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Radiosurgery for Secondary Trigeminal Neuralgia: Revisiting the Treatment Paradigm
Accepted Manuscript Radiosurgery for Secondary Trigeminal Neuralgia: Revisiting the Treatment Paradigm Srinivas Chivukula, M.D., Won Kim, M.D., Xiaoyi Zhuo, B.S., Stephen Tenn, Ph.D., Tania Kaprealian, M.D., Antonio DeSalles, M.D., Ph.D., Nader Pouratian, M.D., Ph.D. PII:
S1878-8750(16)30932-9
DOI:
10.1016/j.wneu.2016.09.087
Reference:
WNEU 4627
To appear in:
World Neurosurgery
Received Date: 19 February 2016 Revised Date:
21 September 2016
Accepted Date: 22 September 2016
Please cite this article as: Chivukula S, Kim W, Zhuo X, Tenn S, Kaprealian T, DeSalles A, Pouratian N, Radiosurgery for Secondary Trigeminal Neuralgia: Revisiting the Treatment Paradigm, World Neurosurgery (2016), doi: 10.1016/j.wneu.2016.09.087. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title:
Radiosurgery for Secondary Trigeminal Neuralgia: Revisiting the Treatment Paradigm
Authors:
Srinivas Chivukula, M.D.1 Won Kim, M.D.1 Xiaoyi Zhuo, B.S.1 Stephen Tenn, Ph.D.2 Tania Kaprealian, M.D.2 Antonio DeSalles, M.D., Ph.D.1 Nader Pouratian, M.D., Ph.D.1,2-5
Affiliations:
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Department of Neurological Surgery Department of Radiation Oncology 3 Interdepartmental Program in Neuroscience 4 Department of Bioengineering 5 Brain Research Institute University of California, Los Angeles 10945 Le Conte Ave Suite 2120 Los Angeles, CA 90095
11000 Weyburn Drive Apt 404 Los Angeles, CA 90024
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Corresponding Author: Srinivas Chivukula, M.D. Department of Neurological Surgery UCLA Health System
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Email: [email protected] Phone: 774-208-2509 Sources of Support:
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Running Title: Radiosurgery for Secondary Trigeminal Neuralgia
Financial Disclosure/Disclaimer: The authors have no vested financial interests in this study.
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Keywords: trigeminal neuralgia; secondary; radiosurgery; tumor; target; stereotactic
ACCEPTED MANUSCRIPT ABSTRACT Background The mechanisms by which surgery and radiation elicit pain relief in trigeminal neuralgia (TN) secondary to mass lesions vary widely. We aimed to evaluate the outcomes of radiation to the nerve rather than to the lesion in the treatment of secondary TN. Methods We retrospectively reviewed all patients who underwent radiation at the University of California, Los Angeles for TN secondary to tumors. The Barrow Neurological Institute (BNI) pain score was used to evaluate pain outcomes.
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Results Twelve patients were identified; 4 were male and 8 were female. Their mean age at treatment was 59.8 years (range, 47.7 – 84.7 years). Tumor pathologies included meningioma (n=8), squamous cell carcinoma (n=2), vestibular schwannoma (n=1) and hemangiopericytoma (n=1). No patient suffered from multiple sclerosis. Ten patients underwent initial radiation targeting their tumors – radiosurgery in 3 and fractionated radiation therapy in 7 others. Only 6 amongst these 10 experienced at least partial relief, which lasted a mean 6 months. Radiosurgery targeting the trigeminal nerve was eventually performed. Overall, 10 of 12 (83.3%) patients experienced good initial pain relief, complete in 6 (50%) patients. Pain recurred in 6 (60%) patients, at a mean 41 months after radiosurgery to the trigeminal nerve. Three patient experienced facial sensory dysfunction post-procedurally at a mean follow up duration of 57 months.
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Conclusion In contrast to tumor radiation, radiosurgery to the trigeminal nerve root resulted in reasonable and longer pain reduction, on par with the literature regarding surgical resection, with low risk of additional complications.
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Keywords: trigeminal neuralgia; secondary; radiosurgery; tumor; target; stereotactic
ACCEPTED MANUSCRIPT INTRODUCTION
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Trigeminal neuralgia (TN) typically manifests as intense paroxysmal, brief, electric or stabbing unilateral facial pain along the distribution of one or more branches of the trigeminal nerve.1 Although most cases of trigeminal neuralgia are believed to be primary and due to vascular compression of the trigeminal nerve by an aberrant arterial loop or venous compression, facial pain in a fraction of patients with TN is secondary to compressive lesions including tumors, benign or malignant, or aneurysmal dilatations along the trigeminal pathway in the middle or posterior fossa.2-6 Surgical options for their management include resection of the mass lesion, radiofrequency or glycerol rhizotomy, and balloon compression.1-3 Radiosurgery is a noninvasive alternative, yet literature regarding its effective use in the treatment of secondary TN – lesion control versus pain control – and outcomes, remains scant.7-14 Moreover, when opting for radiotherapy, there remains a question of whether pain relief is best achieved by targeting and treating the primary lesion or the trigeminal nerve (as we would do in the case of idiopathic trigeminal neuralgia).
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Despite the apparently lower risk of morbidity and mortality that radiation for tumor control carries, its outcomes have not been as promising as with surgical tumor resection alone or in combination with microvascular decompression (MVD) for secondary TN.2,3,5,7,8,15 In contrast with a rate of over 80% of patients experiencing complete initial pain relief with surgery, Regis et al. reported in at least one large series that although 84% of patients with secondary TN experienced initial pain improvement, only 47% maintained pain relief at approximately two years.3,7,8 Our increased understanding of radiobiology today suggests that early pain relief from radiosurgery may stem from inactivation of ephaptic transmission, and persistent benefit may result from demyelination or injury to nerve microvasculature, indicating that radiation targeting the nerve rather than the mass but the nerve itself may provide greater pain relief in patients with intractable tumor related TN.1,2,5 To our knowledge, no systematic evaluation of radiosurgery in the treatment of secondary TN with regard targeting tumor versus nerve has been undertaken to date. We describe in this report our experience in a cohort of patients who underwent radiosurgery for secondary TN, and discuss outcomes including extent and duration of pain relief, with particular attention to treatment target, in an attempt to begin to optimize the radiosurgical management of trigeminal neuralgia related to mass lesions. METHODS
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Patient population
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Following institutional review board approval, the records of all patients who underwent radiosurgery for secondary trigeminal neuralgia at the University of California, Los Angeles (UCLA) Medical Center were identified. Secondary trigeminal neuralgia was defined as tumor-related, and type I in nature, that is, unilateral, lancinating, and electric shock-like along one or more trigeminal dermatomes.1 Twelve such patients were identified who underwent SRS between 1997 and 2014. Pre- and post-SRS clinical and radiographic data were assessed at a median follow-up period of 55.6 months (range, 10.3 – 125.3 months) via records from outpatient visits or phone interviews.
