Trigeminal neuralgia and neuropathy in large sporadic vestibular schwannomas

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1 CLINICAL ARTICLE J Neurosurg 127: , 2017 Trigeminal neuralgia and neuropathy in large sporadic vestibular schwannomas Brian A. Neff, MD, 1 Matthew L. Carlson, MD, 1 Megan M. O Byrne, MA, 3 Jamie J. Van Gompel, 2 MD, Colin L. W. Driscoll, MD, 1 and Michael J. Link, MD 2 Departments of 1 Otorhinolaryngology and 2 Neurologic Surgery, School of Medicine, and 3 Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota OBJECTIVE The aim of this study was to evaluate the incidence, presentation, and treatment outcomes of trigeminal nerve mediated symptoms secondary to large vestibular schwannomas (VSs) with trigeminal nerve contact. Specifically, the symptomatic results of pain, paresthesias, and numbness after microsurgical resection or stereotactic radiosurgery (SRS) were examined. METHODS The authors conducted a retrospective review of a database for concomitant diagnosis of trigeminal neuralgia (TN) or trigeminal neuropathy and VS between 1994 and 2014 at a tertiary academic center. All patients with VS with TN or neuropathy were included, with the exception of those patients with neurofibromatosis Type 2 and patients who elected observation. Patient demographic data, symptom evolution, and treatment outcomes were collected. Population data were summarized, and outcome comparisons between microsurgery and SRS were analyzed at last follow-up. RESULTS Sixty (2.2%) of 2771 total patients who had large VSs and either TN or neuropathy symptoms met inclusion criteria. The average age of trigeminal symptom onset was 53.6 years (range years), the average age at VS diagnosis was 54.4 years (range years), and the average follow-up for the microsurgery and SRS groups was 30 and 59 months, respectively (range months). Of these patients, 50 (83%) had facial numbness, 16 (27%) had TN pain, and 13 (22%) had paresthesias (i.e., burning or tingling). Subsequently, 50 (83%) patients underwent resection and 10 (17%) patients received SRS. Treatment of VS with SRS did not improve trigeminal symptoms in any patient. This included 2 subjects with unimproved facial numbness and 4 patients with worsened numbness. Similarly, SRS worsened TN pain and paresthesias in 5 patients and failed to improve pain in 2 additional patients. The Barrow Neurological Institute neuralgia and hypesthesia scale scores were significantly worse for patients undergoing SRS compared with microsurgery. Resection alleviated facial numbness in 22 (50%) patients, paresthesias in 5 (42%) patients, and TN in 7 (70%) patients. In several patients, surgery was not successful in relieving facial numbness, which failed to improve in 17 (39%) cases and became worse in 5 (11%) cases. Also, surgery did not change the intensity of facial paresthesias or neuralgia in 6 (50%) and 3 (25%) patients, respectively. Microsurgery exacerbated facial paresthesias in 1 (8%) patient but, notably, did not aggravate TN in any patient. CONCLUSIONS Overall, resection of large VSs provided improved outcomes for patients with concomitant TN, facial paresthesia, and numbness compared with SRS. However, caution should be used when counseling surgical candidates because a number of patients did not experience improvement. This was especially true in patients with preoperative facial numbness and paresthesias, who frequently reported that these symptoms were unchanged following surgery. KEY WORDS vestibular schwannoma; acoustic neuroma; trigeminal neuralgia; trigeminal neuropathy; surgery; radiosurgery; oncology; pain ABBREVIATIONS BNI = Barrow Neurological Institute; CPA = cerebellopontine angle; GKS = Gamma Knife surgery; SRS = stereotactic radiosurgery; TN = trigeminal neuralgia; VS = vestibular schwannoma. SUBMITTED February 29, ACCEPTED September 15, INCLUDE WHEN CITING Published online January 13, 2017; DOI: / JNS J Neurosurg Volume 127 November 2017 AANS, 2017

