The clinical significance of persistent trigeminal nerve contrast enhancement in patients who undergo repeat radiosurgery

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1 CLINICAL ARTICLE J Neurosurg 127: , 2017 The clinical significance of persistent trigeminal nerve contrast enhancement in patients who undergo repeat radiosurgery Seyed H. Mousavi, MD, 1 Berkcan Akpinar, BA, 2 Ajay Niranjan, MD, 1 Vikas Agarwal, MD, 3 Jonathan Cohen, BA, 2 John C. Flickinger, MD, 4 Douglas Kondziolka, MD, 5 and L. Dade Lunsford, MD 1,4 Departments of 1 Neurological Surgery, 3 Radiology, and 4 Radiation Oncology, University of Pittsburgh Medical Center; 2 University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and 5 Department of Neurological Surgery, New York University Medical Center, New York, New York OBJECTIVE Contrast enhancement of the retrogasserian trigeminal nerve on MRI scans frequently develops after radiosurgical ablation for the management of medically refractory trigeminal neuralgia (TN). The authors sought to evaluate the clinical significance of this imaging finding in patients who underwent a second radiosurgical procedure for recurrent TN. METHODS During a 22-year period, 360 patients underwent Gamma Knife stereotactic radiosurgery (SRS) as their first surgical procedure for TN at the authors center. The authors retrospectively analyzed the data from 59 patients (mean age 72 years, range years) who underwent repeat SRS for recurrent pain at a median of 30 months (range months) after the first SRS. The isocenter was 4 mm, and the median maximum doses for the first and second procedures were 80 Gy and 70 Gy, respectively. A neuroradiologist and a neurosurgeon blinded to the treated side evaluated the presence of nerve contrast enhancement on MRI series at the time of the repeat procedure. The authors correlated the presence of this imaging change with clinical outcomes. Pain outcomes and development of trigeminal sensory dysfunction were evaluated with the Barrow Neurological Institute (BNI) Pain Scale and BNI Numbness Scale, respectively. The mean length of follow-up after the second SRS was 58 months (95% CI months). RESULTS At the time of the repeat SRS, contrast enhancement of the trigeminal nerve on MRI scans was observed in 31 patients (53%). Five years after the SRS, patients with this enhancement had lower actuarial rates of complete pain relief after the repeat SRS (27% [95% CI 7% 47%]) than patients without the enhancement (76% [95% CI 58% 94%]) (p < 0.001). At the 5-year follow-up, patients with the contrast enhancement also had a higher risk for trigeminal sensory loss after repeat SRS (75% [95% CI 59% 91%]) than patients without contrast enhancement (26% [95% CI 10% 42%]) (p = 0.001). Dysesthetic pain after repeat SRS was observed for 8 patients with and for 2 patients without contrast enhancement. CONCLUSIONS Trigeminal nerve contrast enhancement on MRI scans observed at the time of a repeat SRS for TN was associated with less satisfactory pain control and more frequently detected facial sensory loss. Residual contrast enhancement at the time of a repeat SRS may warrant consideration of dose reduction or further separation of the radiosurgical targets. KEY WORDS trigeminal neuralgia; stereotactic radiosurgery; MRI; contrast enhancement; pain Stereotactic radiosurgery (SRS) is the least invasive procedure for managing medically refractory typical trigeminal neuralgia (TN). 10,14,18 In some cases, a 3- to 5-mm zone of contrast enhancement develops after SRS ablation at the radiosurgical trigeminal target seen on high-definition MRI scans. 9,22 In a baboon model, this contrast enhancement was observed at 6 months after SRS and correlated with pathological evidence of both small and large myelinated fiber degeneration and regional inflammation in the retrogasserian nerve. 8 Although the ABBREVIATIONS BNI = Barrow Neurological Institute; BNI-NS = BNI Numbness Scale; BNI-PS = BNI Pain Scale; SRS = stereotactic radiosurgery; TN = trigeminal neuralgia. SUBMITTED January 14, ACCEPTED May 13, INCLUDE WHEN CITING Published online July 29, 2016; DOI: / JNS AANS,