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The demographics of our series are outlined in Tables 1 and 2. Tumor pathologies included meningioma (n=8, 66.7%), squamous cell carcinoma (n=2, 16.7%), vestibular schwnanoma (n=1, 8.3%) and hemangiopericytoma (n=1, 8.3%), and originated in the following locations: petroclivus (n=5, 41.7%), cavernous sinus (n=2, 16.7%), sphenoid wing (n=2, 16.7%), maxillary sinus (n=2, 16.7%), and the cerebellopontine angle (CPA, n=1, 8.3%) It is to be noted that in no case included in this series did the tumor encase the trigeminal nerve. In all cases the tumor touched the nerve or nerve roots and caused at least mild compression of the nerve. A detailed analysis of the degree of nerve compression and the outcome is beyond the limited scope of this retrospective study. Mean age at the time of SRS was 59.8 years (range, 47.7 – 84.7 years). Pain was most commonly right sided (8 patients, 61.5%), and along the V2 and V3 dermatomal distributions (5 patients, 38.5%) or the V3 distribution (4 patients, 30.8%). Four patients (33.3%) experienced facial sensory dysfunction prior to the SRS procedure - numbness in three patients (25.0%), and burning pain in one other (8.3%). Ten patients (83.3%) underwent prior procedures for their trigeminal neuralgia, including radiosurgery or radiation therapy in all (n=10, 83.3%) targeting their tumors (and not the trigeminal nerve itself). Radiosurgical procedures Patient simulation: In seven of 12 patients (58.3%), a stereotactic frame was applied under local anesthesia and intravenous conscious sedation. In the other 5 patients, a head and neck thermoplastic mask was made and used for stereotaxy. The patients were simulated on a Siemens sensation open CT scanner with 1.5 mm slice thickness. The patients were immobilized in either the stereotactic frame
ACCEPTED MANUSCRIPT or the Brainlab's head and neck thermoplastic mask system and scanned with a localization frame that was attached to the baseplate of the mask immobilization system. We acquired a 1 mm isotropic MPRAGE with contrast and a 1 mm CISS/FIESTA T2 weighted MRI. Fusion of the CT and MRI scans were done in iPlan RT Image software. Structures at risk were contoured on the MR images.
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Planning: We used either a 4-mm (n=8, 66.7%) or a 5-mm (n=4, 33.3%) diameter stereotactic radiosurgery conical collimator (SRS cone) and 6 MV photons on a Varian Novalis Tx linear accelerator. We treat with 7 equally spaced arcs of 100-degree arc length each that result in a slightly prolate spheroid shaped 50% isodose surface. The dose calculation grid was set to 1 mm. The dose was specified as 90 Gy to the isocenter in a single fraction. The isocenter was placed on the nerve such that the 50% isodose surface just touched or was slightly off of the brainstem at the trigeminal REZ. We ensured that the brainstem volume that received 12 Gy (V12 Gy) was less than 0.3 cc (typically with correct placement the V12 Gy is around 0.15 cc). Patient localization for treatment delivery: We aligned the patients in the treatment room using the Brainlab Exactrac stereotactic xray image guidance system. The setup tolerance was set to 0.5 mm and the patients were imaged and positioning corrected before each arc was delivered. Prior to the first arc being delivered we also verifed positioning with Varian's on-board cone beam CT system; however, final positioning was always performed with the Exactrac system.
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It is to be noted that the root entry zone was localized for targeting the radiation and the radiation was not directed at the tumor. The tumor volume did not appreciably change in any case before and after the radiation delivery. Consequently, assessments of pain relief outcomes in the context of tumor volume are beyond the scope of this report. A team consisting of a neurosurgeon, radiation oncologist, and medical physicist performed dose selection and treatment planning. Follow-up evaluations
Data and analyses
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Follow-up information was obtained from the patients, their families, or their referring physicians. Data pertaining to the degree of pain relief, latency interval to pain relief, the need for further surgical procedures or medication, and new symptoms such as facial sensory dysfunction were obtained. The Barrow Neurological Institute (BNI) pain intensity criteria were used to grade the pain outcome for all patients in this study. Specifically, grade I (no pain, no medication); grade II (occasional pain, not requiring medication); grade IIIa (no pain, but continued medication); grade IIIb (pain controlled with medication); grade IV, (pain improved, but not adequately controlled with medication); and grade V (persistent inadequately controlled).16 For the purposes of this report, we defined BNI grade I as complete relief, BNI grades II-IIIb as incomplete relief (but adequate), and BNI grades IV and V as no significant relief. BNI grades I-IIIb were considered as adequate pain relief. Grades II-IIIb were considered adequate relief because pain was controlled, albeit on medication in the cases of grades IIIa and IIIb, and grade II pain is considered tolerable and not unconducive to a good quality of life.
RESULTS
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Patient demographics and outcomes were analyzed using descriptive statistics. The rates of initial pain improvement and the maintenance of pain relief among those showing initial response were analyzed by the product-limit method of Kaplan and Meier. Data were collected using Excel (Microsoft Corp.) and were analyzed using SPSS (version 20.0, IBM).
Ten of 12 (83.3%) patients with tumors underwent initial radiosurgery (n=3, 30.0%) or fractionated radiation therapy (n=7, 70.0%) for tumor control with the intent of treating their trigeminal neuralgia. These details are presented in Table 2. These tumors included 7 meningiomas (70.0%) and a single case each of a vestibular schwannoma, squamous cell carcinoma and hemangiopericytoma. Tumors were of the petroclivus (n=5, 50.0%), cavernous sinus (n=2, 20.0%), sphenoid wing (n=2, 20.0%), the maxillary sinus (n=2, 20.0%) or the cerebellopontine angle in the case of the vestibular schwannoma. Radiation doses were 14 Gy and 13 Gy in the three patients who underwent stereotactic radiosurgery (SRS), and either 57.6 Gy or 50.4 Gy in those who underwent fractionated stereotactic radiotherapy (SRT). Six (60.0%) patients experienced at least some pain relief, incomplete in all (BNI pain score II-IIIb), which lasted a brief 5.8 months (range, 5-8 months). Treatment characteristics of all patients are presented in Table 3. Excepting a single patient (n=1, 8.3%), all experienced BNI grade V pain at the time of radiosurgery. Following radiosurgery, 10 patients (83.3%) experienced at least some pain relief, complete in six
ACCEPTED MANUSCRIPT patients (50.0%). Two patients (16.7%) failed to experience any relief. The trigeminal pain recurred at a mean of 41.2 months (range, 1-61 months) in six patients (50.0%) who underwent repeat treatment for their trigeminal pain at a mean of 17.8 months (range, 4-35 months). One patient underwent repeat SRS of the TN, and experienced subsequent complete relief from pain that persisted to the last available follow-up 23 months later. Another patient underwent SRS targeting his underlying tumor, and failed to experience any relief.
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Outcomes from SRS to the trigeminal nerve for secondary TN are shown in Table 4. In all, the mean time to initial response was 4.1 weeks (range, 1-8 weeks). Three of a total of ten patients (30.0%) that experienced at least some pain relief in response to radiosurgery for trigeminal neuralgia also developed facial sensory dysfunction at a mean 3.8 weeks following radiosurgery (range, 3-5 weeks). In all, four patients (33.3%) showed radiographic changes subsequent to radiosurgery, which included pontine and/or trigeminal nerve root enhancement on MRI, within the total mean follow up of 55.6 months in our series (range, 10-125 months). It should be noted that in all cases tumor volume was at least stable after radiosurgery, with no appreciable decrement in size. DISCUSSION
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Mass lesions involving structures of the trigeminal nerve pathway such as the cavernous sinus, Meckel’s cave, petrous apex and petroclivus, whether benign or malignant, can cause trigeminal neuralgia.3-5,7,8,17-21 Although various reports have outlined the noninvasive benefits of radiation over surgery for symptomatic relief, their outcomes have compared unfavorably to surgery with regard amount and duration of relief, and rate of success.3,7,8 Evidence indicates that radiation directed at tumor control might be inferior to nerve targeting in achieving maximal benefit in cases of secondary TN, suggesting a need for a change in the treatment paradigm.2,5,7,8,9-16 In this report, we describe an evaluation of our experience with radiation for tumor related trigeminal neuralgia, with a special emphasis on treatment targets and outcomes.
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Of 12 patients in our current series, the tumor was the initial target for radiation in ten patients (83.3%) – radiosurgery in three patients (25.0%) and fractionated radiation therapy in seven others (58.3%). Only 50% of these patients experienced at least incomplete pain relief that lasted on average for a brief six months. These outcomes are disappointing at best when compared to rates of initial pain relief of over 80% reported in patients undergoing surgical resection for tumor related TN.3 In addition, the mean latency prior to relief in these patients was seven months; although our sample is limited, no relationship was noted between the extent or occurrence of pain relief and tumor volume reduction. In fact, even amongst patients who experienced initial relief in response to radiation, recurrence was unanimous and unrelated to tumor progression (tumors were at least stable in all patients between the time of radiation to the lesion and subsequent radiation to the nerve).