2 Trigeminal neuralgia in vestibular schwannoma Tumor-related facial pain accounts for approximately 1% 13% of patients with clinical trigeminal neuralgia (TN) symptoms. 4,23 Many of these cases are caused by trigeminal schwannomas or petroclival meningiomas, but trigeminal nerve symptoms are also seen with posterior fossa cerebellopontine angle (CPA) tumors such as vestibular schwannomas (VSs). VS-related TN and trigeminal neuropathy are thought to occur from direct tumor pressure on the trigeminal nerve, which causes demyelination of the somatosensory and pain fibers or, less likely, from a tumor pushing the trigeminal nerve and an artery into contact. 6,14,21 The incidence of TN and trigeminal neuropathy varies among publications, with higher rates observed in series containing larger VSs. A few VS studies report pretreatment TN and trigeminal neuropathy in 9.8% 15% of presenting patients. 2,20 Currently, there is a paucity of reports on the best VS treatment approach for those patients who present with trigeminal symptoms. Small case series and expert opinion promote microsurgical tumor removal for treatment of the tumor while simultaneously providing decompression of the fifth cranial nerve. 34 A surgical bias is also probably present due to the fact that many patients with trigeminal symptoms tend to have larger tumors that are also causing brainstem compression and hydrocephalus, which require surgical treatment. It is for this reason that most radiosurgery centers will not perform stereotactic radiosurgery (SRS) for treatment of tumors > 3 cm. 33,34 However, there are very few studies to guide treatment decisions in those tumors that are amenable to either SRS or surgery. Methods Following institutional review board approval, a prospectively maintained VS clinical database was retrospectively queried for concomitant diagnosis of TN or trigeminal neuropathy and VS between 1994 and The study population included patients with only sporadic VS because patients with neurofibromatosis Type 2 associated VS can often develop trigeminal schwannomas or petroclival meningiomas during their clinical course, making VS causality of trigeminal symptomatology difficult to determine. A total of 2771 patients with VSs were seen during that time, of whom 100 patients also had a concomitant diagnosis of TN. Patients had typical (Type 1) TN or atypical (Type 2) TN. Typical TN was defined as a paroxysmal pain that was either lancinating, boring, stabbing, or an intense electrical zap in the trigeminal nerve distribution. Atypical TN was defined as typical TN symptoms with concomitant persistent facial pain between paroxysms. 36 To have the pain symptoms attributed to the VS, only tumors with physical contact with the trigeminal nerve were included. For example, internal auditory canal tumors on the same side as the TN were excluded from analysis. For the purpose of this study, paresthesia (dysesthesia) was defined as a sensation of pricking, tingling, itchypricking, or creeping on the skin, usually associated with irritation of a sensory nerve or nerve root. Numbness was defined as a reduced sensitivity to touch. 36 The minimum required length of follow-up to be included was 3 months. Of the 100 patients, only 60 met all study inclusion criteria, with the other 40 patients excluded due to the following reasons: the neuralgia or numbness only occurred after treatment; no follow-up; tumor diagnosis and TN were unrelated (either tumor was too small to contact the trigeminal nerve or the conditions were present on opposite sides); incomplete charting on a few earlier entries; 3 cases were neurofibromatosis Type 2 associated VSs; and 5 patients elected tumor observation. Retrospective data analysis included age at time of VS and TN diagnosis; sex; side; presence of pretreatment neuralgia, numbness, or paresthesias; Barrow Neurological Institute (BNI) neuralgia and numbness scale scores; coexisting headache or pain disorder; previous medical or TN treatments; surgical approach; tumor resection completeness; inadvertent intraoperative fifth nerve injury (partial or complete transection); presence of a compressive vessel on the trigeminal nerve; concurrent microvascular decompression with tumor removal; postoperative neuralgia, numbness, or paresthesia outcome; time until symptom improvement; tumor size; cystic nature of tumor; pain medication reduction; SRS treatment details including treatment volume, central and marginal dose, number of isocenters, surgical and radiation complications (e.g., facial paralysis); and duration of follow-up (defined as the time from the date of treatment to the last follow-up visit that mentioned trigeminal symptom or sign outcomes). The BNI neuralgia scale was used to classify TN outcome: Class I, no trigeminal pain, no medication; Class II, occasional pain, not requiring medication; Class IIIa, no pain with continued medication; Class IIIb, pain controlled with medication; Class IV, some pain, not adequately controlled with medication; and Class V, severe pain, no pain relief. 