Stereotactic Radiosurgery for Trigeminal Neuralgia in Patients With Multiple Sclerosis: A Multicenter Study

Stereotactic Radiosurgery for Trigeminal Neuralgia in Patients With Multiple Sclerosis: A... Abstract BACKGROUND Facial pain response (PR) to various surgical interventions in patients with multiple sclerosis (MS)-related trigeminal neuralgia (TN) is much less optimal. No large patient series regarding stereotactic radiosurgery (SRS) has been published. OBJECTIVE To evaluate the clinical outcomes of MS-related TN treated with SRS. METHODS This is a retrospective cohort study. A total of 263 patients contributed by 9 member tertiary referral Gamma Knife centers (2 in Canada and 7 in USA) of the International Gamma Knife Research Consortium (IGKRF) constituted this study. RESULTS The median latency period of PR after SRS was 1 mo. Reasonable pain control (Barrow Neurological Institute [BNI] Pain Scores I-IIIb) was achieved in 232 patients (88.2%). The median maintenance period from SRS was 14.1 months (range, 10 days to 10 years). The actuarial reasonable pain control maintenance rates at 1 yr, 2 yr, and 4 yr were 54%, 35%, and 24%, respectively. There was a correlation between the status of achieving BNI-I and the maintenance of facial pain recurrence-free rate. The median recurrence-free rate was 36 mo and 12.2 mo in patients achieving BNI-I and BNI > I, respectively (P = .046). Among 210 patients with known status of post-SRS complications, the new-onset of facial numbness (BNI-I or II) after SRS occurred in 21 patients (10%). CONCLUSION In this largest series SRS offers a reasonable benefit to risk profile for patients who have exhausted medical management. More favorable initial response to SRS may predict a long-lasting pain control. Gamma Knife radiosurgery, Multiple sclerosis, Pain relief, Stereotactic radiosurgery, Trigeminal neuralgia ABBREVIATIONS ABBREVIATIONS BNI Barrow Neurological Institute GKRS Gamma Knife radiosurgery LINAC linear particle accelerator MRI magnetic resonance imaging MS multiple sclerosis MVD microvascular decompression PBC percutaneous balloon compression SRS stereotactic radiosurgery TN trigeminal neuralgia Trigeminal neuralgia (TN) develops in approximately 2% of patients with multiple sclerosis (MS), and this incidence is 20 times more than within the general population.1 No consensus has been reached regarding the best surgical treatment modality owing to the lack of prospective studies.2 The clinical outcomes of the most commonly employed surgical interventions including microvascular decompression (MVD)3 and percutaneous glycerol or radiofrequency rhizotomy provide a lower rate of response and durability of pain relief in this cohort of patients.4-6 For idiopathic TN, stereotactic radiosurgery (SRS) plays an important role in treatment owing to its reasonable efficacy and the low profile of potential complications, which include facial hypoesthesia.7-12 The utilization of SRS to treat MS-related TN was a natural extension based upon its prior success with treating classic TN patients. In several small studies of MS-related TN patients, the pain relief after SRS has been achieved in a majority of patients treated with a range of 80% to 97%.3,6-10 MS-related TN patients represent a challenging demographic to treat. Within the SRS subspecialty, no large series has been published to date. Therefore, a multicenter study systematically investigating the safety and effectiveness of SRS in MS-related patients is warranted. We aimed to evaluate the clinical outcome regarding pain control and prognostic factors including the radiation dose, time interval between the last surgical procedure and SRS, and other common patient characteristics. METHODS Patient Selection The approval of the institutional review boards at individual institutions was obtained prior to the investigation. The consent form was not required. The inclusion criteria are as follows: (1) diagnosed medically refractory TN in patients with clinically confirmed MS at each of the participating institutions, (2) adequate patient demographics, treatment course of MS and MS-related TN, Gamma Knife radiosurgery (GKRS; Elekta Instruments AB, Stockholm, Sweden) parameters, and adequate clinical follow-up. We excluded those patients who were previously treated with GKRS or Linear particle accelerator (LINAC)-based SRS at other institutions, or other secondary TN patients in whom facial pain was attributed to a tumor or arteriovenous malformation involving the GKRS-treated nerve. Notably, the goal of this study was to investigate the response to GKRS. Therefore, patients were censored prior to the initiation of the further treatment following the first GKRS including repeat GKRS. Nine institutions contributed 263 patients (81 male and 182 female) with MS-related medically intractable TN to this study shown as follows: Beaumont Health System (25 patients), University of Pittsburgh Medical Center (35 patients), University of Virginia Health System (36 patients), Cleveland Clinic (56 patients), New York University (6 patients), University of Pennsylvania (24 patients), University of Manitoba (17 patients), University of Sherbrooke (60 patients), and Yale University School of Medicine (4 patients). Exclusion criteria were composed of loss to follow-up (33 patients [11%]), and the inability to complete the questionnaire due to confusion (1 patient). Among them, there were 17 patients who claimed no improvement following GKRS, although the actual latency time interval was unknown. The records of MS-related TN patients who underwent GKRS between 1994 and 2015 were reviewed by each institution for inclusion (Table 1). In the 22 patients (8.4%) who developed bilateral facial pain, the analysis was conducted to the treated side with GKRS or the first treated side by GKRS. Prior to the GKRS, 87 patients (33%) had undergone at least one surgical procedure including MVD, percutaneous balloon compression, radiofrequency rhizotomy, glycerol rhizotomy, and infraorbital neurectomy (Table 2). The median follow-up after GKRS in the entire cohort of patients was 17 mo (range, 0.5-144 mo). TABLE 1. Patient Characteristics and GKRS Parameters Variable  Patient number  Median  Range, L  Range, H  Age (yr)    57  31  90   Male  81 (31%)  58  36  79   Female  182 (69%)  57  31  90  Sidea           Left side  110 (42%)         Right side  153 (58%)        Bilateral facial pain  22 (8.4%)        Time interval Sxb (mo)    24  1  204  Margin dose (Gy)    40  20  45  Variable  Patient number  Median  Range, L  Range, H  Age (yr)    57  31  90   Male  81 (31%)  58  36  79   Female  182 (69%)  57  31  90  Sidea           Left side  110 (42%)         Right side  153 (58%)        Bilateral facial pain  22 (8.4%)        Time interval Sxb (mo)    24  1  204  Margin dose (Gy)    40  20  45  aIn patients with bilateral TN and treated with GKRS, only the first treated side was counted here. bTime interval between the last surgical procedure and GKS. View Large TABLE 1. Patient Characteristics and GKRS Parameters Variable  Patient number  Median  Range, L  Range, H  Age (yr)    57  31  90   Male  81 (31%)  58  36  79   Female  182 (69%)  57  31  90  Sidea           Left side  110 (42%)         Right side  153 (58%)        Bilateral facial pain  22 (8.4%)        Time interval Sxb (mo)    24  1  204  Margin dose (Gy)    40  20  45  Variable  Patient number  Median  Range, L  Range, H  Age (yr)    57  31  90   Male  81 (31%)  58  36  79   Female  182 (69%)  57  31  90  Sidea           Left side  110 (42%)         Right side  153 (58%)        Bilateral facial pain  22 (8.4%)        Time interval Sxb (mo)    24  1  204  Margin dose (Gy)    40  20  45  aIn patients with bilateral TN and treated with GKRS, only the first treated side was counted here. bTime interval between the last surgical procedure and GKS. View Large TABLE 2. Surgical Procedures Prior to GKRS No of Intervention  Patient number  % in subgroup  % in entire group  1  n = 53    61   PBC  7  13     GR  28  53     MVD  6  11     RF  12  23    2  n = 20    23   PBC + GR  2  10     GR + IN  2  10     PBC + RF  1  5     RF × 2  2  10     PBC × 2  1  5     GR × 2  n = 10  50     MVD × 2  1  5     MVD + IN  1  5    3  n = 6    7  >3  n = 8    9  No of Intervention  Patient number  % in subgroup  % in entire group  1  n = 53    61   PBC  7  13     GR  28  53     MVD  6  11     RF  12  23    2  n = 20    23   PBC + GR  2  10     GR + IN  2  10     PBC + RF  1  5     RF × 2  2  10     PBC × 2  1  5     GR × 2  n = 10  50     MVD × 2  1  5     MVD + IN  1  5    3  n = 6    7  >3  n = 8    9  GKRS, Gamma Knife radiosurgery; PBC, percutaneous balloon compression; GR, glycerol rhizotomy; MVD, microvascular decompression; RF, radiofrequency rhizotomy; IN, infraorbital neurectomy. View Large TABLE 2. Surgical Procedures Prior to GKRS No of Intervention  Patient number  % in subgroup  % in entire group  1  n = 53    