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We must consider the mechanism by which radiation achieves pain control in trigeminal neuralgia to understand its failure when targeting the lesion in tumor related TN. It has been hypothesized that early pain relief occurs as a result of cessation of ephaptic transmission and that a delayed, persistent relief is achieved from demyelination injury, or injury to the nerve microvasculature.2-5,15,2224 Tumors tend to cause pain by direct compression of the nerve root, or by vascular compression from displacement by tumor, which in turn causes abnormal electrical transmission.3,4,22 Although surgical resection dissects tumor off the nerve and minimizes this transmission to achieve significant pain relief, radiation to the lesion can only achieve at best tumor volume reduction without causing significant morbidity; tumor remains around the nerve and pathological electrical propagation unavoidably continues. Targeting the nerve root, therefore, and not the lesion itself, may provide greatest pain relief in these cases. Accordingly, the rate of initial pain relief in our series with targeting the root entry zone (REZ) in cases of tumor related TN was 83.3% with a mean latency period of four weeks, and 50% of these patients experienced complete relief. Recurrences occurred in 50% of patients overall, at a mean 41 months from treatment, and in three (25%) cases were due to tumor progression. Our sample is small but our results compare favorably to those reported by Barker et al. in patients that were surgically treated, with 81% of patients experiencing excellent pain relief and another 4% experiencing partial relief.3 When patients are not surgical candidates due to age or medical comorbidities, or when tumor cannot be completely excised for maximal relief, it appears that radiation targeting the trigeminal nerve root may offer at least similar benefit, and noninvasively. Tumor related trigeminal neuralgia poses a particular challenge – although radiation to the nerve may provide excellent relief, tumor growth can cause recurrence and require retreatment. Barker et al. reported a recurrence rate of 17%, noting that 50% of their recurrences correlated with tumor recurrence.3 Régis et al. noted a recurrence rate of 13%, with tumor regrowth in 7%.7,8,23 Although radiated patients can be retreated with radiation, the high dose of 90Gy to the trigeminal nerve root causes cumulative nerve injury; as has been described by Tempel et al., although increasing doses of radiation can provide increasing relief in TN both essential and
ACCEPTED MANUSCRIPT secondary, the rate of facial dysesthetic complications increases in parallel and must be weighed in treatment decision making.1 A single tumor patient in our series was treated with repeat radiation to the REZ, and experienced complete relief for 22 months post treatment. Another patient was treated with radiation to the tumor; notably, this failed to provide relief.
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Dysesthetic complications in radiation treatment for TN include mostly hypesthesia and paresthesias.1-7 In our series, three patients treated with radiation for TN experienced sensory dysfunction post procedurally. This rate of 25% is higher than the 6-20% reported in other series, but comparison is difficult given the discrepancy in study sample sizes.9-16 Moreover, two of the three patients that had post procedural sensory dysfunction also had facial paresthesias along the same trigeminal distribution prior to their radiation treatment, likely related to the tumor induced nerve damage itself, which worsened after radiation. Facial sensory dysfunction is believed to arise from brainstem injury because of the radiation dose to the trigeminal pathway within the pons.1-4,20-27
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Although the literature regarding the safety and efficacy of radiosurgery for secondary TN is limited, our sample is small, and our report subject to the biases of a retrospective study. Our follow up duration is fairly long, yet based on our results there is a decrease in success rate over the months from initial treatment, and the rate of pain recurrence over an extended period of time is therefore unknown. Prolonged follow up is necessary to identify long term recurrence rates and identify the possibility of delayed radiation induced complications, although it would appear that this is low. The four and five millimeter collimators largely used in our series produce a sharp dose decline so that <1cm from the iscocenter, tissues receive less than 10% (9Gy) of the maximum dose (90Gy). Nonetheless, although this report may suffice for a preliminary evaluation of optimal treatment targets for radiation in the treatment of secondary TN, future prospective, randomized trials may be ideal to more precisely determine the best form of treatment for these pathologies. CONCLUSION
REFERENCES
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Tempel ZJ, Chivukula S, Monaco III EA, Bowden G, Kano H, Niranjan A, et al. The results of a third gamma knife procedure for recurrent trigeminal neuralgia. J Neurosurg. 2015;122:169-179. 2. Chang JW, Chang JH, Park YG, Chung SS. Gamma knife radiosurgery for idiopathic and secondary trigeminal neuralgia. J Neurosur. 2000;93:147-151. 3. Barker FG, Jannetta PJ, Babu RP, Pomonis S, Bissonette DJ, Jho HD. Long-term outcome after operation for trigeminal neuralgia in patients with posterior fossa tumors. J Neurosurg. 1996;84:818-825. 4. Bullitt E, Tew JM, Boyd J. Intracranial tumors in patients with facial pain. J Neurosurg. 1986;64:865-871. 5. Cheng TMW, Cascino TL, Onofrio BM. Comprehensive study of diagnosis and treatment of trigeminal neuralgia secondary to tumors. Neurology. 1993;43:2298-2302. 6. Marco JKD, Hesselink JR. Trigeminal neuropathy. Neurosurg Clin North Am. 1997;8:103-130. 7. Régis J, Métellus P, Dufour H. Long-term outcome after gamma knife surgery for secondary trigeminal neuralgia. J Neurosur. 2001;95:199-205. 8. Régis J, Métellus P, Lazorthes Y, Porcheron D, Peragut JC. Effect of gamma knife on secondary trigeminal neuralgia. Stereotact Funct Neurosurg. 1998;70:210-217. 9. Huang CF, Kondziolka D, Flickinger JC. Stereotactic radiosurgery for trigeminal schwannomas. Neurosurgery. 1999;45:1116. 10. Kondziolka D, Lunsford LD. Radiosurgery of meningiomas. Neurosurg Clin North Am. 1992;3:219-230. 11. Lunsford LD, Kondziolka DS, Flickinger JC. Radiosurgery of tumors of the cerebellopontine angle. Clin Neurosur. 1994;41:168-184. 12. Muthukumar N, Kondziolka D, Lunsford LD. Stereotactic radiosurgery for tentorial meningiomas. Acta Neurochir. 1998;140:315-321.
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Tumors are not infrequent causes of trigeminal neuralgia. Although surgical tumor resection may offer significant pain relief in cases of secondary TN, radiation treatment of tumors does not provide the same benefit. Targeting the nerve root rather than the lesion itself provides maximal pain relief, and this may relate to the differential mechanisms of action of radiosurgery and traditional surgery. In cases of secondary trigeminal neuralgia, radiosurgery to the nerve root offers a safe and efficacious solution to symptomatic pain relief with excellent outcomes maintained over greater than a mean two years of follow up, and may offer an especially valuable treatment option in patients who may be poor surgical candidates.