28,31 For purposes of statistical comparison, Groups IIIa and IIIb were combined into a single Group III. The degree of hypesthesia was reported using the BNI facial hypesthesia scale: Class I, no facial numbness; Class II, mild facial numbness, not bothersome; Class III, facial numbness, somewhat bothersome; and Class IV, facial numbness, very bothersome. 28 Descriptive statistics were used to summarize demographic and clinical data. Patients who received SRS were compared with those who received surgery across several parameters, and only univariate results were reported. Ordinal parameters, such as BNI pain (I V, with V being worst) and postoperative change in pain (better, same, or worse), were analyzed with Mantel-Haenszel chi-square tests using ridit scores to account for the ordering of the levels. 3 A significant p value from the ridit analysis can be interpreted as meaning that 1 treatment showed significantly better outcomes than the other, and this was unlikely to be due to chance alone. For unordered variables, Fisher s exact tests were used. A p value < 0.05 was considered significant for all tests. All analyses were run with SAS version 9.4 (SAS Institute). Results A total of 2771 patients with the diagnosis of VS were evaluated between 1994 and One hundred of these J Neurosurg Volume 127 November

3 B. A. Neff et al. patients had a concomitant diagnosis of TN or trigeminal neuropathy. Of these 2771 patients, 60 (2.2%) had trigeminal nerve related symptoms that could be directly attributed to the tumor, whether they were neuralgia, paresthesia, hypesthesia, or a combination, prior to treatment with microsurgery or radiosurgery. In the microsurgery cohort, 37 patients perceived only 1 symptom, and 13 patients reported multiple symptoms, which are outlined in Table 1. Of the microsurgery patients, 44 of 50 (88%) perceived numbness, 12 of 50 (24%) suffered paresthesia, and 10 of 50 (20%) reported neuralgia. In the radiosurgery group, 7 patients experienced only 1 symptom prior to treatment, whereas 3 patients experienced multiple symptoms, which are summarized in Table 1. In the Gamma Knife Surgery (GKS) treated cohort, 6 of 10 (60%) patients had numbness, 6 of 10 (60%) had neuralgia, and 1 of 10 (10%) had facial paresthesia. Of these 60 patients, 50 were treated with microsurgery (39 retrosigmoid, 11 translabyrinthine) and 10 patients were treated with SRS. At our center, patients with a tumor > 2.5 cm were primarily counseled to undergo surgery; however, there were a few patients in this group who refused surgery and were treated with GKS. For cases in which tumors were 2.5 cm, the patient was given the choice between microsurgery or radiosurgery, unless medical comorbidities precluded microsurgery. The average age at TN or neuropathy diagnosis was younger than the average age at VS diagnosis (53.6 years vs 54.4 years, respectively). There were 31 women and 29 men, with an average follow-up of 30 months for the microsurgery group and 59 months for the SRS group. The average tumor size for all patients was 3.0 cm, using the greatest CPA measurement from the axial or coronal MR images, and the average tumor size was significantly larger in the microsurgery group compared with the radiosurgery patients (3.2 cm vs 2.1 cm, respectively, p < , range cm vs cm, respectively). Of the 60 patients with VS, 13 (22%) had macrocystic tumors on MRI, which were confirmed with surgical findings (Fig. 1). Eight of the patients who underwent GKS were treated to a marginal dose of Gy, and 2 patients received higher marginal doses of 14 Gy and 18 Gy. No radiosurgery cases received a boost dose to the trigeminal nerve. In the microsurgery group, 20 patients had complete tumor resection, 11 patients had near-total resection (defined as a tumor remnant < mm), and 19 patients had a subtotal resection of their VS. All of the subtotal resections were relatively aggressive, with > 90% of the tumor removed, and the brainstem was always decompressed. The main reason for leaving tumor in the subtotal and near-total groups was due to severe splaying of the facial nerve with unfavorable surgical planes. Other reasons, in descending order of frequency, included the following: unfavorable surgical plane with the brainstem; preservation of the fifth cranial nerve or lower cranial nerves; excessive tumor bleeding; and preservation of critical vasculature that could not be separated from the tumor. There were 4 cases where tumor was left on the trigeminal nerve to preserve neural