61   PBC  7  13     GR  28  53     MVD  6  11     RF  12  23    2  n = 20    23   PBC + GR  2  10     GR + IN  2  10     PBC + RF  1  5     RF × 2  2  10     PBC × 2  1  5     GR × 2  n = 10  50     MVD × 2  1  5     MVD + IN  1  5    3  n = 6    7  >3  n = 8    9  No of Intervention  Patient number  % in subgroup  % in entire group  1  n = 53    61   PBC  7  13     GR  28  53     MVD  6  11     RF  12  23    2  n = 20    23   PBC + GR  2  10     GR + IN  2  10     PBC + RF  1  5     RF × 2  2  10     PBC × 2  1  5     GR × 2  n = 10  50     MVD × 2  1  5     MVD + IN  1  5    3  n = 6    7  >3  n = 8    9  GKRS, Gamma Knife radiosurgery; PBC, percutaneous balloon compression; GR, glycerol rhizotomy; MVD, microvascular decompression; RF, radiofrequency rhizotomy; IN, infraorbital neurectomy. View Large Each participating center had prospectively maintained their own dataset of patients who had undergone GKRS for MS-related TN. Selected variables organized on an Excel spreadsheet (Microsoft Inc, Redmond, Washington) were designed and created by the first author (Z.X.) with the modifications suggested by various co-authors. All the patients’ medical records were reviewed, and the data were de-identified and shared with an independent third party who confirmed regulatory compliance before sending the data to the first author (Z.X.), who drafted this assessment on behalf of the IGKRF. Gamma Knife Radiosurgery Model U, B, C, 4C, or Perfexion GK units (Elekta Instrument AB) were used, depending on the technology available and time of treatment at participating centers. Generally, a Leksell Model G stereotactic frame (Elekta Instrument AB) was placed to each patient under local anesthesia. Thereafter, a high-resolution, stereotactic magnetic resonance imaging (MRI) was performed. Thin-sliced (1 mm) T1-weighted and constructive interference in steady state magnetic resonance images were obtained after the administration of paramagnetic contrast. GKRS dose planning was then conducted by a medical team comprised of a neurosurgeon, a radiation oncologist, and a medical physicist at each institution. Radiosurgery targeted the afflicted trigeminal nerve. The targeting location along the trigeminal nerve varied based upon the anatomy as well as the experience and preference of each clinical team. In general, a single isocenter was used, the 4-mm collimator was targeted 2 to 8 mm anterior to the junction of the trigeminal nerve and pons. As a result, the radiation dose at the lateral edge of the brainstem varied up to a highest dose of 24 Gy. The median prescription dose delivered to the nerve was 40 Gy (range 20-45 Gy) and the corresponding isodose line used was 50%. The maximum dose to the afflicted nerve varied from 40 to 90 Gy (median 80 Gy; Figure 1). GKRS was the upfront treatment option for MS-related TN in 153 patients (58.2%). A neurovascular compression was identified on MRI in 35 patients (13.3%). FIGURE 1. View largeDownload slide Distribution of maximum dose in all patients. FIGURE 1. View largeDownload slide Distribution of maximum dose in all patients. Definition and Statistical Analysis No consensus has been reached with respect to the pain relief outcome in MS-related TN patients. Herein, we employed the well-established Barrow Neurological Institute (BNI) pain intensity scale,13,14 whereas SRS-induced facial numbness was defined using BNI Scores I to IV as previously described.13,14 Treatment failure was defined as a reported pain score that was classified as a BNI pain score of IV or V after the initial GKRS. Reasonable pain relief was defined as a BNI score from I to IIIb. For those patients, only data from the first GKRS were statistically analyzed in this study; pain control after further GKRS was not included in the statistical analyses. The comparison of length of pain relief maintenance was performed using the Kaplan–Meier product-limit method. Patients were censored if they were lost to follow-up or remained pain recurrence-free at the last follow-up assessing the pain level. The correlations of clinical outcomes were investigated using the Cox proportional hazards regression models in terms of patient characteristics and treatment parameters detailed in Table 1. Those investigated variables were selected based upon the clinical experience and previous publications. Generally, patients were contacted by phone within 2 mo after SRS concerning the pain improvement. The clinical and imaging follow-up was completed up to 6 mo after SRS at the initial evaluation. All statistical analyses were conducted using R programing (R Core Team (2016)). R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL: https://www.R-project.org. All statistical analyses were 2-tailed and a P-value less than .05 was deemed statistically significant. RESULTS Initial Response to SRS After SRS, the initial pain response of BNI-I was achieved in 54 patients (29.3%) with a median time interval of one month (range, 1 d to 14.1 mo) among 184 patients whose initial response was known. No correlation was identified using prognostic factors including age at the initial SRS, gender, laterality (unilateral vs bilateral), afflicted side, time interval between the last surgical procedure and SRS, status of previous surgical management, and maximum dose to the afflicted nerve (Table 3). Seventeen patients claimed no pain improvement at all; however, no follow-up time was documented. In this case, we can only assume that adequate follow-up was performed in each participating center before no improvement was declared by the clinical team. TABLE 3. Binary Logistic Regression Analysis of Achieving Pain Relief of BNI-I After the Initial GKS Variable  P-value  HR  95% CI_lower  95% CI_upper  Age (parametric)  .94  1.00  0.97  1.03  Gender (male vs female)  .49  1.26  0.64  2.44  Bilateral vs unilateral  .14  0.32  0.05  1.22  Afflicted side (left vs right)  .86  1.06  0.55  2.03  Time interval Sxa  .66  1.00  0.99  1.02  Margin dose (parametric)  .93  0.99  0.85  1.15  Variable  P-value  HR  95% CI_lower  95% CI_upper  Age (parametric)  .94  1.00  0.97  1.03  Gender (male vs female)  .49  1.26  0.64  2.44  Bilateral vs unilateral  .14  0.32  0.05  1.22  Afflicted side (left vs right)  .86  1.06  0.55  2.03  Time interval Sxa  .66  1.00  0.99  1.02  Margin dose (parametric)  .93  0.99  0.85  1.15  aTime interval between the last surgical procedure and the first GKRS; CI, confidence interval. View Large TABLE 3. Binary Logistic Regression Analysis of Achieving Pain Relief of BNI-I After the Initial GKS Variable  P-value  HR  95% CI_lower  95% CI_upper  Age (parametric)  .94  1.00  0.97  1.03  Gender (male vs female)  .49  1.26  0.64  2.44  Bilateral vs unilateral  .14  0.32  0.05  1.22  Afflicted side (left vs right)  .86  1.06  0.55  2.03  Time interval Sxa  .66  1.00  0.99  1.02  Margin dose (parametric)  .93  0.99  0.85  1.15  Variable  P-value  HR  95% CI_lower  95% CI_upper  Age (parametric)  .94  1.00  0.97  1.03  Gender (male vs female)  .49  1.26  0.64  2.44  Bilateral vs unilateral  .14  0.32  0.05  1.22  Afflicted side (left vs right)  .86  1.06  0.55  2.03  Time interval Sxa  .66  1.00  0.99  1.02  Margin dose (parametric)  .93  0.99  0.85  1.15  aTime interval between the last surgical procedure and the first GKRS; CI, confidence interval. View Large Maintenance of Pain Relief Following initial SRS, reasonable pain control (defined as BNI-I-IIIb) was achieved in 232 patients (88.2%). The maintenance of a reasonable pain relief is illustrated in Figure 2. The median maintenance time interval was 14.1 mo (range, 10 d-10 yr). The actuarial pain recurrence-free rates were 54%, 35%, and 24% at 1 yr, 2 yr, and 4 yr following the first SRS, respectively. Interestingly, there was a statistically significant correlation between achieving BNI-I and the maintenance of facial pain recurrence-free rate (Figure 3). The median recurrence-free rate was 36 mo and 12.2 mo in patients achieving BNI-I and those of BNI greater than I, respectively (log-rank test, P = .046). Further analyses did not reveal any correlation between the maintenance of facial pain recurrence-free rate and the following prognostic factors including age at the first SRS, gender, laterality, afflicted side, maximum dose, status of previous surgical management, and the time interval between the last surgical procedure prior to SRS and SRS (Table 4). FIGURE 2. View largeDownload slide Kaplan–Meier plot of reasonable facial pain relief maintenance in the entire cohort. FIGURE 2. View largeDownload slide Kaplan–Meier plot of reasonable facial pain relief maintenance in the entire cohort. FIGURE 3. View largeDownload slide Comparison of cumulative facial pain recurrence-free rate in relation to the status of initial facial pain relief using Kaplan–Meier method. FIGURE 3. View largeDownload slide Comparison of cumulative facial pain recurrence-free rate in relation to the status of initial