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13. Pollock BE, Lunsford LD, Kondziolka D, Flickinger JC, Bissonette DJ, Kelsey SF, et al. Outcome analysis of acoustic neuroma management: a comparison of microsurgery and stereotactic radiosurgery. Neurosurgery. 1995;36:215-229. 14. Subach BR, Lunsford LD, Kondziolka D, Maitz AH, Flickinger JC. Management of petroclival meningiomas by stereotactic radiosurgery. Neurosurgery. 1998;42:437-445. 15. Young RF, Vermeulen SS, Grimm P, Blasko J, Posewitz A. Gamma knife radiosurgery for treatment of trigeminal neuralgia: idiopathic and tumor related. Neurology. 1997;48:608-614. 16. 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;47:1013-1019. 17. Delfini R, Innocenzi G, Ciappetta P, Domenicucci M, Cantore G. Meningiomas of Meckel’s cave. Neurosurgery. 1992;31:1000-1007. 18. McCormick PC, Bello JA, Post KD. Trigeminal schwannoma. Surgical series of 14 cases with review of the literature. J Neurosurg. 1988;69:850-860. 19. Ogleznev KY, Grigoryan YA, Slavin KV. Parapontine epidermoid tumors presenting as trigeminal neuralgias: anatomical findings and operative results. Acta Neurochir. 1991;110:116-119. 20. Pollack IF, Sekhar LN, Jannetta PJ, Janecka IP. Neurilemomas of the trigeminal nerve. J Neurosurg. 1989;70:737-745. 21. Puca A, Meglio M, Tamburrini G, Vari R. Trigeminal involvement in intracranial tumors. Anatomical and clinical observations on 73 patients. Acta Neurochir. 1993;125:47-51. 22. Kondziolka D, Lunsford D, Flickinger JC, Young RF, Vermeulen S, Duma CM, et al. Stereotactic radiosurgery for trigeminal neuralgia: a multiinstitutional study using the gamma unit. J Neurosurg. 1996;84:940-945. 23. Régis J, Bartolemi F, Metellus P, Rey M, Genton P, Dravet C, et al. Radiosurgery for trigeminal neuralgia and epilepsy. Neurosurg Clin North Am. 1999;10:359-377. 24. Urgosik D, Vymazal J, Vladyka V, Liscák R, et al. Gamma knife treatment of trigeminal neuralgia: clinical and electrophysiological study. Stereotact Funct Neurosurg. 1998;70:200-209. 25. Ildan F, Göcer AL, Bagdatoglu H, Uzuneyüpoglu Z, Tuna M, Cetinalp E. Isolated trigeminal neuralgia secondary to distal anterior inferior cerebellar artery aneurysm. Neurosurg Rev. 1996;19:43-46. 26. Conforti R, Parlato RS, De Paulis D, Cirillo M, Marrone V, Cirillo S, et al. Trigeminal neuralgia and persistent trigeminal artery. Neurol Sci. 2012;33:1455-1458. 27. Nomura T, Ikezaki K, Matshushima T, Fukui M. Trigeminal neuralgia: differentiation between intracranial mass lesions and ordinary vascular compression as causative lesions. Neurosurg Rev. 1994;17:51-57.
ACCEPTED MANUSCRIPT Table 1. Patient demographics Total N=12
Characteristic
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Patient population 4 (33.3) Male 8 (66.7) Female Age at SRS* 59.8 (11.2) Mean (SD) 47.7–84.7 Range Pain distribution 2 (15.4) V2 4 (30.8) V3 1 (7.7) V1 & V2 5 (38.5) V2 & V3 1 (7.7) V1, V2 & V3 8 (61.5) Right 5 (38.5) Left Preexisting facial sensory dysfunction 3 (25.0) Numbness 1 (8.3) Allodynia/burning pain Prior treatment 10 (83.3) No. of patients Treatment 10 (83.3) Radiation to lesion (not TN) Stereotactic radiosurgery 3 (25.0) Stereotactic radiation therapy 7 (58.3) Other Surgical resection 2 Biopsy 1 Balloon compression 1 Ganglion block 1 MVD 1 SRS, stereotactic radiosurgery, refers to the treatment of trigeminal neuralgia, not tumor; SD, standard deviation; TN, trigeminal nerve; MVD, microvascular decompression
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Parameter
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Prior treatment/surgery Number of patients 10 (83.3) Radiation to lesion (not TN) Stereotactic radiosurgery 3 (30.0) Stereotactic radiation therapy 7 (70.0) Other Surgical resection 2 Biopsy 1 Balloon compression 1 Ganglion block 1 MVD 1 Pathology Meningioma 7 (70.0) Squamous cell carcinoma 1 (10.0) Vestibular schwannoma 1 (10.0) Hemangiopericytoma 1 (10.0) Location Petroclivus 5 (50.0) Cavernous sinus 2 (20.0) Sphenoid wing 2 (20.0) Maxillary sinus 2 (20.0) Cerebellopontine angle 1 (10.0) Total radiation dose 40.7 (19.1) Mean (SD) Fractionated 57.6 Gy 2 (20.0) 50.4Gy 5 (50.0) Unfractionated 14 Gy 1 (10.0) 13 Gy 2 (20.0) Pain relief following initial SRS/SRT No pain relief (BNI score IV-V) 4 (40.0) At least some pain relief (BNI score I-IIIb) Complete (BNI pain score I) 0 Incomplete (BNI pain score II-IIIb) 6 (60.0) Time to onset of relief Mean number of weeks (range) 7.2 (2.0–9.0) Duration of relief Mean number of months (range) 5.8 (5.0–8.0) Interval prior to SRS for TN Mean number of months (range) 21.8 (8.0-72.0) TN, trigeminal neuralgia; MVD, microvascular decompression; SRS, stereotactic radiosurgery; SRT, stereotactic radiation therapy; BNI, Barrow Neurological Institute
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Table 3. Treatment characteristics of patients who underwent SRS for trigeminal neuralgia Total Parameter N=12 Pre-treatment BNI Pain score 0 I 0 II 0 IIIa 1 (8.3) IIIb 1 (8.3) IV 10 (83.3) V Treatment 90.0 (90) Mean maximum dose (Gy) (range) Frame 7 (58.3) Yes 5 (41.7) No Collimator size 4 mm 8 (66.7) 5 mm 4 (33.3) Pain relief 2 (16.7) No pain relief (BNI score IV-V) 10 (83.3) At least some pain relief (BNI score I-IIIb) Complete (BNI pain score I) 6 (50.0) Incomplete (BNI pain score II-IIIb) 4 (33.3) Recurrence 6 (50.0) No. of patients 41.2 (1-61) Mean time to recurrence (months) (range) Subsequent treatment (# of patients experiencing relief) Repeat SRS to TN REZ 1 (1) Balloon compression 3 (0) RFA 1 (1) MVD 1 (1) Other 4 (2) SRS to tumor/alternate target 1 (0) Tumor resection 3 (3) Mean time to treatment (months) (range) 17.8 (4-35) SRS, stereotactic radiosurgery; BNI, Barrow Neurological Institute; Gy, Gray; TN, trigeminal nerve; REZ, root entry zone; RFA, radiofrequency ablation; MVD, microvascular decompression
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Time to initial response (weeks) 4.1 (1-8) Mean (range) Facial sensory dysfunction Among responders, number of patients 1 Numbness 1 Tingling 1 Mean time in weeks to onset of symptoms (range) 3.0 (NA) Among non-responders, number of patients 2 Numbness 1 Tingling 1 Mean time in weeks to onset of symptoms (range) 4.5 (4-5) Post-radiation radiographic changes 4 (33.3) Pontine/TN root enhancement Number of patients experiencing at least incomplete relief 3 (25.0) 55.6 (10.3-125.3) Mean follow-up in months (range) SRS, stereotactic radiosurgery; NA, not applicable; TN, trigeminal neuralgia
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Trigeminal neuralgia may be secondary to mass lesions such as tumors Radiation to the tumor does not provide lasting relief in cases of secondary trigeminal neuralgia Radiosurgery to the nerve root provides safe and efficacious pain relief
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ACCEPTED MANUSCRIPT ABBREVIATIONS
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TN, trigeminal neuralgia BNI, Barrow Neurological Institute MVD, microvascular decompression UCLA, University of California, Los Angeles SRS, stereotactic radiosurgery CT, computed tomography MRI, magnetic resonance imaging REZ, root entry zone Gy, Gray SRT, stereotactic radiotherapy
ACCEPTED MANUSCRIPT DISCLOSURES/CONFLICTS OF INTEREST
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The authors do not have any conflicts of interests to disclose. The information reviewed and/or presented within this manuscript was not supported by a commercial grant or by commercial interests.