function. In all of these cases, it was believed that removing the majority of the tumor TABLE 1. Pretreatment symptoms in 60 patients with VS Variable* Value (%) Microsurgery Radiosurgery Total no. of pts Numbness 31 3 Paresthesia 0 1 Neuralgia 6 3 Numbness + neuralgia 1 3 Numbness + paresthesia 8 0 Numbness + paresthesia + neuralgia 4 0 Total pts w/ numbness 44 (88) 6 (60) Total pts w/ paresthesia 12 (24) 1 (10) Total pts w/ neuralgia 10 (20) 6 (60) Mean age at trigeminal symptom onset, yrs Mean age at tumor presentation, yrs Mean tumor size, cm in CPA Range of tumor size, cm in CPA Length of follow-up, mos pts = patients. * The combination of paresthesia and neuralgia had 0 pts in the microsurgery or radiosurgery group. Statistically significant difference. relieved the mass effect on the nerve, and 3 of 5 preexisting trigeminal-related symptoms in these 4 patients were improved postoperatively. This constituted too few cases to analyze whether this detrimentally affected symptom outcomes compared with removing the entire tumor from around the trigeminal nerve. There was only 1 case where the trigeminal nerve was thought to be partially transected (< 50% of the nerve). This was in a patient with preoperative numbness, which did not improve or worsen after surgery. There was only 1 case where a vessel (superior cerebellar artery) was causing significant compression of the trigeminal nerve. In this instance, a microvascular decompression with Teflon felt was performed after tumor removal. Patient-reported outcomes for post-treatment symptoms are reported in Figs. 2 and 3. Surgery was more likely to relieve numbness (22 of 44 [50%]) than GKS, in which group there was no patient improvement. Surgery was also more likely to relieve paresthesias (5 of 12 [42%]) and neuralgia (7 of 10 [70%]) than GKS, which did not result in any improvements in either symptom in any patient. All of these results were statistically significant. The BNI provides a validated outcome scale for these subjective symptoms, and the results are summarized in Figs. 4 and 5. Again, microsurgery provided statistically significant, greater symptom relief than GKS when evaluating the BNI scales. There were no cases, in either group, with recurrent trigeminal nerve symptoms (defined as a period of complete symptom relief followed by recurrence of trigeminal symptoms). Several demographic variables and patient factors were analyzed to assess whether anything was predictive of a poor symptom outcome after treatment, and the results 994 J Neurosurg Volume 127 November 2017

4 Trigeminal neuralgia in vestibular schwannoma FIG. 1. A C: Left-sided, 4-cm cystic VS resulting in brainstem compression (white arrows) and left facial numbness. The fifth cranial nerve can be seen on thin-slice heavy T2-weighted images (white arrowhead). D F: Following gross-total resection, the patient reported an improvement in preoperative trigeminal neuropathy and no associated neuralgia. The white arrowhead shows an intact and decompressed trigeminal nerve after tumor resection. are summarized in Table 2. Tumor size 3 cm, age of trigeminal symptom onset 55 years, and presence of pretreatment numbness were the pretreatment predictors of persistent TN after microsurgery or GKS. Post-treatment numbness had several predictors, including tumor size 3 cm, age of trigeminal symptom onset 55 years, presence of neuralgia prior to treatment, pain medication use before treatment, and previous TN treatment that failed (e.g., glycerol injection). Discussion A significant proportion of the existing data regarding the radiosurgical management of tumor-related TN and facial pain is derived from subset analyses of series of benign intracranial tumors treated with SRS. 31 In these mixed series, pain and numbness relief rates following SRS have ranged from 33% to 96%, 13,24,26,33 and the rate of persistent TN and trigeminal neuropathy has varied from 1.6% to 36%. 2,12,16,25 Paradoxically, many VS SRS series report the onset of new TN or numbness in up to 1% 39% of patients, 11,17,20,32 and the radiation dose seems to correlate with the risk of developing this complication. Patients with VS receiving a < 13-Gy marginal dose are significantly less likely to develop such pain, paresthesias, or numbness. 19,32,35 The large differences in trigeminal symptom SRS outcomes are probably related to patient selection bias, variable tumor size exclusion (3 4 cm), failure to systematically inquire about patient symptoms (missing data), and the inclusion of variable marginal radiation dosages (12 18 Gy). Persistent or worsened trigeminal symptoms after SRS are hypothesized to occur from a combination of factors. First, the treatment does not usually shrink the tumor and thus does not relieve the mass effect and compression on the trigeminal nerve. Second, many patients experience a FIG. 2. Patient-perceived post-treatment neuralgia and paresthesia. FIG. 3. Patient-perceived post-treatment numbness. J Neurosurg Volume 127 November