facial pain relief using Kaplan–Meier method. TABLE 4. Univariate Analysis of Maintenance of Reasonable Pain Relief After the Initial GKS Variable  P-value  HR  95% CI_L  95% CI_U  Age  .3  0.99  0.97  1.01  Gendera  .12  0.72  0.48  1.09  Bilateralb  .27  0.67  0.32  1.38  Afflicted side  .95  0.99  0.66  1.48  Time intervalc  .7  1.07  0.77  1.48  Maximum dose  .27  0.96  0.88  1.04  Initial pain reliefd  .046  0.609  0.374  0.991  Variable  P-value  HR  95% CI_L  95% CI_U  Age  .3  0.99  0.97  1.01  Gendera  .12  0.72  0.48  1.09  Bilateralb  .27  0.67  0.32  1.38  Afflicted side  .95  0.99  0.66  1.48  Time intervalc  .7  1.07  0.77  1.48  Maximum dose  .27  0.96  0.88  1.04  Initial pain reliefd  .046  0.609  0.374  0.991  CI, confidence interval. aMale vs female. bBilateral involvement vs unilateral. cBetween the last surgical procedure and GKS. dBNI score > I vs BNI-I. View Large TABLE 4. Univariate Analysis of Maintenance of Reasonable Pain Relief After the Initial GKS Variable  P-value  HR  95% CI_L  95% CI_U  Age  .3  0.99  0.97  1.01  Gendera  .12  0.72  0.48  1.09  Bilateralb  .27  0.67  0.32  1.38  Afflicted side  .95  0.99  0.66  1.48  Time intervalc  .7  1.07  0.77  1.48  Maximum dose  .27  0.96  0.88  1.04  Initial pain reliefd  .046  0.609  0.374  0.991  Variable  P-value  HR  95% CI_L  95% CI_U  Age  .3  0.99  0.97  1.01  Gendera  .12  0.72  0.48  1.09  Bilateralb  .27  0.67  0.32  1.38  Afflicted side  .95  0.99  0.66  1.48  Time intervalc  .7  1.07  0.77  1.48  Maximum dose  .27  0.96  0.88  1.04  Initial pain reliefd  .046  0.609  0.374  0.991  CI, confidence interval. aMale vs female. bBilateral involvement vs unilateral. cBetween the last surgical procedure and GKS. dBNI score > I vs BNI-I. View Large Post-SRS Complications In 210 patients with known status of complications following the first SRS, only 21 patients (10%) experienced hypoesthesia, while 2 patients (0.95%) developed paresthesia, and 1 patient (0.48%) experienced both symptoms. Owing to the limited number of post-SRS complication events, no inferential statistical analysis was performed. None of the patients had facial hypoesthesia was greater than BNI-II in this cohort of patients with a median time interval of 3 mo (range, 1 wk-55.7 mo) following the first SRS. None of patients experienced a trigeminal motor deficit, any other cranial nerve deficit, or anesthesia dolorosa following SRS. Further Treatment After Failed SRS Further surgical interventions for the failure of pain control were observed in 116 patients (44%). Table 5 displays the first surgical intervention after the failure of the initial SRS. Among 44 patients undergoing repeat SRS, 17 patients had a detailed follow-up. The median maximum dose was 70 Gy (range 65 Gy-90 Gy). BNI-I facial pain control was achieved in nine patients (53%), BNI-IIIa in 7 patients (41%), and no pain relief in 1 patient (6%). In general, those patients underwent multiple surgical procedures or combinations with various responses. TABLE 5. The First Further Surgical Intervention After the Failed GKRS Intervention  Patient number  Median time interval after first failed GKRS (mo)  Range, low (mo)  Range, high (mo)  GKRSa  44 (19%)  27.5  12 d  144  Percutaneous balloon compression  20 (8.5%)  10.6  15 d  46  Glycerol rhizotomy  38 (16%)  11.5  2  96  Radiofrequency rhizotomy  11 (4.7%)  9  4  58.3  Infraorbital neurolectomy  2 (0.8%)  15  10  20  Microvascular decompression  1 (0.4%)  6.2  6.2  6.2  Intervention  Patient number  Median time interval after first failed GKRS (mo)  Range, low (mo)  Range, high (mo)  GKRSa  44 (19%)  27.5  12 d  144  Percutaneous balloon compression  20 (8.5%)  10.6  15 d  46  Glycerol rhizotomy  38 (16%)  11.5  2  96  Radiofrequency rhizotomy  11 (4.7%)  9  4  58.3  Infraorbital neurolectomy  2 (0.8%)  15  10  20  Microvascular decompression  1 (0.4%)  6.2  6.2  6.2  aGKRS: Gamma Knife radiosurgery (Elekta Instruments AB). View Large TABLE 5. The First Further Surgical Intervention After the Failed GKRS Intervention  Patient number  Median time interval after first failed GKRS (mo)  Range, low (mo)  Range, high (mo)  GKRSa  44 (19%)  27.5  12 d  144  Percutaneous balloon compression  20 (8.5%)  10.6  15 d  46  Glycerol rhizotomy  38 (16%)  11.5  2  96  Radiofrequency rhizotomy  11 (4.7%)  9  4  58.3  Infraorbital neurolectomy  2 (0.8%)  15  10  20  Microvascular decompression  1 (0.4%)  6.2  6.2  6.2  Intervention  Patient number  Median time interval after first failed GKRS (mo)  Range, low (mo)  Range, high (mo)  GKRSa  44 (19%)  27.5  12 d  144  Percutaneous balloon compression  20 (8.5%)  10.6  15 d  46  Glycerol rhizotomy  38 (16%)  11.5  2  96  Radiofrequency rhizotomy  11 (4.7%)  9  4  58.3  Infraorbital neurolectomy  2 (0.8%)  15  10  20  Microvascular decompression  1 (0.4%)  6.2  6.2  6.2  aGKRS: Gamma Knife radiosurgery (Elekta Instruments AB). View Large Upfront or Secondary SRS There was no statistically significant difference regarding the maintenance of pain control in patients treated with an upfront SRS or a secondary SRS (log-rank test, P = .487). Meanwhile, there was also no difference regarding the possibility of achieving a BNI-I pain control in these two groups (logistic regression, P = .172, odds ratio = 0.632, 95% confidence interval, 0.328-1.228; Table 3). Furthermore, facial hypoesthesia developed in 17 patients and paresthesia in 2 patients in the upfront SRS group whereas new-onset of hypoesthesia was in 4 patients and both hypoesthesia and paresthesia developed in one patient treated twice with SRS (Fisher's exact test, P = .124). DISCUSSION To the best of our knowledge, the current report represents the largest multicenter series regarding the treatment of MS-related TN patients with SRS. Furthermore, this report's cohort size permitted the computation of detailed inferential statistical analyses. The findings suggested that patients achieving BNI-I following the first SRS were likely to maintain the reasonable pain control for a longer period of time compared with those whose response score was greater than I on the BNI facial pain scale. This information is valuable for clinical decision making and in particular helps guide the timing of treatment for patients and their clinicians. SRS has been utilized as an established treatment modality for this group of patients, which was reported sporadically. Previous small series studies on SRS-treating patients with MS-related TN revealed that a pain relief rate of 60% to 80% was obtained (Table 6).15-20 MS is considered a negative predictive factor in most series including MVD and percutaneous rhizotomy. In one study, Rogers et al18 achieved a high level of success in a study of 15 MS-associated TN patients undergoing SRS. At a mean follow-up of 17 mo, 80% of patients had experienced pain relief using an initial dose of 70 to 90 Gy. Five patients underwent repeat SRS to the same treatment area with a mean maximum dose of 48 Gy. All 5 patients attained some pain relief and 60% were able to discontinue their pain medication.18 Most recently, Weller et al15 reported the clinical outcomes of a series of 35 patients with MS-related TN treated with SRS with a median maximum dose of 90 Gy. With a median follow-up of 39 mo, 88% patients experienced a BNI I to III at 3 mo after SRS and the actuarial freedom from BNI IV-V pain relapse was 57, 57, and 52% at 1, 2, and 5 yr, respectively. Nonbothersome facial numbness secondary to SRS developed in 39% of patients.15 To date, one of the largest series published by the Pittsburgh group reveals that in 37 patients including 78% who failed the previous surgeries, 23 patients achieved complete pain relief (BNI-I), and 36 patients (97%) had a reasonable pain control (BNI I-IIIb) at a median follow-up of 57 mo.16 Reasonable pain relief maintenance was obtained in 83%, 74%, and 54% of patients at 1, 3, and 5 yr, respectively following SRS. Nondisabling paresthesias developed in 5.4% patients. Although more investigations are warranted to assess the long-term success and toxicity (in particular the development of troublesome facial numbness) of SRS, SRS proves effective and safe due to a reasonably favorable complication profile. TABLE 6. Literature Review of SRS for Patients With MS-Related TN Author/year  No.  Median follow-up (mo)  Age (M)  Median maximum dose/range (Gy)  time to pain response (d)  Initial response (%)  Pain control 1 yr  Pain control 2/3 yr  Pain control 5year  Facial numbness (%)  Weller 201415  35  39  62 (39-86)  90 (80-90)  42 (2-170)  82  57  57  52  39  Zorro 200916  37  56.7  59 (38-74)  80 (70-90)  7 (1-90)  97.3  82.6  73.9  54  5  Huang 200217  7  17  63 (45-85)  80 (70-90)  13 (1-61)  80  –  –  -  13  Rogers 200218  15  19 (2-96)  68  85 (70-90)  –  –  –  –  -  -  Mathieu 201219  27  39 (13-69)  59 (42-78)  80 (80-90)  –  81.5  –  –  -  22  Tuleasca 201420  43  53.8  57 (36-83)  85 (75-90)  30 (0-90)  90.7  87.2a  71.8a  43.1a  16  Author/year  No.  