S1878-8750(16)30932-9
DOI:
10.1016/j.wneu.2016.09.087
Reference:
WNEU 4627
To appear in:
World Neurosurgery
Received Date: 19 February 2016 Revised Date:
21 September 2016
Accepted Date: 22 September 2016
Please cite this article as: Chivukula S, Kim W, Zhuo X, Tenn S, Kaprealian T, DeSalles A, Pouratian N, Radiosurgery for Secondary Trigeminal Neuralgia: Revisiting the Treatment Paradigm, World Neurosurgery (2016), doi: 10.1016/j.wneu.2016.09.087. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title:
Radiosurgery for Secondary Trigeminal Neuralgia: Revisiting the Treatment Paradigm
Authors:
Srinivas Chivukula, M.D.1 Won Kim, M.D.1 Xiaoyi Zhuo, B.S.1 Stephen Tenn, Ph.D.2 Tania Kaprealian, M.D.2 Antonio DeSalles, M.D., Ph.D.1 Nader Pouratian, M.D., Ph.D.1,2-5
Affiliations:
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Department of Neurological Surgery Department of Radiation Oncology 3 Interdepartmental Program in Neuroscience 4 Department of Bioengineering 5 Brain Research Institute University of California, Los Angeles 10945 Le Conte Ave Suite 2120 Los Angeles, CA 90095
11000 Weyburn Drive Apt 404 Los Angeles, CA 90024
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Corresponding Author: Srinivas Chivukula, M.D. Department of Neurological Surgery UCLA Health System
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Email: [email protected] Phone: 774-208-2509 Sources of Support:
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Running Title: Radiosurgery for Secondary Trigeminal Neuralgia
Financial Disclosure/Disclaimer: The authors have no vested financial interests in this study.
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Keywords: trigeminal neuralgia; secondary; radiosurgery; tumor; target; stereotactic
ACCEPTED MANUSCRIPT ABSTRACT Background The mechanisms by which surgery and radiation elicit pain relief in trigeminal neuralgia (TN) secondary to mass lesions vary widely. We aimed to evaluate the outcomes of radiation to the nerve rather than to the lesion in the treatment of secondary TN. Methods We retrospectively reviewed all patients who underwent radiation at the University of California, Los Angeles for TN secondary to tumors. The Barrow Neurological Institute (BNI) pain score was used to evaluate pain outcomes.
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Results Twelve patients were identified; 4 were male and 8 were female. Their mean age at treatment was 59.8 years (range, 47.7 – 84.7 years). Tumor pathologies included meningioma (n=8), squamous cell carcinoma (n=2), vestibular schwannoma (n=1) and hemangiopericytoma (n=1). No patient suffered from multiple sclerosis. Ten patients underwent initial radiation targeting their tumors – radiosurgery in 3 and fractionated radiation therapy in 7 others. Only 6 amongst these 10 experienced at least partial relief, which lasted a mean 6 months. Radiosurgery targeting the trigeminal nerve was eventually performed. Overall, 10 of 12 (83.3%) patients experienced good initial pain relief, complete in 6 (50%) patients. Pain recurred in 6 (60%) patients, at a mean 41 months after radiosurgery to the trigeminal nerve. Three patient experienced facial sensory dysfunction post-procedurally at a mean follow up duration of 57 months.
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Conclusion In contrast to tumor radiation, radiosurgery to the trigeminal nerve root resulted in reasonable and longer pain reduction, on par with the literature regarding surgical resection, with low risk of additional complications.
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Keywords: trigeminal neuralgia; secondary; radiosurgery; tumor; target; stereotactic
ACCEPTED MANUSCRIPT INTRODUCTION
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Trigeminal neuralgia (TN) typically manifests as intense paroxysmal, brief, electric or stabbing unilateral facial pain along the distribution of one or more branches of the trigeminal nerve.1 Although most cases of trigeminal neuralgia are believed to be primary and due to vascular compression of the trigeminal nerve by an aberrant arterial loop or venous compression, facial pain in a fraction of patients with TN is secondary to compressive lesions including tumors, benign or malignant, or aneurysmal dilatations along the trigeminal pathway in the middle or posterior fossa.2-6 Surgical options for their management include resection of the mass lesion, radiofrequency or glycerol rhizotomy, and balloon compression.1-3 Radiosurgery is a noninvasive alternative, yet literature regarding its effective use in the treatment of secondary TN – lesion control versus pain control – and outcomes, remains scant.7-14 Moreover, when opting for radiotherapy, there remains a question of whether pain relief is best achieved by targeting and treating the primary lesion or the trigeminal nerve (as we would do in the case of idiopathic trigeminal neuralgia).
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Despite the apparently lower risk of morbidity and mortality that radiation for tumor control carries, its outcomes have not been as promising as with surgical tumor resection alone or in combination with microvascular decompression (MVD) for secondary TN.2,3,5,7,8,15 In contrast with a rate of over 80% of patients experiencing complete initial pain relief with surgery, Regis et al. reported in at least one large series that although 84% of patients with secondary TN experienced initial pain improvement, only 47% maintained pain relief at approximately two years.3,7,8 Our increased understanding of radiobiology today suggests that early pain relief from radiosurgery may stem from inactivation of ephaptic transmission, and persistent benefit may result from demyelination or injury to nerve microvasculature, indicating that radiation targeting the nerve rather than the mass but the nerve itself may provide greater pain relief in patients with intractable tumor related TN.1,2,5 To our knowledge, no systematic evaluation of radiosurgery in the treatment of secondary TN with regard targeting tumor versus nerve has been undertaken to date. We describe in this report our experience in a cohort of patients who underwent radiosurgery for secondary TN, and discuss outcomes including extent and duration of pain relief, with particular attention to treatment target, in an attempt to begin to optimize the radiosurgical management of trigeminal neuralgia related to mass lesions. METHODS
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Patient population
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Following institutional review board approval, the records of all patients who underwent radiosurgery for secondary trigeminal neuralgia at the University of California, Los Angeles (UCLA) Medical Center were identified. Secondary trigeminal neuralgia was defined as tumor-related, and type I in nature, that is, unilateral, lancinating, and electric shock-like along one or more trigeminal dermatomes.1 Twelve such patients were identified who underwent SRS between 1997 and 2014. Pre- and post-SRS clinical and radiographic data were assessed at a median follow-up period of 55.6 months (range, 10.3 – 125.3 months) via records from outpatient visits or phone interviews.
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The demographics of our series are outlined in Tables 1 and 2. Tumor pathologies included meningioma (n=8, 66.7%), squamous cell carcinoma (n=2, 16.7%), vestibular schwnanoma (n=1, 8.3%) and hemangiopericytoma (n=1, 8.3%), and originated in the following locations: petroclivus (n=5, 41.7%), cavernous sinus (n=2, 16.7%), sphenoid wing (n=2, 16.7%), maxillary sinus (n=2, 16.7%), and the cerebellopontine angle (CPA, n=1, 8.3%) It is to be noted that in no case included in this series did the tumor encase the trigeminal nerve. In all cases the tumor touched the nerve or nerve roots and caused at least mild compression of the nerve. A detailed analysis of the degree of nerve compression and the outcome is beyond the limited scope of this retrospective study. Mean age at the time of SRS was 59.8 years (range, 47.7 – 84.7 years). Pain was most commonly right sided (8 patients, 61.5%), and along the V2 and V3 dermatomal distributions (5 patients, 38.5%) or the V3 distribution (4 patients, 30.8%). Four patients (33.3%) experienced facial sensory dysfunction prior to the SRS procedure - numbness in three patients (25.0%), and burning pain in one other (8.3%). Ten patients (83.3%) underwent prior procedures for their trigeminal neuralgia, including radiosurgery or radiation therapy in all (n=10, 83.3%) targeting their tumors (and not the trigeminal nerve itself). Radiosurgical procedures Patient simulation: In seven of 12 patients (58.3%), a stereotactic frame was applied under local anesthesia and intravenous conscious sedation. In the other 5 patients, a head and neck thermoplastic mask was made and used for stereotaxy. The patients were simulated on a Siemens sensation open CT scanner with 1.5 mm slice thickness. The patients were immobilized in either the stereotactic frame
ACCEPTED MANUSCRIPT or the Brainlab's head and neck thermoplastic mask system and scanned with a localization frame that was attached to the baseplate of the mask immobilization system. We acquired a 1 mm isotropic MPRAGE with contrast and a 1 mm CISS/FIESTA T2 weighted MRI. Fusion of the CT and MRI scans were done in iPlan RT Image software. Structures at risk were contoured on the MR images.