2 S. H. Mousavi et al. development of contrast enhancement of the trigeminal nerve is reported to be a sign of radiosurgical targeting accuracy, 1,12,13 this imaging change is usually verified only at the time of a second SRS procedure. The timing of the development and resolution of this change is not clear. In this report, we sought to evaluate whether residual contrast enhancement of the trigeminal nerve at the time of a repeat SRS procedure correlated with clinical outcomes, that is, with pain relief and trigeminal sensory dysfunction. Methods Patients and Clinical Management Between January 1, 1993, and December 31, 2014, a total of 360 patients with medically refractory typical unilateral TN underwent radiosurgical ablation as initial surgical treatment (Fig. 1). Eighty-one of these patients underwent repeat SRS, 13 of whom were excluded because of neuropathies, resulting in 68 patients who were included in this study and who underwent a repeat SRS for medically refractory and recurrent typical trigeminal pain months after undergoing the first procedure. All patients underwent MRI examinations for target selection, and none had trigeminal neuropathies associated with demyelinating disease, space-occupying lesions, or a previous stroke. Six patients without recent follow-up and 3 patients who died of other causes shortly after the repeat SRS were excluded from this study. As shown in Fig. 1, imaging and clinical outcome data were available for 59 patients (31 of whom were women). The mean age at the time of the repeat SRS was 72 years (range years). Patient follow-ups were arranged by a team member who was not involved in the patients care, and clinical assessments were derived from medical records or by contacting a patient s primary care physician or the patient. Pain outcomes were scored with the Barrow Neurological Institute (BNI) Pain Scale (BNI-PS), 14 in which a score of I is defined as no pain without medications, a score of II as occasional pain but no medication is needed, a score of III as pain free with medications, a score of IV as pain improved with medications but still not controlled, and a score of V is no pain relief with medications. Trigeminal sensory dysfunction following a repeat SRS was assessed with the BNI Numbness Scale (BNI-NS), 4 in which a score of I is defined as preservation of trigeminal sensory function, a score of II as mild trigeminal sensory dysfunction with no bothersome features, a score of III as bothersome trigeminal sensory dysfunction, and a score of IV as very bothersome trigeminal sensory loss. Our institutional review board approved this study. Radiosurgery Method and MRI Protocol The first and second SRSs were performed as previously described. 14 Briefly, after the patient underwent local scalp anesthesia and intravenous sedation, the Leksell model G frame was fitted to the head. To visualize the retrogasserian trigeminal nerve, MRI series were acquired with Gd-enhanced, 3D spoiled gradient recalled acquisition in steady state sequence involving a matrix with 1-mm slice thickness (flip angle 20, TR 19 msec, FIG. 1. Flow chart of patient selection in the present study. number of excitations 2, and field of view mm). These imaging sequences were usually acquired in conjunction with a 3-mm T2-weighted imaging series of the entire head ( matrix, TR 2500 msec, ETL 15, and number of excitations 2) in the axial plane and a 3D fast spin echo 1-mm T2-weighted MRI sequence ( matrix, TR 3000 msec, ETL 32, and number of excitations 1). The acquired MRI series were exported to Leksell Gamma Knife computers, and a team consisting of a neurosurgeon, a radiation oncologist, and medical physicists used the Leksell Gamma Plan to develop the radiosurgical treatment plan. For the first SRS, a single 4-mm beam diameter col- 220

3 Trigeminal nerve contrast enhancement after radiosurgery limator was placed 3 8 mm anterior from the junction of the trigeminal nerve and the pons. After placing of a single isocenter, the 50% and 20% isodose lines were projected. The isocenter was usually located on the trigeminal nerve so that the 20% isodose line touched the brainstem surface. A median maximum target dose of 80 Gy (range Gy) was prescribed. For the second SRS, the dose plan used for the first radiosurgical procedure was coregistered with the stereotactic MRI scans acquired at the time of the second procedure as shown in Fig. 2. The second SRS was conducted at a median of 30 months (range months) after the initial SRS, and the isocenter was placed on the trigeminal nerve 3 4 mm further away from the brainstem than the isocenter in the first SRS to reduce radiation to the brainstem and to limit overlap of the first and second 50% volumes to usually close to 50%. The exact position for the second isocenter depended on the length of the nerve, position of the first isocenter, and resulting dose to the ipsilateral temporal lobe. A 4-mm collimator was used to deliver the median target dose in the second SRS. The median maximum prescription dose for the repeat