5 B. A. Neff et al. FIG. 4. Bar graph showing results in this study according to the BNI neuralgia scale. transient post-treatment tumor swelling that can lead to a transient or permanent worsening of symptoms. 22 Last, it has been postulated that pain and numbness can be permanently exacerbated from direct radiation-induced damage to the trigeminal nerve or the intra-axial trigeminal fibers within the pons, because a trigeminal nerve in contact with the tumor capsule will receive a radiation dose approximating the prescribed marginal dose to the tumor. 10,30 The fate of trigeminal nerve dysfunction after microsurgery for VS is even more sparsely reported than radiosurgery treatment series in the existing literature (Table 3). Karkas et al. found that 1 of 3 patients with VS-related TN improved after surgery and that 4 of 29 (14%) patients with facial numbness improved; however, the follow-up of 2 weeks for many patients was exceedingly short. 15 It is hypothesized that surgery relieves trigeminal symptoms by removing the mass compression of the nerve. Another hypothesized mechanism for VS-related TN is that the tumor pushes the trigeminal nerve and an artery such as the superior cerebellar artery into contact, thus mimicking the neurovascular etiology seen in the typical TN that is not associated with tumor compression. 1,14,29 In our series, the trigeminal nerve was routinely decompressed of as much tumor as possible, and a systematic inspection for a compressive artery was performed. In the vast majority of cases, we did not find that a vascular etiology of neuralgia was present. To our knowledge, this is the first retrospective pretreatment TN and trigeminal neuropathy outcomes report, dedicated to only patients with VS, comparing microsurgery and radiosurgery. Microsurgery was significantly superior to GKS at treating VS and the trigeminal symptoms. This was so despite a surgical selection bias for tumors > 2.5 cm or tumors causing significant mass effect on the brainstem. There were certainly other biases, given that this study did not randomly assign patients; however, the BNI scale outcomes were vastly different in favor of microsurgery. In all patients, the goal going into surgery was total tumor removal. In cases with preoperative trigeminal symptoms, subtotal tumor resection was performed in 38% of our cases to preserve vital neurovascular structures and function. In nearly all of these cases, tumor remnants were left for facial nerve preservation, and in each subtotal resection, FIG. 5. Bar graph showing results in this study according to the BNI hypesthesia scale. > 90% of the tumor was removed to provide trigeminal nerve decompression even if a small tumor remnant was left along the trigeminal nerve. In addition, lysis of adhesions, if present, was always performed around the fifth cranial nerve as well as vascular decompression if it was believed that there was a vessel compressing the trigeminal nerve. Tumor was left along the trigeminal nerve in a minority of cases (4 of 50 [8%]), and only 1 case required a concomitant microvascular decompression. There were no improvements in pretreatment neuralgia, paresthesias, or numbness in the GKS patient group, TABLE 2. Pretreatment predictors of post-treatment TN and hypesthesia Post-treatment Outcome p Value TN Predictive Tumor size 3 cm Age 55 yrs Pretreatment numbness Not predictive Sex Pretreatment paresthesias Comorbid headache diagnosis 1.00 Pretreatment use of pain medication Failure of other TN treatments (e.g., glycerol injections) Cystic tumor Hypesthesia Predictive Pretreatment neuralgia Pretreatment use of pain medication Age 55 yrs Tumor 3 cm Failure of other TN treatments Not predictive Sex Pretreatment paresthesias Comorbid headache diagnosis Cystic tumor J Neurosurg Volume 127 November 2017