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Planning: We used either a 4-mm (n=8, 66.7%) or a 5-mm (n=4, 33.3%) diameter stereotactic radiosurgery conical collimator (SRS cone) and 6 MV photons on a Varian Novalis Tx linear accelerator. We treat with 7 equally spaced arcs of 100-degree arc length each that result in a slightly prolate spheroid shaped 50% isodose surface. The dose calculation grid was set to 1 mm. The dose was specified as 90 Gy to the isocenter in a single fraction. The isocenter was placed on the nerve such that the 50% isodose surface just touched or was slightly off of the brainstem at the trigeminal REZ. We ensured that the brainstem volume that received 12 Gy (V12 Gy) was less than 0.3 cc (typically with correct placement the V12 Gy is around 0.15 cc). Patient localization for treatment delivery: We aligned the patients in the treatment room using the Brainlab Exactrac stereotactic xray image guidance system. The setup tolerance was set to 0.5 mm and the patients were imaged and positioning corrected before each arc was delivered. Prior to the first arc being delivered we also verifed positioning with Varian's on-board cone beam CT system; however, final positioning was always performed with the Exactrac system.
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It is to be noted that the root entry zone was localized for targeting the radiation and the radiation was not directed at the tumor. The tumor volume did not appreciably change in any case before and after the radiation delivery. Consequently, assessments of pain relief outcomes in the context of tumor volume are beyond the scope of this report. A team consisting of a neurosurgeon, radiation oncologist, and medical physicist performed dose selection and treatment planning. Follow-up evaluations
Data and analyses
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Follow-up information was obtained from the patients, their families, or their referring physicians. Data pertaining to the degree of pain relief, latency interval to pain relief, the need for further surgical procedures or medication, and new symptoms such as facial sensory dysfunction were obtained. The Barrow Neurological Institute (BNI) pain intensity criteria were used to grade the pain outcome for all patients in this study. Specifically, grade I (no pain, no medication); grade II (occasional pain, not requiring medication); grade IIIa (no pain, but continued medication); grade IIIb (pain controlled with medication); grade IV, (pain improved, but not adequately controlled with medication); and grade V (persistent inadequately controlled).16 For the purposes of this report, we defined BNI grade I as complete relief, BNI grades II-IIIb as incomplete relief (but adequate), and BNI grades IV and V as no significant relief. BNI grades I-IIIb were considered as adequate pain relief. Grades II-IIIb were considered adequate relief because pain was controlled, albeit on medication in the cases of grades IIIa and IIIb, and grade II pain is considered tolerable and not unconducive to a good quality of life.
RESULTS
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Patient demographics and outcomes were analyzed using descriptive statistics. The rates of initial pain improvement and the maintenance of pain relief among those showing initial response were analyzed by the product-limit method of Kaplan and Meier. Data were collected using Excel (Microsoft Corp.) and were analyzed using SPSS (version 20.0, IBM).
Ten of 12 (83.3%) patients with tumors underwent initial radiosurgery (n=3, 30.0%) or fractionated radiation therapy (n=7, 70.0%) for tumor control with the intent of treating their trigeminal neuralgia. These details are presented in Table 2. These tumors included 7 meningiomas (70.0%) and a single case each of a vestibular schwannoma, squamous cell carcinoma and hemangiopericytoma. Tumors were of the petroclivus (n=5, 50.0%), cavernous sinus (n=2, 20.0%), sphenoid wing (n=2, 20.0%), the maxillary sinus (n=2, 20.0%) or the cerebellopontine angle in the case of the vestibular schwannoma. Radiation doses were 14 Gy and 13 Gy in the three patients who underwent stereotactic radiosurgery (SRS), and either 57.6 Gy or 50.4 Gy in those who underwent fractionated stereotactic radiotherapy (SRT). Six (60.0%) patients experienced at least some pain relief, incomplete in all (BNI pain score II-IIIb), which lasted a brief 5.8 months (range, 5-8 months). Treatment characteristics of all patients are presented in Table 3. Excepting a single patient (n=1, 8.3%), all experienced BNI grade V pain at the time of radiosurgery. Following radiosurgery, 10 patients (83.3%) experienced at least some pain relief, complete in six
ACCEPTED MANUSCRIPT patients (50.0%). Two patients (16.7%) failed to experience any relief. The trigeminal pain recurred at a mean of 41.2 months (range, 1-61 months) in six patients (50.0%) who underwent repeat treatment for their trigeminal pain at a mean of 17.8 months (range, 4-35 months). One patient underwent repeat SRS of the TN, and experienced subsequent complete relief from pain that persisted to the last available follow-up 23 months later. Another patient underwent SRS targeting his underlying tumor, and failed to experience any relief.
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Outcomes from SRS to the trigeminal nerve for secondary TN are shown in Table 4. In all, the mean time to initial response was 4.1 weeks (range, 1-8 weeks). Three of a total of ten patients (30.0%) that experienced at least some pain relief in response to radiosurgery for trigeminal neuralgia also developed facial sensory dysfunction at a mean 3.8 weeks following radiosurgery (range, 3-5 weeks). In all, four patients (33.3%) showed radiographic changes subsequent to radiosurgery, which included pontine and/or trigeminal nerve root enhancement on MRI, within the total mean follow up of 55.6 months in our series (range, 10-125 months). It should be noted that in all cases tumor volume was at least stable after radiosurgery, with no appreciable decrement in size. DISCUSSION
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Mass lesions involving structures of the trigeminal nerve pathway such as the cavernous sinus, Meckel’s cave, petrous apex and petroclivus, whether benign or malignant, can cause trigeminal neuralgia.3-5,7,8,17-21 Although various reports have outlined the noninvasive benefits of radiation over surgery for symptomatic relief, their outcomes have compared unfavorably to surgery with regard amount and duration of relief, and rate of success.3,7,8 Evidence indicates that radiation directed at tumor control might be inferior to nerve targeting in achieving maximal benefit in cases of secondary TN, suggesting a need for a change in the treatment paradigm.2,5,7,8,9-16 In this report, we describe an evaluation of our experience with radiation for tumor related trigeminal neuralgia, with a special emphasis on treatment targets and outcomes.
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Of 12 patients in our current series, the tumor was the initial target for radiation in ten patients (83.3%) – radiosurgery in three patients (25.0%) and fractionated radiation therapy in seven others (58.3%). Only 50% of these patients experienced at least incomplete pain relief that lasted on average for a brief six months. These outcomes are disappointing at best when compared to rates of initial pain relief of over 80% reported in patients undergoing surgical resection for tumor related TN.3 In addition, the mean latency prior to relief in these patients was seven months; although our sample is limited, no relationship was noted between the extent or occurrence of pain relief and tumor volume reduction. In fact, even amongst patients who experienced initial relief in response to radiation, recurrence was unanimous and unrelated to tumor progression (tumors were at least stable in all patients between the time of radiation to the lesion and subsequent radiation to the nerve).