SRS was 70 Gy (range Gy). This protocol ensures less radiation to the brainstem at each subsequent radiosurgical procedure, while providing additional dose along the trigeminal nerve more proximal to the gasserian ganglion. Image Review Two independent observers, an experienced neurosurgeon (A.N.) and a neuroradiologist (V.A.), who were both blinded to the side of pain and to clinical outcomes, independently reviewed the MRI scans obtained at the time of the second procedure. The contrast enhancement intensity was compared with that on the initial radiosurgical-planning MRI scan. Presence of trigeminal contrast enhancement was scored as present (1) or absent (0). Two additional team members (B.A. and J.C.F.), who were unaware of the presence or absence of nerve contrast enhancement, then correlated this finding with the patients clinical pain response as well as with the degree of trigeminal sensory loss (i.e., dysfunction). The mean follow-up lengths after the first and second radiosurgical procedures were 97 months (95% CI months) and 58 months (95% CI months), respectively. Statistical Analysis Kaplan-Meier analysis was used to assess rates of pain relief and trigeminal sensory dysfunction. Using the Greenwood method, 95% CIs were determined for each estimate presented in Results or tables, and comparisons between subgroups were performed with the Mantel-Cox log-rank test. Time interval and radiation dose comparisons between subgroups were performed with the Wilcoxon rank-sum test. Outcome comparisons of trigeminal sensory loss before and after the second SRS were done with either the Fisher exact test or the chi-square test as appropriate. A Cox proportional hazards regression model was performed by including potential variables contributing to pain relief or sensory loss after the repeat SRS to determine the hazards ratio of nerve contrast enhancement FIG. 2. MRI scans at the time of repeat SRS. A and B: Patient without trigeminal nerve contrast enhancement at the time of repeat SRS. Axial T1-weighted Gd-enhanced MRI series acquired at the time of repeat SRS (B) and T2-weighted MRI scan (A). C and D: Patient with trigeminal nerve contrast enhancement at the time of repeat SRS. Axial T1-weighted Gd-enhanced MRI series acquired at the time of repeat SRS (D) and T2-weighted MRI scan (C). In each panel, the blue circle indicates the 4-mm isocenter in the first SRS, and the yellow circle indicates the 4-mm isocenter in the repeat SRS. Figure is available in color online only. with respect to both outcomes. A p < 0.05 was deemed statistically significant. Patient age at the second SRS (continuous variable), sex (male vs female), side of pain (right vs left), pain-free interval after the first SRS (continuous variable), duration of pain before the first SRS (< 3 years vs 3 years), length of time between first and second SRS (continuous variable), and sensory loss development (yes vs no) were assessed in a stepwise Cox proportional hazards model to assess pain relief.14 Variables deemed significant in the stepwise analysis were included in a nonstepwise Cox proportional hazards regression model including presence versus absence of nerve contrast enhancement at the second SRS to determine the statistical significance of the contrast enhancement in the presence of potentially confounding variables. The above regression analysis was repeated to assess the association of contrast enhancement with the risk for trigeminal sensory dysfunction after repeat SRS. Except for sensory loss, the variables used in the hazards model analyzing pain relief outcomes were used in the initial stepwise analysis. To control for the effect of treatment timing (i.e., the length of the interval after the initial SRS) on the correlation between presence or absence of contrast enhancement and clinical outcome, we performed a case-control analysis by matching patients according to the length of the time intervals between the first and second SRS procedures to within 2 months of each complementary case. Cases and 221

