients with vestibular schwannoma. J Neurosurg 99: , Ylikoski J, Savolainen S: Pathological features of human facial nerve after central injury during tumor removal, with special reference to the non-motor component. Acta Otolaryngol 93: , Zhao X, Wang Z, Ji Y, Wang C, Yu R, Ding X, et al: Long-term facial nerve function evaluation following surgery for large acoustic neuromas via retrosigmoid transmeatal approach. Acta Neurochir (Wien) 152: , 2010 Manuscript submitted April 12, Accepted October 2, Please include this information when citing this paper: published online October 26, 2012; DOI: / JNS Address correspondence to: Seong-Hyun Park, M.D., Department of Neurosurgery, Kyungpook National University Hospital, 50, Samduk-2-ga, Jung-gu, Daegu, , South Korea. nsdoctor@naver.com. 570 J Neurosurg / Volume 118 / March 2013