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We must consider the mechanism by which radiation achieves pain control in trigeminal neuralgia to understand its failure when targeting the lesion in tumor related TN. It has been hypothesized that early pain relief occurs as a result of cessation of ephaptic transmission and that a delayed, persistent relief is achieved from demyelination injury, or injury to the nerve microvasculature.2-5,15,2224 Tumors tend to cause pain by direct compression of the nerve root, or by vascular compression from displacement by tumor, which in turn causes abnormal electrical transmission.3,4,22 Although surgical resection dissects tumor off the nerve and minimizes this transmission to achieve significant pain relief, radiation to the lesion can only achieve at best tumor volume reduction without causing significant morbidity; tumor remains around the nerve and pathological electrical propagation unavoidably continues. Targeting the nerve root, therefore, and not the lesion itself, may provide greatest pain relief in these cases. Accordingly, the rate of initial pain relief in our series with targeting the root entry zone (REZ) in cases of tumor related TN was 83.3% with a mean latency period of four weeks, and 50% of these patients experienced complete relief. Recurrences occurred in 50% of patients overall, at a mean 41 months from treatment, and in three (25%) cases were due to tumor progression. Our sample is small but our results compare favorably to those reported by Barker et al. in patients that were surgically treated, with 81% of patients experiencing excellent pain relief and another 4% experiencing partial relief.3 When patients are not surgical candidates due to age or medical comorbidities, or when tumor cannot be completely excised for maximal relief, it appears that radiation targeting the trigeminal nerve root may offer at least similar benefit, and noninvasively. Tumor related trigeminal neuralgia poses a particular challenge – although radiation to the nerve may provide excellent relief, tumor growth can cause recurrence and require retreatment. Barker et al. reported a recurrence rate of 17%, noting that 50% of their recurrences correlated with tumor recurrence.3 Régis et al. noted a recurrence rate of 13%, with tumor regrowth in 7%.7,8,23 Although radiated patients can be retreated with radiation, the high dose of 90Gy to the trigeminal nerve root causes cumulative nerve injury; as has been described by Tempel et al., although increasing doses of radiation can provide increasing relief in TN both essential and
ACCEPTED MANUSCRIPT secondary, the rate of facial dysesthetic complications increases in parallel and must be weighed in treatment decision making.1 A single tumor patient in our series was treated with repeat radiation to the REZ, and experienced complete relief for 22 months post treatment. Another patient was treated with radiation to the tumor; notably, this failed to provide relief.
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Dysesthetic complications in radiation treatment for TN include mostly hypesthesia and paresthesias.1-7 In our series, three patients treated with radiation for TN experienced sensory dysfunction post procedurally. This rate of 25% is higher than the 6-20% reported in other series, but comparison is difficult given the discrepancy in study sample sizes.9-16 Moreover, two of the three patients that had post procedural sensory dysfunction also had facial paresthesias along the same trigeminal distribution prior to their radiation treatment, likely related to the tumor induced nerve damage itself, which worsened after radiation. Facial sensory dysfunction is believed to arise from brainstem injury because of the radiation dose to the trigeminal pathway within the pons.1-4,20-27
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Although the literature regarding the safety and efficacy of radiosurgery for secondary TN is limited, our sample is small, and our report subject to the biases of a retrospective study. Our follow up duration is fairly long, yet based on our results there is a decrease in success rate over the months from initial treatment, and the rate of pain recurrence over an extended period of time is therefore unknown. Prolonged follow up is necessary to identify long term recurrence rates and identify the possibility of delayed radiation induced complications, although it would appear that this is low. The four and five millimeter collimators largely used in our series produce a sharp dose decline so that <1cm from the iscocenter, tissues receive less than 10% (9Gy) of the maximum dose (90Gy). Nonetheless, although this report may suffice for a preliminary evaluation of optimal treatment targets for radiation in the treatment of secondary TN, future prospective, randomized trials may be ideal to more precisely determine the best form of treatment for these pathologies. CONCLUSION
REFERENCES
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Tempel ZJ, Chivukula S, Monaco III EA, Bowden G, Kano H, Niranjan A, et al. The results of a third gamma knife procedure for recurrent trigeminal neuralgia. J Neurosurg. 2015;122:169-179. 2. Chang JW, Chang JH, Park YG, Chung SS. Gamma knife radiosurgery for idiopathic and secondary trigeminal neuralgia. J Neurosur. 2000;93:147-151. 3. Barker FG, Jannetta PJ, Babu RP, Pomonis S, Bissonette DJ, Jho HD. Long-term outcome after operation for trigeminal neuralgia in patients with posterior fossa tumors. J Neurosurg. 1996;84:818-825. 4. Bullitt E, Tew JM, Boyd J. Intracranial tumors in patients with facial pain. J Neurosurg. 1986;64:865-871. 5. Cheng TMW, Cascino TL, Onofrio BM. Comprehensive study of diagnosis and treatment of trigeminal neuralgia secondary to tumors. Neurology. 1993;43:2298-2302. 6. Marco JKD, Hesselink JR. Trigeminal neuropathy. Neurosurg Clin North Am. 1997;8:103-130. 7. Régis J, Métellus P, Dufour H. Long-term outcome after gamma knife surgery for secondary trigeminal neuralgia. J Neurosur. 2001;95:199-205. 8. Régis J, Métellus P, Lazorthes Y, Porcheron D, Peragut JC. Effect of gamma knife on secondary trigeminal neuralgia. Stereotact Funct Neurosurg. 1998;70:210-217. 9. Huang CF, Kondziolka D, Flickinger JC. Stereotactic radiosurgery for trigeminal schwannomas. Neurosurgery. 1999;45:1116. 10. Kondziolka D, Lunsford LD. Radiosurgery of meningiomas. Neurosurg Clin North Am. 1992;3:219-230. 11. Lunsford LD, Kondziolka DS, Flickinger JC. Radiosurgery of tumors of the cerebellopontine angle. Clin Neurosur. 1994;41:168-184. 12. Muthukumar N, Kondziolka D, Lunsford LD. Stereotactic radiosurgery for tentorial meningiomas. Acta Neurochir. 1998;140:315-321.
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Tumors are not infrequent causes of trigeminal neuralgia. Although surgical tumor resection may offer significant pain relief in cases of secondary TN, radiation treatment of tumors does not provide the same benefit. Targeting the nerve root rather than the lesion itself provides maximal pain relief, and this may relate to the differential mechanisms of action of radiosurgery and traditional surgery. In cases of secondary trigeminal neuralgia, radiosurgery to the nerve root offers a safe and efficacious solution to symptomatic pain relief with excellent outcomes maintained over greater than a mean two years of follow up, and may offer an especially valuable treatment option in patients who may be poor surgical candidates.