4 S. H. Mousavi et al. TABLE 1. Patient characteristics* Characteristic All (n = 59) Patients w/ Nerve Contrast Enhancement (n = 31) w/o Nerve Contrast Enhancement (n = 28) p Value Mean age in yrs at 1st SRS (range) 68 (32 38) 69 (64 73) 68 (64 73) 0.95 Mean age in yrs at 2nd SRS (range) 72 (33 89) 71 (66 75) 73 (68 77) 0.48 M/F ratio (%) 28:31 (48:52) 18:13 (55:45) 10:18 (36:64) 0.11 Pain incidence (%) 0.59 Rt side 37 (63) 18 (55) 19 (68) Lt side 22 (37) 13 (45) 9 (32) Preexisting facial numbness (%) Yes 11 (19) 9 (29) 2 (7) No 48 (81) 22 (71) 26 (93) Mean duration of pain before 1st SRS in mos (95% CI) 71 (53 89) 94 (64 123) 46 (31 62) Mean interval btwn 1st & 2nd SRS in mos (95% CI) 39 (30 48) 26 (17 35) 53 (39 67) Mean pain-free interval after 1st SRS in mos (95% CI) 32 (24 40) 20 (11 29) 45 (33 58) Mean dose Margin at 1st SRS in Gy (95% CI) 40 (40 41) 40 (39 41) 40 (40 41) 0.32 Margin at 2nd SRS in Gy (95% CI) 34 (33 35) 33 (32 34) 34 (34 35) Max at 1st SRS in Gy (95% CI) 80 (79 81) 80 (77 82) 81 (80 81) 0.32 Max at 2nd SRS in Gy (95% CI) 67 (66 68) 67 (65 68) 68 (67 70) Brainstem at 1st SRS in Gy (95% CI) 25 (22 28) 24 (20 28) 26 (21 31) 0.63 Brainstem at 2nd SRS in Gy (95% CI) 17 (14 20) 18 (13 23) 16 (12 20) 0.96 Temporal at 1st SRS in Gy (95% CI) 12 (10 14) 10 (8 12) 13 (10 17) 0.45 Temporal at 2nd SRS in Gy (95% CI) 13 (10 15) 9 (6 12) 16 (12 21) * Data represent number of patients, unless indicated otherwise. p value was determined with Wilcoxon rank-sum test; p < 0.05 was considered statistically significant. p value was determined with Fisher exact test; p < 0.05 was considered statistically significant. controls were also matched by age at treatment and by sex. This yielded a subcohort of 10 patients with trigeminal nerve contrast enhancement (mean interval between first and second procedure 36 months, 95% CI months) and 10 patients without contrast enhancement (mean interval between first and second SRS 36 months, 95% CI months). For both groups, no difference in this interval was observed among radiosurgical procedures (p = 0.733, Wilcoxon rank-sum test), and beam blocking was not performed in any of the selected patients. These subcohorts were further analyzed for pain relief and sensory loss. Results The characteristics of the patients in the present study are summarized in Table 1. The 2 independent imaging reviewers both reported the same observations related to the presence or absence of trigeminal nerve contrast enhancement. Of the 59 patients in the present study, 31 had enhancement on the treated side, and 28 had no enhancement on the treated side. None of the patients had enhancement on the untreated side. In one patient asymptomatic contrast enhancement developed in the pons. At the time of the repeat SRS, the maximum dose was reduced to 50 Gy for this particular patient. None of the patients developed contrast enhancement or any other imaging changes in the temporal lobe. Nerve Contrast Enhancement and Initial SRS The development of trigeminal nerve contrast enhancement was significantly associated with a longer mean duration of TN before the initial SRS (i.e., 94 months vs 46 months, p = 0.022) (Table 1). This observation indicated that the presence of contrast enhancement was more common in patients who had a longer history of TN. In addition, patients with contrast enhancement had a significantly shorter interval between the first and second SRS procedures than patients without enhancement (26 months vs 53 months, p = 0.001); patients with contrast enhancement also had a significantly shorter mean period of pain relief after the initial SRS (20 months vs 45 months, p = 0.001). Nerve Contrast Enhancement and Repeat SRS Pain Outcome Patients with nerve contrast enhancement had a shorter duration of pain relief without medication (i.e., a BNI-PS score of I) than patients without enhancement (p = 0.006) (Table 2). At the 5-year follow-up, actuarial rate of medication-free pain relief, that is, a BNI-PS score of I, was 21% (95% CI 5% 37%) and 59% (95% CI 41% 77%) for patients with and without contrast enhancement, respectively. In addition, patients with enhancement had a significantly shorter duration of complete pain relief with or without medications (i.e., of BNI-PS scores of I-III) than 222

5 Trigeminal nerve contrast enhancement after radiosurgery TABLE 2. Clinical outcomes Characteristic No. of Patients (95% CI) w/ Nerve Contrast Enhancement (n = 31) w/o Nerve Contrast Enhancement (n = 28) Actuarial rates of BNI-PS Score I outcomes 1 yr 48 (30 66) 96 (88 100) 3 yrs 38 (20 6) 71 (53 89) 5 yrs 21 (5 37) 59 (41 77) 10 yrs 15 (0 31) 21 (0 43) Actuarial rates of BNI-PS Score I III outcomes 1 yr 51 (33 69) 89 (77 100) 3 yrs 40 (22 58) 81 (65 97) 5 yrs 27 (7 47) 76 (58 94) 10 yrs 21 (3 39) 58 (31 85) Actuarial rates of facial numbness 1 yr 45 (27 63) 4 (0 12) 3 yrs 71 (55 87) 26 (10 42) 5 yrs 75 (59 91) 26 (10 42) 10 yrs 83 (65 100) 26 (10 42) p Value* < * p values were determined with the Mantel-Cox log-rank test; p values < 0.05 were considered statistically significant. had patients without enhancement (p < 0.001, Mantel-Cox log-rank test). Five