Median follow-up (mo)  Age (M)  Median maximum dose/range (Gy)  time to pain response (d)  Initial response (%)  Pain control 1 yr  Pain control 2/3 yr  Pain control 5year  Facial numbness (%)  Weller 201415  35  39  62 (39-86)  90 (80-90)  42 (2-170)  82  57  57  52  39  Zorro 200916  37  56.7  59 (38-74)  80 (70-90)  7 (1-90)  97.3  82.6  73.9  54  5  Huang 200217  7  17  63 (45-85)  80 (70-90)  13 (1-61)  80  –  –  -  13  Rogers 200218  15  19 (2-96)  68  85 (70-90)  –  –  –  –  -  -  Mathieu 201219  27  39 (13-69)  59 (42-78)  80 (80-90)  –  81.5  –  –  -  22  Tuleasca 201420  43  53.8  57 (36-83)  85 (75-90)  30 (0-90)  90.7  87.2a  71.8a  43.1a  16  No, number of patients. aBNI-I; –, not applicable or available. View Large TABLE 6. Literature Review of SRS for Patients With MS-Related TN Author/year  No.  Median follow-up (mo)  Age (M)  Median maximum dose/range (Gy)  time to pain response (d)  Initial response (%)  Pain control 1 yr  Pain control 2/3 yr  Pain control 5year  Facial numbness (%)  Weller 201415  35  39  62 (39-86)  90 (80-90)  42 (2-170)  82  57  57  52  39  Zorro 200916  37  56.7  59 (38-74)  80 (70-90)  7 (1-90)  97.3  82.6  73.9  54  5  Huang 200217  7  17  63 (45-85)  80 (70-90)  13 (1-61)  80  –  –  -  13  Rogers 200218  15  19 (2-96)  68  85 (70-90)  –  –  –  –  -  -  Mathieu 201219  27  39 (13-69)  59 (42-78)  80 (80-90)  –  81.5  –  –  -  22  Tuleasca 201420  43  53.8  57 (36-83)  85 (75-90)  30 (0-90)  90.7  87.2a  71.8a  43.1a  16  Author/year  No.  Median follow-up (mo)  Age (M)  Median maximum dose/range (Gy)  time to pain response (d)  Initial response (%)  Pain control 1 yr  Pain control 2/3 yr  Pain control 5year  Facial numbness (%)  Weller 201415  35  39  62 (39-86)  90 (80-90)  42 (2-170)  82  57  57  52  39  Zorro 200916  37  56.7  59 (38-74)  80 (70-90)  7 (1-90)  97.3  82.6  73.9  54  5  Huang 200217  7  17  63 (45-85)  80 (70-90)  13 (1-61)  80  –  –  -  13  Rogers 200218  15  19 (2-96)  68  85 (70-90)  –  –  –  –  -  -  Mathieu 201219  27  39 (13-69)  59 (42-78)  80 (80-90)  –  81.5  –  –  -  22  Tuleasca 201420  43  53.8  57 (36-83)  85 (75-90)  30 (0-90)  90.7  87.2a  71.8a  43.1a  16  No, number of patients. aBNI-I; –, not applicable or available. View Large No other treatment options fare better for this group of patients. Symptom recurrence rate was as high as 86% in a very small cohort of 17 patients treated with percutaneous balloon compression (PBC) for MS-related TN. In the meantime, complications secondary to PBC including dysesthesia, cheek hematoma, masseter weakness, abducens palsy, and meningitis were common, although they were relatively mild or transient as described by the investigators.21 In our study, we did not observe any severe complications. The results further underscored the low-risk profile in the SRS treatment modality. Of note, in contrast to GKRS, LINAC-based SRS could lead to a severe clinic sequela. Recently, there is one case report which indicated that LINAC-based ExacTrac was likely to be attributed to a severe neurological deficit in a patient with late-diagnosed MS-related TN.22 Limitations Although this is the largest series in the field of SRS for MS-related TN patients, it still contains some intrinsic limitations. First, as a retrospective study, recall bias inevitably proves to be an issue. Second, the location of targeting was unknown in the majority of patients, which rendered the analysis inconclusive. We posit this might be a prognostic factor based on our previous study.13 Third, the outcome of multiple centers varies due to selection bias. Fourth, the different response to GKRS was likely attributed to the type of MS, these data may provide better insight to predict the outcome in this cohort of patients. Fifth, the lack of complete complication status in some patients is noticeable. CONCLUSION The current largest series of MS-related TN patients treated with SRS suggested that, given a very favorable low-risk complication profile, SRS should be considered as a first-line treatment option or an adjunct one. Patients who experienced an initial favorable response (BNI-I) were more likely to achieve an extended reasonable pain control. Multimodality treatment is the key in managing those subgroup of MS-related TN patients. Disclosures Dr Lunsford is a consultant and shareholder in AB Elekta, the manufacturer of Gamma Knife®. Dr Grills has a stock ownership in a company called Greater Michigan Gamma Knife, and also holds a grant from Elekta Collaborative Lung Research Group. The other authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. Notes This material was presented as an e-poster at the 2017 annual ASTRO meeting, September 25, 2017, in San Diego, California. REFERENCES 1. Love S, Gradidge T, Coakham HB. Trigeminal neuralgia due to multiple sclerosis: ultrastructural findings in trigeminal rhizotomy specimens. Neuropathol Appl Neurobiol . 2001; 27( 3): 238– 244. Google Scholar CrossRef Search ADS PubMed  2. Montano N, Papacci F, Cioni B, Di Bonaventura R, Meglio M. What is the best treatment of drug-resistant trigeminal neuralgia in patients affected by multiple sclerosis? A literature analysis of surgical procedures. Clin Neurol Neurosurg . 2013; 115( 5): 567– 572. Google Scholar CrossRef Search ADS PubMed  3. Sandell T, Eide PK. The effect of microvascular decompression in patients with multiple sclerosis and trigeminal neuralgia. Neurosurgery . 2010; 67( 3): 749– 754; discussion 753-744. Google Scholar CrossRef Search ADS PubMed  4. Cheng JS, Sanchez-Mejia RO, Limbo M, Ward MM, Barbaro NM. Management of medically refractory trigeminal neuralgia in patients with multiple sclerosis. Neurosurg Focus . 2005; 18( 5): 1– 5. Google Scholar CrossRef Search ADS   5. Ariai MS, Mallory GW, Pollock BE. Outcomes after microvascular decompression for patients with trigeminal neuralgia and suspected multiple sclerosis. World Neurosurg . 2014; 81( 3-4): 599– 603. Google Scholar CrossRef Search ADS PubMed  6. Resnick DK, Jannetta PJ, Lunsford LD, Bissonette DJ. Microvascular decompression for trigeminal neuralgia in patients with multiple sclerosis. Surg Neurol . 1996; 46( 4): 358– 361; discussion 361-352. Google Scholar CrossRef Search ADS PubMed  7. Martinez Moreno NE, Gutierrez-Sarraga J, Rey-Portoles G, Jimenez-Huete A, Martinez Alvarez R. Long-term outcomes in the treatment of classical trigeminal neuralgia by gamma knife radiosurgery: a retrospective study in patients with minimum 2-year follow-up. Neurosurgery . 2016; 79( 6): 879– 888. Google Scholar CrossRef Search ADS PubMed  8. Regis J, Tuleasca C, Resseguier N et al.   Long-term safety and efficacy of Gamma Knife surgery in classical trigeminal neuralgia: a 497-patient historical cohort study. J Neurosurg . 2016; 124( 4): 1079– 1087. Google Scholar CrossRef Search ADS PubMed  9. Sheehan JP, Ray DK, Monteith S et al.   Gamma Knife radiosurgery for trigeminal neuralgia: the impact of magnetic resonance imaging-detected vascular impingement of the affected nerve. J Neurosurg . 2010; 113( 1): 53– 58. Google Scholar CrossRef Search ADS PubMed  10. Kondziolka D, Zorro O, Lobato-Polo J et al.   Gamma Knife stereotactic radiosurgery for idiopathic trigeminal neuralgia. J Neurosurg . 2010; 112( 4): 758– 765. Google Scholar CrossRef Search ADS PubMed  11. Verheul JB, Hanssens PE, Lie ST, Leenstra S, Piersma H, Beute GN. Gamma Knife surgery for trigeminal neuralgia: a review of 450 consecutive cases. J Neurosurg . 2010; 113( Suppl): 160– 167. Google Scholar PubMed  12. Marshall K, Chan MD, McCoy TP et al.   Predictive variables for the successful treatment of trigeminal neuralgia with gamma knife radiosurgery. Neurosurgery . 2012; 70( 3): 566– 573; discussion 572-563. Google Scholar CrossRef Search ADS PubMed  13. Xu Z, Schlesinger D, Moldovan K et al.   Impact of target location on the response of trigeminal neuralgia to stereotactic radiosurgery. J Neurosurg . 2014; 120( 3): 716– 724. Google Scholar CrossRef Search ADS PubMed  14. Rogers CL, Shetter AG, Fiedler JA, Smith KA, Han PP, Speiser BL. Gamma knife radiosurgery for trigeminal neuralgia: the initial experience of The Barrow Neurological Institute. Int J Radiat Oncol Biol Phys . 2000; 47( 4): 1013– 1019. Google Scholar CrossRef Search ADS PubMed  15. Weller M, Marshall K, Lovato JF et al.   Single-institution retrospective series of gamma knife radiosurgery in the treatment of multiple sclerosis-related trigeminal neuralgia: factors that predict efficacy. Stereotact Funct Neurosurg . 2014; 92( 1): 53– 58. Google Scholar CrossRef Search ADS PubMed  16. Zorro O, Lobato-Polo J, Kano H, Flickinger JC, Lunsford LD, Kondziolka D. Gamma knife radiosurgery for multiple sclerosis-related trigeminal neuralgia. Neurology . 2009; 73( 14): 1149– 1154. Google Scholar CrossRef Search ADS PubMed  17. Huang E, Teh BS, Zeck O et al.   Gamma knife radiosurgery for treatment of trigeminal neuralgia in multiple sclerosis patients. Stereotact Funct Neurosurg . 