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13. Pollock BE, Lunsford LD, Kondziolka D, Flickinger JC, Bissonette DJ, Kelsey SF, et al. Outcome analysis of acoustic neuroma management: a comparison of microsurgery and stereotactic radiosurgery. Neurosurgery. 1995;36:215-229. 14. Subach BR, Lunsford LD, Kondziolka D, Maitz AH, Flickinger JC. Management of petroclival meningiomas by stereotactic radiosurgery. Neurosurgery. 1998;42:437-445. 15. Young RF, Vermeulen SS, Grimm P, Blasko J, Posewitz A. Gamma knife radiosurgery for treatment of trigeminal neuralgia: idiopathic and tumor related. Neurology. 1997;48:608-614. 16. 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;47:1013-1019. 17. Delfini R, Innocenzi G, Ciappetta P, Domenicucci M, Cantore G. Meningiomas of Meckel’s cave. Neurosurgery. 1992;31:1000-1007. 18. McCormick PC, Bello JA, Post KD. Trigeminal schwannoma. Surgical series of 14 cases with review of the literature. J Neurosurg. 1988;69:850-860. 19. Ogleznev KY, Grigoryan YA, Slavin KV. Parapontine epidermoid tumors presenting as trigeminal neuralgias: anatomical findings and operative results. Acta Neurochir. 1991;110:116-119. 20. Pollack IF, Sekhar LN, Jannetta PJ, Janecka IP. Neurilemomas of the trigeminal nerve. J Neurosurg. 1989;70:737-745. 21. Puca A, Meglio M, Tamburrini G, Vari R. Trigeminal involvement in intracranial tumors. Anatomical and clinical observations on 73 patients. Acta Neurochir. 1993;125:47-51. 22. Kondziolka D, Lunsford D, Flickinger JC, Young RF, Vermeulen S, Duma CM, et al. Stereotactic radiosurgery for trigeminal neuralgia: a multiinstitutional study using the gamma unit. J Neurosurg. 1996;84:940-945. 23. Régis J, Bartolemi F, Metellus P, Rey M, Genton P, Dravet C, et al. Radiosurgery for trigeminal neuralgia and epilepsy. Neurosurg Clin North Am. 1999;10:359-377. 24. Urgosik D, Vymazal J, Vladyka V, Liscák R, et al. Gamma knife treatment of trigeminal neuralgia: clinical and electrophysiological study. Stereotact Funct Neurosurg. 1998;70:200-209. 25. Ildan F, Göcer AL, Bagdatoglu H, Uzuneyüpoglu Z, Tuna M, Cetinalp E. Isolated trigeminal neuralgia secondary to distal anterior inferior cerebellar artery aneurysm. Neurosurg Rev. 1996;19:43-46. 26. Conforti R, Parlato RS, De Paulis D, Cirillo M, Marrone V, Cirillo S, et al. Trigeminal neuralgia and persistent trigeminal artery. Neurol Sci. 2012;33:1455-1458. 27. Nomura T, Ikezaki K, Matshushima T, Fukui M. Trigeminal neuralgia: differentiation between intracranial mass lesions and ordinary vascular compression as causative lesions. Neurosurg Rev. 1994;17:51-57.
ACCEPTED MANUSCRIPT Table 1. Patient demographics Total N=12
Characteristic
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Patient population 4 (33.3) Male 8 (66.7) Female Age at SRS* 59.8 (11.2) Mean (SD) 47.7–84.7 Range Pain distribution 2 (15.4) V2 4 (30.8) V3 1 (7.7) V1 & V2 5 (38.5) V2 & V3 1 (7.7) V1, V2 & V3 8 (61.5) Right 5 (38.5) Left Preexisting facial sensory dysfunction 3 (25.0) Numbness 1 (8.3) Allodynia/burning pain Prior treatment 10 (83.3) No. of patients Treatment 10 (83.3) Radiation to lesion (not TN) Stereotactic radiosurgery 3 (25.0) Stereotactic radiation therapy 7 (58.3) Other Surgical resection 2 Biopsy 1 Balloon compression 1 Ganglion block 1 MVD 1 SRS, stereotactic radiosurgery, refers to the treatment of trigeminal neuralgia, not tumor; SD, standard deviation; TN, trigeminal nerve; MVD, microvascular decompression
ACCEPTED MANUSCRIPT Table 2. Initial treatment for tumor related TN Total N=12
Parameter
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Prior treatment/surgery Number of patients 10 (83.3) Radiation to lesion (not TN) Stereotactic radiosurgery 3 (30.0) Stereotactic radiation therapy 7 (70.0) Other Surgical resection 2 Biopsy 1 Balloon compression 1 Ganglion block 1 MVD 1 Pathology Meningioma 7 (70.0) Squamous cell carcinoma 1 (10.0) Vestibular schwannoma 1 (10.0) Hemangiopericytoma 1 (10.0) Location Petroclivus 5 (50.0) Cavernous sinus 2 (20.0) Sphenoid wing 2 (20.0) Maxillary sinus 2 (20.0) Cerebellopontine angle 1 (10.0) Total radiation dose 40.7 (19.1) Mean (SD) Fractionated 57.6 Gy 2 (20.0) 50.4Gy 5 (50.0) Unfractionated 14 Gy 1 (10.0) 13 Gy 2 (20.0) Pain relief following initial SRS/SRT No pain relief (BNI score IV-V) 4 (40.0) At least some pain relief (BNI score I-IIIb) Complete (BNI pain score I) 0 Incomplete (BNI pain score II-IIIb) 6 (60.0) Time to onset of relief Mean number of weeks (range) 7.2 (2.0–9.0) Duration of relief Mean number of months (range) 5.8 (5.0–8.0) Interval prior to SRS for TN Mean number of months (range) 21.8 (8.0-72.0) TN, trigeminal neuralgia; MVD, microvascular decompression; SRS, stereotactic radiosurgery; SRT, stereotactic radiation therapy; BNI, Barrow Neurological Institute
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Table 3. Treatment characteristics of patients who underwent SRS for trigeminal neuralgia Total Parameter N=12 Pre-treatment BNI Pain score 0 I 0 II 0 IIIa 1 (8.3) IIIb 1 (8.3) IV 10 (83.3) V Treatment 90.0 (90) Mean maximum dose (Gy) (range) Frame 7 (58.3) Yes 5 (41.7) No Collimator size 4 mm 8 (66.7) 5 mm 4 (33.3) Pain relief 2 (16.7) No pain relief (BNI score IV-V) 10 (83.3) At least some pain relief (BNI score I-IIIb) Complete (BNI pain score I) 6 (50.0) Incomplete (BNI pain score II-IIIb) 4 (33.3) Recurrence 6 (50.0) No. of patients 41.2 (1-61) Mean time to recurrence (months) (range) Subsequent treatment (# of patients experiencing relief) Repeat SRS to TN REZ 1 (1) Balloon compression 3 (0) RFA 1 (1) MVD 1 (1) Other 4 (2) SRS to tumor/alternate target 1 (0) Tumor resection 3 (3) Mean time to treatment (months) (range) 17.8 (4-35) SRS, stereotactic radiosurgery; BNI, Barrow Neurological Institute; Gy, Gray; TN, trigeminal nerve; REZ, root entry zone; RFA, radiofrequency ablation; MVD, microvascular decompression
ACCEPTED MANUSCRIPT Table 4. Patient outcomes following SRS
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Time to initial response (weeks) 4.1 (1-8) Mean (range) Facial sensory dysfunction Among responders, number of patients 1 Numbness 1 Tingling 1 Mean time in weeks to onset of symptoms (range) 3.0 (NA) Among non-responders, number of patients 2 Numbness 1 Tingling 1 Mean time in weeks to onset of symptoms (range) 4.5 (4-5) Post-radiation radiographic changes 4 (33.3) Pontine/TN root enhancement Number of patients experiencing at least incomplete relief 3 (25.0) 55.6 (10.3-125.3) Mean follow-up in months (range) SRS, stereotactic radiosurgery; NA, not applicable; TN, trigeminal neuralgia
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Total N=12
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Trigeminal neuralgia may be secondary to mass lesions such as tumors Radiation to the tumor does not provide lasting relief in cases of secondary trigeminal neuralgia Radiosurgery to the nerve root provides safe and efficacious pain relief
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TN, trigeminal neuralgia BNI, Barrow Neurological Institute MVD, microvascular decompression UCLA, University of California, Los Angeles SRS, stereotactic radiosurgery CT, computed tomography MRI, magnetic resonance imaging REZ, root entry zone Gy, Gray SRT, stereotactic radiotherapy
ACCEPTED MANUSCRIPT DISCLOSURES/CONFLICTS OF INTEREST
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The authors do not have any conflicts of interests to disclose. The information reviewed and/or presented within this manuscript was not supported by a commercial grant or by commercial interests.