years after the repeat SRS, maintenance of low BNI-PS scores, that is, of a score of I-III, was achieved in 27% (95% CI 7%-47%) of patients with contrast enhancement and in 76% (95% CI 58%-94%) of patients without enhancement. The proportions of patients with contrast enhancement and BNI-PS scores of I III at 1-, 3-, 5-, and 10-year follow-ups were 51%, 40%, 27%, and 21%, respectively. The corresponding proportions for the patients without enhancement and BNI-PS scores of I III were 89%, 81%, 76%, and 58%, respectively (Table 2 and Fig. 3 left). Stepwise Cox proportional hazards regression analysis indicated that patient age at the second SRS, sex, side of pain, length of the interval between the 2 SRS procedures, duration of pain before the first SRS, duration of pain relief after the first SRS, and development of sensory loss after the second SRS did not significantly contribute to pain relief outcomes after the second SRS. Patients with versus those without nerve enhancement had significantly less satisfactory pain relief after the second SRS (hazard ratio 4.05, 95% CI , p = 0.001) as indicated by this regression analysis. In patients with enhancement who did not respond to the repeat SRS, pain quality remained unchanged. Nerve Contrast Enhancement and Trigeminal Sensory Loss Eleven patients (9 with contrast enhancement and 2 without enhancement, p = 0.045, Fisher exact test) had minimal trigeminal sensory loss (i.e., a BNI-NS score of II) before the repeat SRS. At the end of the follow-up period after the second SRS, additional trigeminal sensory dysfunction was noted in 31 patients (53%, 24 with nerve enhancement vs 7 without enhancement, p < 0.001, chisquare test). At the 5-year follow-up after the second SRS, additional or new trigeminal sensory loss (i.e., BNI-NS Score II or higher) was observed in 75% (95% CI 59%- 91%) of patients with trigeminal enhancement and in 26% (95% CI 10%-42%) of patients who did not have contrast enhancement (p = 0.001) (Table 2 and Fig. 3 right). After the repeat SRS, 10 patients (17%) developed dysesthetic pain, of whom 9 had a BNI-NS score of III and 1 had a BNI-NS score of IV. For 8 of these patients, MRI scans showed contrast enhancement at the time of the second SRS. Patient age at the second SRS, sex, side of pain, length of the interval between the first and second SRS procedures, duration of pain relief after the first SRS, and duration of pain before the first SRS did not significantly contribute to the risk for sensory loss after the second SRS. Cox proportional hazards regression analysis indicated that patients with contrast enhancement had a significantly higher risk for developing sensory loss after the repeat SRS than those without enhancement (hazard ratio 4.00, 95% CI , p = 0.001). Radiosurgical Interval and Case-Matched Outcomes To evaluate the effect of the length of the treatment interval between the 2 SRS procedures on final clinical outcomes, patients with or without contrast enhancement of the trigeminal nerve on MRI scans were grouped into 2 subgroups according to the length of this interval (< 2 years or 2 years, 4 subgroups in total). We found that the interval length between the SRS procedures had no significant effect on the level of pain relief (p = 0.74 and p = 0.15 for < 2-year and 2-year intervals, respectively) or risk for developing sensory loss (p = 0.16 and p = 0.53, respectively). In the case-matched cohort analysis, patients with contrast enhancement had less pain relief (p = 0.002) and higher rates of sensory loss (p = 0.013) after the second SRS. Discussion Stereotactic radiosurgery has been used in the management of TN for more than 60 years. 11 Although it is clear that SRS is a neuroablative procedure, the mechanism of action of SRS-induced pain relief in TN is poorly understood. Postmortem trigeminal nerve studies on humans and primates after SRS suggest that high-dose, singlesession radiation leads to axonal degeneration, loss of myelinated and nonmyelinated nerve fibers, and regional inflammation. 8,20 This pathological finding correlates with the presence of contrast enhancement of the retrogasserian trigeminal nerve target on MRI scans. The frequent appearance of contrast enhancement after SRS was further confirmed in several other independent studies. 1,10,12 In the present study, our aim was to evaluate whether the presence of contrast enhancement on MRI scans predicted clinical outcomes, that is, pain relief and sensory dysfunction, in patients who underwent a repeat SRS for recurrent TN. 223