2002; 79( 1): 44– 50. Google Scholar CrossRef Search ADS PubMed  18. Rogers CL, Shetter AG, Ponce FA, Fiedler JA, Smith KA, Speiser BL. Gamma knife radiosurgery for trigeminal neuralgia associated with multiple sclerosis. J Neurosurg . 2002; 97( 5 suppl): 529– 532. Google Scholar PubMed  19. Mathieu D, Effendi K, Blanchard J, Seguin M. Comparative study of Gamma Knife surgery and percutaneous retrogasserian glycerol rhizotomy for trigeminal neuralgia in patients with multiple sclerosis. J Neurosurg . 2012; 117( Suppl): 175– 180. Google Scholar PubMed  20. Tuleasca C, Carron R, Resseguier N et al.   Multiple sclerosis-related trigeminal neuralgia: a prospective series of 43 patients treated with gamma knife surgery with more than one year of follow-up. Stereotact Funct Neurosurg . 2014; 92( 4): 203– 210. Google Scholar CrossRef Search ADS PubMed  21. Martin S, Teo M, Suttner N. The effectiveness of percutaneous balloon compression in the treatment of trigeminal neuralgia in patients with multiple sclerosis. J Neurosurg . 2015; 123( 6): 1507– 1511. Google Scholar CrossRef Search ADS PubMed  22. Kemp S, Allan RS, Patanjali N, Barnett MH, Jonker BP. Neurological deficit following stereotactic radiosurgery for trigeminal neuralgia. J Clin Neurosci . 2016; 34: 229– 231. Google Scholar CrossRef Search ADS PubMed  Acknowledgements We are grateful to Ms Lisa Baxendell for coordinating affairs between institutions for the International Gamma Knife Research Consortium and facilitating the data collection for this project. Copyright © 2018 by the Congress of Neurological Surgeons http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

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Copyright © 2018 by the Congress of Neurological Surgeons
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Abstract

Abstract BACKGROUND Facial pain response (PR) to various surgical interventions in patients with multiple sclerosis (MS)-related trigeminal neuralgia (TN) is much less optimal. No large patient series regarding stereotactic radiosurgery (SRS) has been published. OBJECTIVE To evaluate the clinical outcomes of MS-related TN treated with SRS. METHODS This is a retrospective cohort study. A total of 263 patients contributed by 9 member tertiary referral Gamma Knife centers (2 in Canada and 7 in USA) of the International Gamma Knife Research Consortium (IGKRF) constituted this study. RESULTS The median latency period of PR after SRS was 1 mo. Reasonable pain control (Barrow Neurological Institute [BNI] Pain Scores I-IIIb) was achieved in 232 patients (88.2%). The median maintenance period from SRS was 14.1 months (range, 10 days to 10 years). The actuarial reasonable pain control maintenance rates at 1 yr, 2 yr, and 4 yr were 54%, 35%, and 24%, respectively. There was a correlation between the status of achieving BNI-I and the maintenance of facial pain recurrence-free rate. The median recurrence-free rate was 36 mo and 12.2 mo in patients achieving BNI-I and BNI > I, respectively (P = .046). Among 210 patients with known status of post-SRS complications, the new-onset of facial numbness (BNI-I or II) after SRS occurred in 21 patients (10%). CONCLUSION In this largest series SRS offers a reasonable benefit to risk profile for patients who have exhausted medical management. More favorable initial response to SRS may predict a long-lasting pain control. Gamma Knife radiosurgery, Multiple sclerosis, Pain relief, Stereotactic radiosurgery, Trigeminal neuralgia ABBREVIATIONS ABBREVIATIONS BNI Barrow Neurological Institute GKRS Gamma Knife radiosurgery LINAC linear particle accelerator MRI magnetic resonance imaging MS multiple sclerosis MVD microvascular decompression PBC percutaneous balloon compression SRS stereotactic radiosurgery TN trigeminal neuralgia Trigeminal neuralgia (TN) develops in approximately 2% of patients with multiple sclerosis (MS), and this incidence is 20 times more than within the general population.1 No consensus has been reached regarding the best surgical treatment modality owing to the lack of prospective studies.2 The clinical outcomes of the most commonly employed surgical interventions including microvascular decompression (MVD)3 and percutaneous glycerol or radiofrequency rhizotomy provide a lower rate of response and durability of pain relief in this cohort of patients.4-6 For idiopathic TN, stereotactic radiosurgery (SRS) plays an important role in treatment owing to its reasonable efficacy and the low profile of potential complications, which include facial hypoesthesia.7-12 The utilization of SRS to treat MS-related TN was a natural extension based upon its prior success with treating classic TN patients. In several small studies of MS-related TN patients, the pain relief after SRS has been achieved in a majority of patients treated with a range of 80% to 97%.3,6-10 MS-related TN patients represent a challenging demographic to treat. Within the SRS subspecialty, no large series has been published to date. Therefore, a multicenter study systematically investigating the safety and effectiveness of SRS in MS-related patients is warranted. We aimed to evaluate the clinical outcome regarding pain control and prognostic factors including the radiation dose, time interval between the last surgical procedure and SRS, and other common patient characteristics. METHODS Patient Selection The approval of the institutional review boards at individual institutions was obtained prior to the investigation. The consent form was not required. The inclusion criteria are as follows: (1) diagnosed medically refractory TN in patients with clinically confirmed MS at each of the participating institutions, (2) adequate patient demographics, treatment course of MS and MS-related TN, Gamma Knife radiosurgery (GKRS; Elekta Instruments AB, Stockholm, Sweden) parameters, and adequate clinical follow-up. We excluded those patients who were previously treated with GKRS or Linear particle accelerator (LINAC)-based SRS at other institutions, or other secondary TN patients in whom facial pain was attributed to a tumor or arteriovenous malformation involving the GKRS-treated nerve. Notably, the goal of this study was to investigate the response to GKRS. Therefore, patients were censored prior to the initiation of the further treatment following the first GKRS including repeat GKRS. Nine institutions contributed 263 patients (81 male and 182 female) with MS-related medically intractable TN to this study shown as follows: Beaumont Health System (25 patients), University of Pittsburgh Medical Center (35 patients), University of Virginia Health System (36 patients), Cleveland Clinic (56 patients), New York University (6 patients), University of Pennsylvania (24 patients), University of Manitoba (17 patients), University of Sherbrooke (60 patients), and Yale University School of Medicine (4 patients). Exclusion criteria were composed of loss to follow-up (33 patients [11%]), and the inability to complete the questionnaire due to confusion (1 patient). Among them, there were 17 patients who claimed no improvement following GKRS, although the actual latency time interval was unknown. The records of MS-related TN patients who underwent GKRS between 1994 and 2015 were reviewed by each institution for inclusion (Table 1). In the 22 patients (8.4%) who developed bilateral facial pain, the analysis was conducted to the treated side with GKRS or the first treated side by GKRS. Prior to the GKRS, 87 patients (33%) had undergone at least one surgical procedure including MVD, percutaneous balloon compression, radiofrequency rhizotomy, glycerol rhizotomy, and infraorbital neurectomy (Table 2). The median follow-up after GKRS in the entire cohort of patients was 17 mo (range, 0.5-144 mo). TABLE 1. Patient Characteristics and GKRS Parameters Variable  Patient number  Median  Range, L  Range, H  Age (yr)    57  31  90   Male  81 (31%)  58  36  79   Female  182 (69%)  57  31  90  Sidea           Left side  110 (42%)         Right side  153 (58%)        Bilateral facial pain  22 (8.4%)        Time interval Sxb (mo)    24  1  204  Margin dose (Gy)    40  20  45  Variable  Patient number  Median  Range, L  Range, H  Age (yr)    57  31  90   Male  81 (31%)  58  36  79   Female  182 (69%)  57  31  90  Sidea           Left side  110 (42%)         Right side  153 (58%)        Bilateral facial pain  22 (8.4%)        Time interval Sxb (mo)    24  1  204  Margin dose (Gy)    40  20  45  aIn patients with bilateral TN and treated with GKRS, only the first treated side was counted here. bTime interval between the last surgical procedure and GKS. View Large TABLE 1. Patient Characteristics and GKRS Parameters Variable  Patient number  Median  Range, L  Range, H  Age (yr)    57  31  90   Male  81 (31%)  58  36  79   Female  182 (69%)  57  31  90  Sidea           Left side  110 (42%)         Right side  153 (58%)        Bilateral facial pain  22 (8.4%)        Time interval Sxb (mo)    24  1  204  Margin dose (Gy)    40  20  45  Variable  Patient number  Median  Range, L  Range, H  Age (yr)    57  31  90   Male  81 (31%)  58  36  79   Female  182 (69%)  57  31  90  Sidea           Left side  110 (42%)         Right side  153 (58%)        Bilateral facial pain  22 (8.4%)        Time interval Sxb (mo)    24  1  204  Margin dose (Gy)    40  20  45  aIn patients with bilateral TN and treated with GKRS, only the first treated side was counted here. bTime interval between the last surgical procedure and GKS. View Large TABLE 2. Surgical Procedures Prior to GKRS No of Intervention  Patient number  % in subgroup  % in entire group  1  n = 53    61   PBC  7  13     GR  28  53     MVD  6  11     RF  12  23    2  n = 20    23   PBC + GR  2  10     GR + IN  2  10     PBC + RF  1  5     RF × 2  2  10     PBC × 2  1  5     GR × 2  n = 10  50     MVD × 2  1  5     MVD + IN  1  5    3  n = 6    7  >3  n = 8    9  No of Intervention  Patient number  % in subgroup  % in entire group  1  n = 53    61   PBC  7  13     GR  28  53     MVD  6  11     RF  12  23    2  n = 20    23   PBC + GR  2  10     GR + IN  2  10     PBC + RF  1  5     RF × 2  2  10     PBC × 2  1  5     GR × 2  n = 10  50     MVD × 2  1  5     MVD + IN  1  5    3  n = 6    7  >3  n = 8    9  GKRS, Gamma Knife radiosurgery; PBC, percutaneous balloon compression; GR, glycerol rhizotomy; MVD, microvascular decompression; RF, radiofrequency rhizotomy; IN, infraorbital neurectomy. View Large TABLE 2. Surgical Procedures Prior to GKRS No of Intervention  Patient number  % in subgroup  % in entire group  1  n = 53    61   PBC  7  13     GR  28  53     MVD  6  11     RF  12  23    2  n = 20    23   PBC + GR  2  10     GR + IN  2  10     PBC + RF  1  5     RF × 2  2  10     PBC × 2  1  5     GR × 2  n = 10  50     MVD × 2  1  5     MVD + IN  1  5    3  n = 6    7  >3  n = 8    9  No of Intervention  Patient number  % in subgroup  % in entire group  1  n = 53    61   PBC  7  13     GR  28  53     MVD  6  11     RF  12  23    2  n = 20    23   PBC + GR  2  10     GR + IN  2  10     PBC + RF  1  5     RF × 2  2  10     PBC × 2  1  5     GR × 2  n = 10  50     MVD × 2  1  5     MVD + IN  1  5    3  n = 6    7  >3  n = 8    9  GKRS, Gamma Knife radiosurgery; PBC, percutaneous balloon compression; GR, glycerol rhizotomy; MVD, microvascular decompression; RF, radiofrequency rhizotomy; IN, infraorbital neurectomy. View Large Each participating center had prospectively maintained their own dataset of patients who had undergone GKRS for MS-related TN. Selected variables organized on an Excel spreadsheet (Microsoft Inc, Redmond, Washington) were designed and created by the first author (Z.X.) with the modifications suggested by various co-authors. All the patients’ medical records were reviewed, and the data were de-identified and shared with an independent third party who confirmed regulatory compliance before sending the data to the first author (Z.X.), who drafted this assessment on behalf of the IGKRF. Gamma Knife Radiosurgery Model U, B, C, 4C, or Perfexion GK units (Elekta Instrument AB) were used, depending on the technology available and time of treatment at participating centers. Generally, a Leksell Model G stereotactic frame (Elekta Instrument AB) was placed to each patient under local anesthesia. Thereafter, a high-resolution, stereotactic magnetic resonance imaging (MRI) was performed. Thin-sliced (1 mm) T1-weighted and constructive interference in steady state magnetic resonance images were obtained after the administration of paramagnetic contrast. GKRS dose planning was then conducted by a medical team comprised of a neurosurgeon, a radiation oncologist, and a medical physicist at each institution. Radiosurgery targeted the afflicted trigeminal nerve. The targeting location along the trigeminal nerve varied based upon the anatomy as well as the experience and preference of each clinical team. In general, a single isocenter was used, the 4-mm collimator was targeted 2 to 8 mm anterior to the junction of the trigeminal nerve and pons. As a result, the radiation dose at the lateral edge of the brainstem varied up to a highest dose of 24 Gy. The median prescription dose delivered to the nerve was 40 Gy (range 20-45 Gy) and the corresponding isodose line used was 50%. The maximum dose to the afflicted nerve varied from 40 to 90 Gy (median 80 Gy; Figure 1). GKRS was the upfront treatment option for MS-related TN in 153 patients (58.2%). A neurovascular compression was identified on MRI in 35 patients (13.3%). FIGURE 1. View largeDownload slide Distribution of maximum dose in all patients. FIGURE 1. View largeDownload slide Distribution of maximum dose in all patients. Definition and Statistical Analysis No consensus has been reached with respect to the pain relief outcome in MS-related TN patients. Herein, we employed the well-established Barrow Neurological Institute (BNI) pain intensity scale,13,14 whereas SRS-induced facial numbness was defined using BNI Scores I to IV as previously described.13,14 Treatment failure was defined as a reported pain score that was classified as a BNI pain score of IV or V after the initial GKRS. Reasonable pain relief was defined as a BNI score from I to IIIb. For those patients, only data from the first GKRS were statistically analyzed in this study; pain control after further GKRS was not included in the statistical analyses. The comparison of length of pain relief maintenance was performed using the Kaplan–Meier product-limit method. Patients were censored if they were lost to follow-up or remained pain recurrence-free at the last follow-up assessing the pain level. The correlations of clinical outcomes were investigated using the Cox proportional hazards regression models in terms of patient characteristics and treatment parameters detailed in Table 1. Those investigated variables were selected based upon the clinical experience and previous publications. Generally, patients were contacted by phone within 2 mo after SRS concerning the pain improvement. The clinical and imaging follow-up was completed up to 6 mo after SRS at the initial evaluation. All statistical analyses were conducted using R programing (R Core Team (2016)). R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL: https://www.R-project.org. All statistical analyses were 2-tailed and a P-value less than .05 was deemed statistically significant. RESULTS Initial Response to SRS After SRS, the initial pain response of BNI-I was achieved in 54 patients (29.3%) with a median time interval of one month (range, 1 d to 14.1 mo) among 184 patients whose initial response was known. No correlation was identified using prognostic factors including age at the initial SRS, gender, laterality (unilateral vs bilateral), afflicted side, time interval between the last surgical procedure and SRS, status of previous surgical management, and maximum dose to the afflicted nerve (Table 3). Seventeen patients claimed no pain improvement at all; however, no follow-up time was documented. In this case, we can only assume that adequate follow-up was performed in each participating center before no improvement was declared by the clinical team. TABLE 3. Binary Logistic Regression Analysis of Achieving Pain Relief of BNI-I After the Initial GKS Variable  P-value  HR  95% CI_lower  95% CI_upper  Age (parametric)  .94  1.00  0.97  1.03  Gender (male vs female)  .49  1.26  0.64  2.44  Bilateral vs unilateral  .14  0.32  0.05  1.22  Afflicted side (left vs right)  .86  1.06  0.55  2.03  Time interval Sxa  .66  1.00  0.99  1.02  Margin dose (parametric)  .93  0.99  0.85  1.15  Variable  P-value  HR  95% CI_lower  95% CI_upper  Age (parametric)  .94  1.00  0.97  1.03  Gender (male vs female)  .49  1.26  0.64  2.44  Bilateral vs unilateral  .14  0.32  0.05  1.22  Afflicted side (left vs right)  .86  1.06  0.55  2.03  Time interval Sxa  .66  1.00  0.99  1.02  Margin dose (parametric)  .93  0.99  0.85  1.15  aTime interval between the last surgical procedure and the first GKRS; CI, confidence interval. View Large TABLE 3. Binary Logistic Regression Analysis of Achieving Pain Relief of BNI-I After the Initial GKS Variable  P-value  HR  95% CI_lower  95% CI_upper  Age (parametric)  .94  1.00  0.97  1.03  Gender (male vs female)  .49  1.26  0.64  2.44  Bilateral vs unilateral  .14  0.32  0.05  1.22  Afflicted side (left vs right)  .86  1.06  0.55  2.03  Time interval Sxa  .66  1.00  0.99  1.02  Margin dose (parametric)  .93  0.99  0.85  1.15  Variable  P-value  HR  95% CI_lower  95% CI_upper  Age (parametric)  .94  1.00  0.97  1.03  Gender (male vs female)  .49  1.26  0.64  2.44  Bilateral vs unilateral  .14  0.32  0.05  1.22  Afflicted side (left vs right)  .86  1.06  0.55  2.03  Time interval Sxa  .66  1.00  0.99  1.02  Margin dose (parametric)  .93  0.99  0.85  1.15  aTime interval between the last surgical procedure