Radiosurgical treatment of trigeminal neuralgia: A follow-up experience over three years

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1 Scientific Research and Essays Vol. 6(12), pp , 18 June, 2011 Available online at DOI: /SRE ISSN Academic Journals Full Length Research Paper Radiosurgical treatment of trigeminal neuralgia: A follow-up experience over three years Guang-jian Shen, Min-hui Xu*, Yong-wen Zhou, Guang-xin Chen, Min-ying Geng and Fei-peng Li Gamma Knife Center of Neurosurgical Department, Research Institute of Surgery and Daping Hospital, Third Military Medical University, Chongqing , P.R. China. Accepted 23 May, 2011 To assess the safety and efficacy of radiosurgical treatment for trigeminal neuralgia (TN), we reviewed a total of 32 patients with refractory TN treated with gamma knife radiosurgery (GKRS) and followed-up for over 3 years. A median maximum dose of 80 Gy was delivered to the involved trigeminal nerve root entry zone. Treatment outcomes were assessed based on patients self-reports. A univariate analysis was used to determine the predictors for treatment outcomes. In a median follow-up of 41 months, an improved response to GKRS was observed in 27 patients (84%). Actuarial analysis showed that the 12, 24, 36, and 58month percentages of improved response were 72, 67, 56 and 47% respectively. Pain relief occurred in a median time of 3.5 months, and was maintained for a median of 21 months. Twelve patients (44%) complained with recurrence of the pain after a median of 10 months. Actuarial analysis revealed that the 12, 24, 36 and 58 month recurrence rates were 7, 15, 15 and 11% respectively. Facial numbness, the only complication, was observed in 3 patients (9.4%). Univariate analysis revealed that a higher maximum dose and a shorter distance between the pontine edge and target center were associated with improved response; that a lower maximum dose and prior surgical treatment experience were associated with increased risk of recurrence of pretreatment pain; and that higher maximum dose and two isocenters were associated with the occurrence of complications. In conclusion, GKRS can effectively relieves the pain with low morbidity, but the long-term benefits that patients derive from it are still limited. Patient outcome is mainly determined by radiation dose and site, and prior surgical treatment experience. Key words: Gamma knife, trigeminal neuralgia, radiosurgery, outcomes. INTRODUCTION Trigeminal neuralgia (TN) is a disorder characterized by a paroxysmal lancinating pain in the face. The pain is so acute that the patient s daily life is affected. The initial treatment in patients with TN is medical therapy. However, patients often require supplemental treatment modalities if their response to medication is suboptimal, transient, or associated with undesirable side effects. Traditionally, further treatment consists of invasive neurosurgical procedures, including microvascular decompression (MVD), and neural modulating procedures, such as glycerol *Corresponding author. littlep7273@sina.com. Tel: Fax: rhizolysis, radiofrequency rhizotomy, percutaneous balloon microcompression, and peripheral nerve blocks. Although these interventions provide pain relief, they are associated with significant risks, potentially permanent sequelae, and definite failure rates and pain recurrence (Barker et al., 1996; Burchiel et al., 1993; Kanpolat et al., 2001; Taha et al., 1995; Tronnier et al., 2001; Brown and Gouda, 1997). Recently, radiosurgery has increasingly become an alternative to surgical procedures due to its minimal invasiveness, better safety, and efficacy (Sheehan et al., 2005; Verheul et al., 2010; Pollock et al., 2002). However, further investigations regarding the advantages and disadvantages of radiosurgery are needed owing to the insufficient long-term follow-up data. In the present study, we reviewed 32 patients followed-up over 3 years to