6 S. H. Mousavi et al. FIG. 3. Kaplan-Meier analyses of SRS treatment outcomes. Left: Probability of pain relief after repeat SRS. Patients with trigeminal nerve contrast enhancement (red line) at the time of the repeat SRS had significantly lower rates of pain relief than patients without nerve enhancement (green line) (p < 0.001). Right: Probability of sensory dysfunction (i.e., facial numbness) after repeat SRS. Patients with contrast enhancement (red line) at the time of the repeat SRS had a significantly higher probability of facial numbness than patients without contrast enhancement (green line) (p = 0.001). Figure is available in color online only. Somewhat to our surprise, we found that patients with persistent contrast enhancement at the time of a repeat SRS procedure had less satisfactory pain control and a higher risk for trigeminal neuropathy than patients without this contrast enhancement. Previous reports have indicated that detection of nerve contrast enhancement after SRS was associated with delivery of a higher radiation dose, although this observation varies among studies. 1,3,12,22 The authors of most of these studies concluded that presence or absence of contrast enhancement after SRS did not correlate with a clinical response. Despite the high rate of an initial positive response to SRS treatment, TN is refractory to this treatment in some patients, 14 and additional procedures are therefore necessary in these patients. Previous studies have reported that repeat SRS is effective in patients who have benefited from an initial SRS to manage TN. These studies have noted variable pain outcomes and rates of trigeminal sensory dysfunction, 2,4 6,15,21 and additional sensory loss was reported as one of the complications of repeat SRS. Although some authors have suggested that the presence of facial numbness after an SRS procedure is associated with better pain relief, others have noted an absence of this correlation. 7,14,16,17,19 Some of these ambiguities in clinical outcomes could be due to heterogeneity of surgical histories for TN, type of TN, short-term follow-up, and lack of blinded evaluation in these reports. To minimize the effects of these potential confounders, we excluded all patients with atypical pain and those with trigeminal neuropathies resulting from previous surgical procedures. Patients often select SRS for TN, and it is also often recommended to them because of its minimally invasive nature. In this series of patients with medically refractory TN, pain relief was achieved in all patients after the first SRS. However, recurrent typical and medically refractory TN developed and warranted a repeat surgical procedure. In the experience reported here, the development and persistence of trigeminal nerve contrast enhancement on MRI scans was associated with less satisfactory pain control and a higher risk for trigeminal sensory dysfunction. Therefore, if a contrast-enhanced MRI scan immediately before a repeat SRS reveals persistent contrast enhancement of the trigeminal nerve, further reduction of the second radiosurgical dose or modification of the anatomical target may be warranted. Strengths and Limitations The clinical relevance of contrast enhancement of the trigeminal nerve at the time of a repeat SRS requires additional study. The current study is limited by its retrospective nature, lack of a control group, and failure to assess whether the contrast enhancement of the trigeminal nerve was also present in patients who did not require a second SRS procedure. Patients with persistent contrast enhancement had a shorter median time interval between the first and second SRS procedures than patients without nerve enhancement and may therefore reflect a subset of patients in whom SRS treatment failed early to control TN. We note that any contrast enhancement may slowly fade over time and may therefore be less likely to be detected in patients in whom pain control failed later. Conclusions Presence of contrast enhancement of the trigeminal nerve on MRI scans observed at the time of a repeat SRS for TN was associated with less satisfactory pain control and more frequently detected facial sensory loss. Residual contrast enhancement at the time of a repeat SRS may warrant consideration of radiation dose reduction or further separation of the radiosurgical targets. References 1. Alberico RA, Fenstermaker RA, Lobel J: Focal enhancement of cranial nerve V after radiosurgery with the Leksell Gamma Knife: experience in 15 patients with medically refractory trigeminal neuralgia. AJNR Am J Neuroradiol 22: ,

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