and the first GKRS; CI, confidence interval. View Large Maintenance of Pain Relief Following initial SRS, reasonable pain control (defined as BNI-I-IIIb) was achieved in 232 patients (88.2%). The maintenance of a reasonable pain relief is illustrated in Figure 2. The median maintenance time interval was 14.1 mo (range, 10 d-10 yr). The actuarial pain recurrence-free rates were 54%, 35%, and 24% at 1 yr, 2 yr, and 4 yr following the first SRS, respectively. Interestingly, there was a statistically significant correlation between achieving BNI-I and the maintenance of facial pain recurrence-free rate (Figure 3). The median recurrence-free rate was 36 mo and 12.2 mo in patients achieving BNI-I and those of BNI greater than I, respectively (log-rank test, P = .046). Further analyses did not reveal any correlation between the maintenance of facial pain recurrence-free rate and the following prognostic factors including age at the first SRS, gender, laterality, afflicted side, maximum dose, status of previous surgical management, and the time interval between the last surgical procedure prior to SRS and SRS (Table 4). FIGURE 2. View largeDownload slide Kaplan–Meier plot of reasonable facial pain relief maintenance in the entire cohort. FIGURE 2. View largeDownload slide Kaplan–Meier plot of reasonable facial pain relief maintenance in the entire cohort. FIGURE 3. View largeDownload slide Comparison of cumulative facial pain recurrence-free rate in relation to the status of initial facial pain relief using Kaplan–Meier method. FIGURE 3. View largeDownload slide Comparison of cumulative facial pain recurrence-free rate in relation to the status of initial facial pain relief using Kaplan–Meier method. TABLE 4. Univariate Analysis of Maintenance of Reasonable Pain Relief After the Initial GKS Variable  P-value  HR  95% CI_L  95% CI_U  Age  .3  0.99  0.97  1.01  Gendera  .12  0.72  0.48  1.09  Bilateralb  .27  0.67  0.32  1.38  Afflicted side  .95  0.99  0.66  1.48  Time intervalc  .7  1.07  0.77  1.48  Maximum dose  .27  0.96  0.88  1.04  Initial pain reliefd  .046  0.609  0.374  0.991  Variable  P-value  HR  95% CI_L  95% CI_U  Age  .3  0.99  0.97  1.01  Gendera  .12  0.72  0.48  1.09  Bilateralb  .27  0.67  0.32  1.38  Afflicted side  .95  0.99  0.66  1.48  Time intervalc  .7  1.07  0.77  1.48  Maximum dose  .27  0.96  0.88  1.04  Initial pain reliefd  .046  0.609  0.374  0.991  CI, confidence interval. aMale vs female. bBilateral involvement vs unilateral. cBetween the last surgical procedure and GKS. dBNI score > I vs BNI-I. View Large TABLE 4. Univariate Analysis of Maintenance of Reasonable Pain Relief After the Initial GKS Variable  P-value  HR  95% CI_L  95% CI_U  Age  .3  0.99  0.97  1.01  Gendera  .12  0.72  0.48  1.09  Bilateralb  .27  0.67  0.32  1.38  Afflicted side  .95  0.99  0.66  1.48  Time intervalc  .7  1.07  0.77  1.48  Maximum dose  .27  0.96  0.88  1.04  Initial pain reliefd  .046  0.609  0.374  0.991  Variable  P-value  HR  95% CI_L  95% CI_U  Age  .3  0.99  0.97  1.01  Gendera  .12  0.72  0.48  1.09  Bilateralb  .27  0.67  0.32  1.38  Afflicted side  .95  0.99  0.66  1.48  Time intervalc  .7  1.07  0.77  1.48  Maximum dose  .27  0.96  0.88  1.04  Initial pain reliefd  .046  0.609  0.374  0.991  CI, confidence interval. aMale vs female. bBilateral involvement vs unilateral. cBetween the last surgical procedure and GKS. dBNI score > I vs BNI-I. View Large Post-SRS Complications In 210 patients with known status of complications following the first SRS, only 21 patients (10%) experienced hypoesthesia, while 2 patients (0.95%) developed paresthesia, and 1 patient (0.48%) experienced both symptoms. Owing to the limited number of post-SRS complication events, no inferential statistical analysis was performed. None of the patients had facial hypoesthesia was greater than BNI-II in this cohort of patients with a median time interval of 3 mo (range, 1 wk-55.7 mo) following the first SRS. None of patients experienced a trigeminal motor deficit, any other cranial nerve deficit, or anesthesia dolorosa following SRS. Further Treatment After Failed SRS Further surgical interventions for the failure of pain control were observed in 116 patients (44%). Table 5 displays the first surgical intervention after the failure of the initial SRS. Among 44 patients undergoing repeat SRS, 17 patients had a detailed follow-up. The median maximum dose was 70 Gy (range 65 Gy-90 Gy). BNI-I facial pain control was achieved in nine patients (53%), BNI-IIIa in 7 patients (41%), and no pain relief in 1 patient (6%). In general, those patients underwent multiple surgical procedures or combinations with various responses. TABLE 5. The First Further Surgical Intervention After the Failed GKRS Intervention  Patient number  Median time interval after first failed GKRS (mo)  Range, low (mo)  Range, high (mo)  GKRSa  44 (19%)  27.5  12 d  144  Percutaneous balloon compression  20 (8.5%)  10.6  15 d  46  Glycerol rhizotomy  38 (16%)  11.5  2  96  Radiofrequency rhizotomy  11 (4.7%)  9  4  58.3  Infraorbital neurolectomy  2 (0.8%)  15  10  20  Microvascular decompression  1 (0.4%)  6.2  6.2  6.2  Intervention  Patient number  Median time interval after first failed GKRS (mo)  Range, low (mo)  Range, high (mo)  GKRSa  44 (19%)  27.5  12 d  144  Percutaneous balloon compression  20 (8.5%)  10.6  15 d  46  Glycerol rhizotomy  38 (16%)  11.5  2  96  Radiofrequency rhizotomy  11 (4.7%)  9  4  58.3  Infraorbital neurolectomy  2 (0.8%)  15  10  20  Microvascular decompression  1 (0.4%)  6.2  6.2  6.2  aGKRS: Gamma Knife radiosurgery (Elekta Instruments AB). View Large TABLE 5. The First Further Surgical Intervention After the Failed GKRS Intervention  Patient number  Median time interval after first failed GKRS (mo)  Range, low (mo)  Range, high (mo)  GKRSa  44 (19%)  27.5  12 d  144  Percutaneous balloon compression  20 (8.5%)  10.6  15 d  46  Glycerol rhizotomy  38 (16%)  11.5  2  96  Radiofrequency rhizotomy  11 (4.7%)  9  4  58.3  Infraorbital neurolectomy  2 (0.8%)  15  10  20  Microvascular decompression  1 (0.4%)  6.2  6.2  6.2  Intervention  Patient number  Median time interval after first failed GKRS (mo)  Range, low (mo)  Range, high (mo)  GKRSa  44 (19%)  27.5  12 d  144  Percutaneous balloon compression  20 (8.5%)  10.6  15 d  46  Glycerol rhizotomy  38 (16%)  11.5  2  96  Radiofrequency rhizotomy  11 (4.7%)  9  4  58.3  Infraorbital neurolectomy  2 (0.8%)  15  10  20  Microvascular decompression  1 (0.4%)  6.2  6.2  6.2  aGKRS: Gamma Knife radiosurgery (Elekta Instruments AB). View Large Upfront or Secondary SRS There was no statistically significant difference regarding the maintenance of pain control in patients treated with an upfront SRS or a secondary SRS (log-rank test, P = .487). Meanwhile, there was also no difference regarding the possibility of achieving a BNI-I pain control in these two groups (logistic regression, P = .172, odds ratio = 0.632, 95% confidence interval, 0.328-1.228; Table 3). Furthermore, facial hypoesthesia developed in 17 patients and paresthesia in 2 patients in the upfront SRS group whereas new-onset of hypoesthesia was in 4 patients and both hypoesthesia and paresthesia developed in one patient treated twice with SRS (Fisher's exact test, P = .124). DISCUSSION To the best of our knowledge, the current report represents the largest multicenter series regarding the treatment of MS-related TN patients with SRS. Furthermore, this report's cohort size permitted the computation of detailed inferential statistical analyses. The findings suggested that patients achieving BNI-I following the first SRS were likely to maintain the reasonable pain control for a longer period of time compared with those whose response score was greater than I on the BNI facial pain scale. This information is valuable for clinical decision making and in particular helps guide the timing of treatment for patients and their clinicians. SRS has been utilized as an established treatment modality for this group of patients, which was reported sporadically. Previous small series studies on SRS-treating patients with MS-related TN revealed that a pain relief rate of 60% to 80% was obtained (Table 6).15-20 MS is considered a negative predictive factor in most series including MVD and percutaneous rhizotomy. In one study, Rogers et al18 achieved a high level of success in a study of 15 MS-associated TN patients undergoing SRS. At a mean follow-up of 17 mo, 80% of patients had experienced pain relief using an initial dose of 70 to 90 Gy. Five patients underwent repeat SRS to the same treatment area with a mean maximum dose of 48 Gy. All 5 patients attained some pain relief and 60% were able to discontinue their pain medication.18 Most recently, Weller et al15 reported the clinical outcomes of a series of 35 patients with MS-related TN treated with SRS with a median maximum dose of 90 Gy. With a median follow-up of 39 mo, 88% patients experienced a BNI I to III at 3 mo after SRS and the actuarial freedom from BNI IV-V pain relapse was 57, 57, and 52% at 1, 2, and 5 yr, respectively. Nonbothersome facial numbness secondary to SRS developed in 39% of patients.15 To date, one of the largest series published by the Pittsburgh group reveals that in 37 patients including 78% who failed the previous surgeries, 23 patients achieved complete pain relief (BNI-I), and 36 patients (97%) had a reasonable pain control (BNI I-IIIb) at a median follow-up of 57 mo.16 Reasonable pain relief maintenance was obtained in 83%, 74%, and 54% of patients at 1, 3, and 5 yr, respectively following SRS. Nondisabling paresthesias developed in 5.4% patients. Although more investigations are warranted to assess the long-term success and toxicity (in particular the development of troublesome facial numbness) of SRS, SRS proves effective and safe due to a reasonably favorable complication profile. TABLE 6. Literature Review of SRS for Patients With MS-Related TN Author/year  No.  