2 2556 Sci. Res. Essays Table 1. Pretreatment characteristics of 32 patients with TN. Characteristics Value Age at time of treatment in years (range) 57 (23 89) Number of male patients (%) 16 (50) Duration of symptoms in months (range) 92 (4 276) Number with right-sided pain (%) 18 (56.3) Number in each pain distribution (%) V1 1 (3.1) V2 9 (28.1) V3 7 (21.9) V1-V2 2 (6.3) V1-V3 0 (0.0) V2-V3 9 (28.1) V1-V2-V3 4 (12.5) Number with microvascular compression (%) 14 (43.8) Number with each prior surgery (%) Glycerol rhizotomy 10 (31.3) Radiofrequency rhizotomy 2 (6.3) Number with atypical features (%) 5 (15.6) assess the efficacy, safety, and predictors of GKRS for TN. MATERIALS AND METHODS Patient characteristics Between November 1997 and April 2006, 180 patients with refractory TN were treated with gamma knife radiosurgery (GKRS) at the Gamma Knife Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, China. Among these patients, 32 were followed-up for over 3 years. The clinical characteristics of 32 of these patients are listed in Table 1. The study group consisted of 16 males (50%) and 16 females (50%) with ages ranging from 23 to 89 years (median: 57 years). Seventeen patients (53.1%) had left-sided pain and 15 (46.9%) had right-sided pain. Twelve patients (37.5%) underwent prior invasive procedures, whereas 20 patients (62.5%) received radiosurgery as their primary treatment when medical treatment failed. The pain was characterized clinically as typical in 27 patients (84.4%) and atypical in 5 (15.6%). MRI examinations revealed that the trigeminal pathway was compressed by a microvessel in 14 patients (43.8%). Clinical and imaging information was collected from medical records, radiologic studies, and relevant physicians. Radiosurgical technique All patients were treated in an OUR-XGD rotating gamma unit by a team consisting of a radiation oncologist, neurosurgeon, and medical physicist. MRI slices with 1 mm thickness were obtained after Leksell Model G stereotactic frame placement under local anesthesia. The images were uploaded into a computer system equipped with the Gamma Plan planning system software, and then treatment planning was performed. The median maximum dose used was 80 Gy, ranging from 70 and 90 Gy. For 25 patients, a single 4 mm isocenter was placed on the trigeminal nerve at a point approximately 2 to 5 mm anterior to the root entry zone (REZ). Seven patients were treated by using two 4 mm isocenters to create an oval dose plan extending more anteriorly. The REZ was irradiated at a distance no greater than the 20% isodose line for any patient. Follow-up The complete follow-up consisted of clinic visits following radiosurgery for 41 months (range: 36 to 58 months). Patients were asked to describe their post-gks pain using the Barrow Neurological Institute Pain Scale (BNI) as shown in Table 2 (Rogers et al., 2000). Patients were also questioned about when pain relief occurred, the duration of relief, pain recurrence, and complications. Outcomes were classified into four grades: excellent (BNI Class I or II), good (BNI Class II), fair (BNI Class IV), or poor (BNI Class V). With the exception of the poor grade, all the grades are considered to indicate improved response. Statistical methods Comparisons among different groups containing ordinal data were conducted using a two-tailed Fisher s exact test. A two-tailed independent samples t-test was used to compare among groups with continuous numerical data. The predictors of treatment prognosis were determined by univariate analysis from the following patient characteristics: age, gender, site of facial pain (left or right side), prior surgical experience, maximum dose, number of isocenters, microvascular compression, and the distance between the pontine edge and target center. RESULTS Treatment response Improved response to GKRS was observed in 27 patients

3 Shen et al Table 2. Barrow neurological institute pain intensity scale. Score Characteristics I No trigeminal pain, no medication II Occasional pain, not requiring medication III Some pain, adequately controlled with medication IV Some pain, not adequately controlled with medication V Severe pain/no pain relief *All patients experience severe pain (BNI Class V) pre-gkrs Cases Improvement Recurrence Months Figure 1. Actuarial incidence of improved response, pain recurrence, and complications at 12, 24, 36, and 56 months after treatment. (84%): BNI Class I in 8 patients, Class II in 5 patients, Class III in 11 patients, and Class IV in 3 patients. As such, excellent outcomes were observed in 13 patients (41%), good outcomes in 11 patients (34%), fair outcomes in 3 patients (9%). The responses of the remaining 5 patients (16%) were poor. Actuarial percentages of improved responses were 72, 67, 56 and 47% at 12, 24, 36, and 56 months, respectively (Figure 1). The median time to pain relief was 3.5 months. Immediate pain relief was observed in 3 patients (11%), and no patient required greater than 14 months for improvement in symptoms. In those patients with improved response to treatment, pain relief was maintained for a median of 21 months (range: 2 to 58 months). Univariate analysis revealed that a higher maximum dose and a shorter distance between the pontine edge and target center were associated with an improved response (Table 3). of recurrence of the pain after a median of 10 months (range: 2 to 52 months). Actuarial analysis revealed 12, 24, 36, and 56 month recurrence rates of 7, 15, 11 and 11% respectively (Figure 1). Repeated GKRS was carried out in 4 of 12 patients for recurrence of the pain. Univariate analysis revealed that a lower maximum dose and prior surgical treatment experience were associated with an increased risk of recurrence of pretreatment pain (Table 3). Facial numbness was the only complication, which was noted in 3 patients (9.4%) after GKRS (Figure 1). Univariate analysis revealed that a higher maximum dose and two isocenters were associated with the occurrence of complications (Table 3). Pain recurrence During the follow-up period, 12 patients (44%) complained DISCUSSION Although radiosurgery has become an important alternative