6 Trigeminal neuralgia in vestibular schwannoma TABLE 3. Summary of recent microsurgery and radiosurgery series of patients with VS and TN Authors & Year Intervention Findings Cheng et al., 1993 Microsurgery Mixed population of tumors, which included 10 VSs. It was not clearly presented how many of these 10 pts underwent surgery. There was no report about trigeminal nerve symptom outcomes after surgery for these 10 pts w/ VS. Samii & Matthies, 1995 Microsurgery Reported 9 cases of small VSs where tumor/nerve contact or compression was not believed to be the cause of TN. Vascular compression was found & treated, w/ good results in most cases. Barker et al., 1996 Microsurgery Multiple tumor types in 26 pts. Only 8 pts had VSs with TN. Although their pt cohort reported arterial compression of the trigeminal nerve & significant pain relief w/ tumor removal, they did not report results specific to their 8 pts w/ VS. Karkas et al., 2014 Microsurgery Among 32 pts who were surgically treated for VS w/ preop trigeminal symptoms, 3/3 had improved neuralgia long term (undefined); 0/1 had improved facial anesthesia; & 4/28 (14%) had improved facial hypesthesia at 10 days. Pollock et al., 2000 Radiosurgery Study included 26 pts w/ tumors involving the trigeminal nerve w/ TN. All were treated w/ SRS. None of the tumors were VSs. Half of the pts were initially free of pain after treatment, w/ variable follow-up. Régis et al., 2001 Huang et al., 2008 Radiosurgery Radiosurgery Study included 53 pts w/ concomitant TN. GKS was used for a mixture of middle and posterior fossa tumors. Seventeen patients had VSs. Overall, 78% of pts were free of pain after GKS. The pts w/ VS were not analyzed as a specific group, so results were difficult to analyze or extrapolate. Study included 21 pts w/ TN treated w/ GKS. Only 9 pts had VS. Overall, 57% of pts achieved complete pain relief & no longer required medication. Only 8 pts were treated for VS, of whom 5 had poor outcomes w/ pain. and 2 patients developed new, permanent neuralgia or paresthesias after treatment. There are 2 foreseeable bias factors that could have negatively influenced the GKS outcomes. First, the follow-up was longer for the radiosurgery group, and thus it could be hypothesized that recurrence of symptoms might be greater given the longer time period. However, this is unlikely to have influenced our results because none of the patients had temporary relief of symptoms followed by late symptom recurrence. Their symptoms were the same or worse at the first post-treatment follow-up, which was usually at 3 months, and the symptoms did not improve over an average of 59 months. Second, 2 patients received a marginal dose of > 13 Gy, which has been shown to increase the rate of post-gks trigeminal symptoms in other reports. 32 However, this still left 8 patients with unimproved symptoms after receiving contemporary dose plans (marginal dose Gy). Several studies have evaluated risk factors or predictors of trigeminal dysfunction after microsurgery and SRS for VS. Premicrosurgical risk factors mentioned in the literature are tumor growth toward the brainstem in an upward direction and tumor cyst formation, although the latter was not statistically correlated with trigeminal nerve symptoms in this present series. 15,29 Conversely, another study failed to elucidate any peri-microsurgery risk factors for post-treatment trigeminal symptoms despite evaluating fifth nerve distortion, compression and nonvisibility of the ipsilateral trigeminal nerve preoperatively, and presence of residual tumor postoperatively. 15 Radiosurgery studies have found variable risk factors. A few larger studies identified target volume and maximum dose delivered to the trigeminal nerve as the only pretreatment predictors of adverse trigeminal SRS effects. Tumor volumes > 5 cm 3 and a maximum trigeminal dose > 9 Gy had an increasingly greater chance of resultant trigeminal nerve side effects. 8,11 A second study demonstrated that the length of the cranial nerve that was irradiated corresponded to the subsequent neuropathy. 7,18 In contrast, a final study highlighted that the brainstem radiation dose was the most significant predictor of trigeminal neuropathy. 