Median follow-up (mo)  Age (M)  Median maximum dose/range (Gy)  time to pain response (d)  Initial response (%)  Pain control 1 yr  Pain control 2/3 yr  Pain control 5year  Facial numbness (%)  Weller 201415  35  39  62 (39-86)  90 (80-90)  42 (2-170)  82  57  57  52  39  Zorro 200916  37  56.7  59 (38-74)  80 (70-90)  7 (1-90)  97.3  82.6  73.9  54  5  Huang 200217  7  17  63 (45-85)  80 (70-90)  13 (1-61)  80  –  –  -  13  Rogers 200218  15  19 (2-96)  68  85 (70-90)  –  –  –  –  -  -  Mathieu 201219  27  39 (13-69)  59 (42-78)  80 (80-90)  –  81.5  –  –  -  22  Tuleasca 201420  43  53.8  57 (36-83)  85 (75-90)  30 (0-90)  90.7  87.2a  71.8a  43.1a  16  Author/year  No.  Median follow-up (mo)  Age (M)  Median maximum dose/range (Gy)  time to pain response (d)  Initial response (%)  Pain control 1 yr  Pain control 2/3 yr  Pain control 5year  Facial numbness (%)  Weller 201415  35  39  62 (39-86)  90 (80-90)  42 (2-170)  82  57  57  52  39  Zorro 200916  37  56.7  59 (38-74)  80 (70-90)  7 (1-90)  97.3  82.6  73.9  54  5  Huang 200217  7  17  63 (45-85)  80 (70-90)  13 (1-61)  80  –  –  -  13  Rogers 200218  15  19 (2-96)  68  85 (70-90)  –  –  –  –  -  -  Mathieu 201219  27  39 (13-69)  59 (42-78)  80 (80-90)  –  81.5  –  –  -  22  Tuleasca 201420  43  53.8  57 (36-83)  85 (75-90)  30 (0-90)  90.7  87.2a  71.8a  43.1a  16  No, number of patients. aBNI-I; –, not applicable or available. View Large TABLE 6. Literature Review of SRS for Patients With MS-Related TN Author/year  No.  Median follow-up (mo)  Age (M)  Median maximum dose/range (Gy)  time to pain response (d)  Initial response (%)  Pain control 1 yr  Pain control 2/3 yr  Pain control 5year  Facial numbness (%)  Weller 201415  35  39  62 (39-86)  90 (80-90)  42 (2-170)  82  57  57  52  39  Zorro 200916  37  56.7  59 (38-74)  80 (70-90)  7 (1-90)  97.3  82.6  73.9  54  5  Huang 200217  7  17  63 (45-85)  80 (70-90)  13 (1-61)  80  –  –  -  13  Rogers 200218  15  19 (2-96)  68  85 (70-90)  –  –  –  –  -  -  Mathieu 201219  27  39 (13-69)  59 (42-78)  80 (80-90)  –  81.5  –  –  -  22  Tuleasca 201420  43  53.8  57 (36-83)  85 (75-90)  30 (0-90)  90.7  87.2a  71.8a  43.1a  16  Author/year  No.  Median follow-up (mo)  Age (M)  Median maximum dose/range (Gy)  time to pain response (d)  Initial response (%)  Pain control 1 yr  Pain control 2/3 yr  Pain control 5year  Facial numbness (%)  Weller 201415  35  39  62 (39-86)  90 (80-90)  42 (2-170)  82  57  57  52  39  Zorro 200916  37  56.7  59 (38-74)  80 (70-90)  7 (1-90)  97.3  82.6  73.9  54  5  Huang 200217  7  17  63 (45-85)  80 (70-90)  13 (1-61)  80  –  –  -  13  Rogers 200218  15  19 (2-96)  68  85 (70-90)  –  –  –  –  -  -  Mathieu 201219  27  39 (13-69)  59 (42-78)  80 (80-90)  –  81.5  –  –  -  22  Tuleasca 201420  43  53.8  57 (36-83)  85 (75-90)  30 (0-90)  90.7  87.2a  71.8a  43.1a  16  No, number of patients. aBNI-I; –, not applicable or available. View Large No other treatment options fare better for this group of patients. Symptom recurrence rate was as high as 86% in a very small cohort of 17 patients treated with percutaneous balloon compression (PBC) for MS-related TN. In the meantime, complications secondary to PBC including dysesthesia, cheek hematoma, masseter weakness, abducens palsy, and meningitis were common, although they were relatively mild or transient as described by the investigators.21 In our study, we did not observe any severe complications. The results further underscored the low-risk profile in the SRS treatment modality. Of note, in contrast to GKRS, LINAC-based SRS could lead to a severe clinic sequela. Recently, there is one case report which indicated that LINAC-based ExacTrac was likely to be attributed to a severe neurological deficit in a patient with late-diagnosed MS-related TN.22 Limitations Although this is the largest series in the field of SRS for MS-related TN patients, it still contains some intrinsic limitations. First, as a retrospective study, recall bias inevitably proves to be an issue. Second, the location of targeting was unknown in the majority of patients, which rendered the analysis inconclusive. We posit this might be a prognostic factor based on our previous study.13 Third, the outcome of multiple centers varies due to selection bias. Fourth, the different response to GKRS was likely attributed to the type of MS, these data may provide better insight to predict the outcome in this cohort of patients. Fifth, the lack of complete complication status in some patients is noticeable. CONCLUSION The current largest series of MS-related TN patients treated with SRS suggested that, given a very favorable low-risk complication profile, SRS should be considered as a first-line treatment option or an adjunct one. Patients who experienced an initial favorable response (BNI-I) were more likely to achieve an extended reasonable pain control. Multimodality treatment is the key in managing those subgroup of MS-related TN patients. Disclosures Dr Lunsford is a consultant and shareholder in AB Elekta, the manufacturer of Gamma Knife®. Dr Grills has a stock ownership in a company called Greater Michigan Gamma Knife, and also holds a grant from Elekta Collaborative Lung Research Group. The other authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. Notes This material was presented as an e-poster at the 2017 annual ASTRO meeting, September 25, 2017, in San Diego, California. REFERENCES 1. Love S, Gradidge T, Coakham HB. Trigeminal neuralgia due to multiple sclerosis: ultrastructural findings in trigeminal rhizotomy specimens. Neuropathol Appl Neurobiol . 2001; 27( 3): 238– 244. Google Scholar CrossRef Search ADS PubMed  2. Montano N, Papacci F, Cioni B, Di Bonaventura R, Meglio M. What is the best treatment of drug-resistant trigeminal neuralgia in patients affected by multiple sclerosis? A literature analysis of surgical procedures. Clin Neurol Neurosurg . 2013; 115( 5): 567– 572. Google Scholar CrossRef Search ADS PubMed  3. Sandell T, Eide PK. The effect of microvascular decompression in patients with multiple sclerosis and trigeminal neuralgia. Neurosurgery . 2010; 67( 3): 749– 754; discussion 753-744. Google Scholar CrossRef Search ADS PubMed  4. Cheng JS, Sanchez-Mejia RO, Limbo M, Ward MM, Barbaro NM. Management of medically refractory trigeminal neuralgia in patients with multiple sclerosis. Neurosurg Focus . 2005; 18( 5): 1– 5. 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Marshall K, Chan MD, McCoy TP et al.   Predictive variables for the successful treatment of trigeminal neuralgia with gamma knife radiosurgery. Neurosurgery . 2012; 70( 3): 566– 573; discussion 572-563. Google Scholar CrossRef Search ADS PubMed  13. Xu Z, Schlesinger D, Moldovan K et al.   Impact of target location on the response of trigeminal neuralgia to stereotactic radiosurgery. J Neurosurg . 2014; 120( 3): 716– 724. Google Scholar CrossRef Search ADS PubMed  14. Rogers CL, Shetter AG, Fiedler JA, Smith KA, Han PP, Speiser BL. Gamma knife radiosurgery for trigeminal neuralgia: the initial experience of The Barrow Neurological Institute. Int J Radiat Oncol Biol Phys . 2000; 47( 4): 1013– 1019. Google Scholar CrossRef Search ADS PubMed  15. Weller M, Marshall K, Lovato JF et al.   Single-institution retrospective series of gamma knife radiosurgery in the treatment of multiple sclerosis-related trigeminal neuralgia: factors that predict efficacy. 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Google Scholar CrossRef Search ADS PubMed  Acknowledgements We are grateful to Ms Lisa Baxendell for coordinating affairs between institutions for the International Gamma Knife Research Consortium and facilitating the data collection for this project. Copyright © 2018 by the Congress of Neurological Surgeons

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NeurosurgeryOxford University Press

Published: Apr 23, 2018

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