4 2558 Sci. Res. Essays Table 3. Univariate analysis for treatment outcome. Factors Treatment response (Improved vs. Poor) P value Pain recurrence (Yes vs. No) (Yes vs. No) Age Gender Site of facial pain (left/right side) Prior surgical experience Maximum dose Number of isocenters Microvascular compression Distance between the pontine edge and target center to surgical procedures for TN, the efficacy and safety associated with the radiosurgical treatment are still under assessment, with particular emphasis on long-term follow-up data. In the present series, which was followed-up for 41 months (36 to 58 months), 84% of the patients had improved response to treatment, with excellent pain outcomes for 41% and excellent or good pain outcomes for 75% of patients. These results are comparable with those reported in several series (Pollock et al., 2002; Kondziolka et al., 2002; Kondziolka et al., 1998; Kondziolka et al., 1996b), and are almost comparable with those associated with MVD, which is commonly recognized as the most effective treatment method for TN (Kanpolat et al., 2001; Tronnier et al., 2001). Furthermore, there were no serious complications reported after GKRS in the study. Facial numbness, which is not bothersome for most patients, was the only complication, and this was noted in 3 patients (9.4%). This incidence of facial numbness is similar to that reported in a published series using typical doses (Kondziolka et al., 1998; Kondziolka et al., 1996b; Sheehan et al., 2005; Maesawa et al., 2001). All of these results suggest that GKRS provides perfect pain relief with low morbidity for most patients. There is a certain amount of controversy regarding pain recurrence in TN patients after GKRS. Early studies on GKRS reported low rates of pain recurrence varying from 6 to 13% (Kondziolka et al., 1998; Kondziolka et al., 1996b; Maesawa et al., 2001), which are relatively favorable compared to those associated with surgical interventions. However, in several reports, Sheehan et al. (2005), McNatt et al. (2005), Urgosik (2005) and Kubicek et al. (2004), the rate of pain recurrence was 27, 23, 25 and 50% respectively, none being optimistic. In the present series, the rate of pain recurrence was 44%. It is possible that different follow-up terms account for the discrepancy in the reported rate of pain recurrence, and that the later series revealed the true rate because they included longer follow-up terms. Accordingly, these results indicate that the long-term benefits patients derive from GKRS are finite and that management of pain recurrence should be considered further. It is necessary to uncover prognostic factors so as to improve the outcome for TN patients after GKRS. In our study, univariate analysis revealed that a higher maximum dose and a shorter distance between the pontine edge and target center were associated with an improved response; that a lower maximum dose and prior surgical treatment experience were associated with an increased risk of recurrence of pretreatment pain; and that a higher maximum dose and two isocenters were associated with the occurrence of complications. These results indicate that radiation dose is a prognostic factor not only for pain relief and pain recurrence but also for the occurrence of complications. Similar results were also reported by Pollock et al. (2001). All these findings suggest that an optimal radiation dose should be studied further in consideration of pain relief, recurrence, and complications. We also observed that the distance between the pontine edge and target center could serve as a prognostic factor for pain relief. This appears to support the conception that a trigeminal nerve close to the pontine edge is more sensitive to radiation because the nerve in this region is sheathed by oligodendrocytes and not by Schwann cells (Kondziolka et al., 1996; Kondziolka et al., 1996a,b). Other groups have attempted to improve radiosurgical outcomes by using two isocenters to create an oval dose plan for increasing the length of nerve irradiated. However, as also reported by Flickinger et al. (2001), the results presented in this paper argues against this approach because of the unproven benefit and increasing complications. Microvascular compression is one of the major factors leading to TN and the indicator for MVD. However, there have been few reports about its effects on GKRS outcomes. Our results indicate that GKRS did not produce worse results, higher pain occurrence, or more complications in patients with microvascular compression, thereby suggesting that microvascular compression is not an exclusive factor for GKRS. It has been formulated that GKRS can be favorably

5 Shen et al applied for TN treatment when medication or other therapies do not take effect. In our study and others, the majority of patients needed a long period to gain pain relief, although a few patients experienced immediate pain relief. It is unbearable for the patients with severe symptoms due to lacking effective therapy for pain relief in such a long period. Given this situation and the slight side effects of GKRS, it seems reasonable that GKRS should be performed more positively compared with other invasive treatments which can produce immediate pain relief. It is the author s suggestion that GKRS should be managed when the medication continues to have an effect but cannot continuously control the symptoms, so as to enable the patients to overcome the pain relief period whilst remaining in a relatively good state of health. Currently, the mechanism by which GKRS alleviates the pain associated with TN remains unknown. It has commonly been observed that pain can be relieved both immediately and over the long term, and that trigeminal function is preserved in most patients after GKRS. The trigeminal nerve lesions, derived from radiation directly or responsible vessel obstruction indirectly, is not sufficient to explain the phenomena. Obstruction of abnormal bypass neural transmission and maintenance of normal neural transmission in the trigeminal nerve may be involved in the mechanism. Conclusions GKRS at typical doses (70 to 90 Gy) provides perfect pain relief with low morbidity. However, the long-term benefits patients derive from GKRS are still finite because of pain recurrence. Patient outcome is mainly determined by radiation dose, distance between the pontine edge and target center, and prior surgical treatment experience, and does not depend on the length of the irradiated nerve or the presence of vascular compression on MRI. 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