9,11,27 Our study was slightly different because it evaluated only patients with trigeminal nerve symptoms prior to therapy and then the fate of these symptoms after treatment. We identified the following risk factors for persistence of trigeminal symptoms in the combined cohort of 60 patients. (There were not enough patients in the SRS cohort to look at the groups separately, and the treatment itself caused poor outcomes that overrode the discovery of any patient factors.) We identified only a few risk factors for persistent post-treatment neuralgia, which were tumor size 3 cm, age at trigeminal symptom onset 55 years, and the presence of pretreatment numbness. There were several risk factors for persistent post-treatment trigeminal neuropathy (numbness), which included the following: age at trigeminal symptom onset 55 years; tumor size 3 cm; use of pretreatment pain medication; a previous TN procedure that failed (e.g., glycerol injection); and the presence of TN pretreatment. The overall risk of any level of persistent TN after microsurgery and SRS was 61% and 100%, respectively, and the risk of any level of numbness or paresthesias was 64% and 100%, respectively. Many of these microsurgery patients indeed had improved neuralgia and numbness/paresthesias (58% and 50%, respectively) despite some residual symptoms; moreover, none of the SRS patients had improvement of any of their trigeminal symptoms. Patients with any of the identified risk factors should be counseled that their risk is even higher than these averages. Overfitting is a potential weakness of this and any multivariable analysis. Overfitting a regression model can occur when attempting to estimate too many parameters from a small sample size. In other words, it is possible that some statistically significant factors in the regression model may not be significant in a much larger patient population. This is because rather than reflecting the overall population, the regression model reflects random noise in a specific sample. J Neurosurg Volume 127 November

7 B. A. Neff et al. Conclusions Trigeminal neuralgia and trigeminal neuropathy can rarely be incited by VS-related neural compression. Many of these large tumors are preferentially treated with surgery to relieve brainstem compression and hydrocephalus. However, there is a subset of these tumors without brainstem mass effect, where treatment of the trigeminal symptoms is a primary goal of the patient and physician. This study demonstrated that microsurgery was significantly better at treating the tumor and improving the trigeminal symptoms compared with SRS, which often exacerbated these preexisting symptoms. Tumor size 3 cm was the primary predictor of continued difficulty with pain, paresthesias, and numbness after treatment. References 1. Barker FG II, Jannetta PJ, Babu RP, Pomonis S, Bissonette DJ, Jho HD: Long-term outcome after operation for trigeminal neuralgia in patients with posterior fossa tumors. 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Am J Otol 20: , Squire SE, Chan MD, Furr RM, Lowell DA, Tatter SB, Ellis TL, et al: Gamma Knife radiosurgery in the treatment of tumor-related facial pain. Stereotact Funct Neurosurg 90: , Sughrue ME, Yang I, Han SJ, Aranda D, Kane AJ, Amoils M, et al: Non-audiofacial morbidity after Gamma Knife surgery for vestibular schwannoma. Neurosurg Focus 27(6):E4, van de Langenberg R, Hanssens PE, Verheul JB, van Overbeeke JJ, Nelemans PJ, Dohmen AJ, et al: Management of large vestibular schwannoma. Part II. Primary Gamma Knife 998 J Neurosurg Volume 127 November 2017

8 Trigeminal neuralgia in vestibular schwannoma surgery: radiological and clinical aspects. J Neurosurg 115: , Yang HC, Kano H, Awan NR, Lunsford LD, Niranjan A, Flickinger JC, et al: Gamma Knife radiosurgery for largervolume vestibular schwannomas. Clinical article. J Neurosurg 114: , Yang I, Sughrue ME, Han SJ, Fang S, Aranda D, Cheung SW, et al: Facial nerve preservation after vestibular schwannoma Gamma Knife radiosurgery. J Neurooncol 93:41 48, Yugrakh MS, Chou DE: Cranial neuralgias and facial pain disorders, in Louis ED, Mayer SA, Rowland LP (eds): Merritt s Neurology, ed 13. Philadelphia: Lippincott Williams & Wilkins, 2015, pp Disclosures 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 Conception and design: Neff. Acquisition of data: Neff. Analysis and interpretation of data: Neff, Van Gompel. Drafting the article: Neff, Carlson, Van Gompel. Critically revising the article: Neff, Carlson, Van Gompel, Driscoll, Link. Reviewed submitted version of manuscript: Neff, Carlson, Driscoll, Link. Approved the final version of the manuscript on behalf of all authors: Neff. Statistical analysis: O Byrne. Supplemental Information Previous Presentations Presented as an oral presentation at the North American Skull Base Society Meeting, Scottsdale, AZ, February 13, Correspondence Brian A. Neff, Department of Otorhinolaryngology, Mayo Clinic, 200 First St. SW, Rochester, MN neff.brian@ mayo.edu. J Neurosurg Volume 127 November