Trigeminal Neuralgia Radiosurgery

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Trigeminal Neuralgia Radiosurgery

  1. 1. Trigeminal Neuralgia Radiosurgery Douglas Kondziolka, M.D., M.Sc., F.R.C.S.C., F.A.C.S.,1,2,3 L. Dade Lunsford, M.D., F.A.C.S.,1,2,3 and John C. Flickinger, M.D., F.A.C.R.1,2,3 ABSTRACT Although medical therapy is of benefit to many patients with trigeminal neuralgia, surgical management is often performed for patients with medically refractory pain. Gamma knife radiosurgery has been advocated as a minimally invasive alternative surgical approach to microvascular decompression or percutaneous surgeries. In this article, we review the safety and efficacy of this technique and discuss potential ways to improve on results. KEYWORDS: Trigeminal neuralgia, radiosurgery, tic douloureux Objectives: Upon completion of this article, the reader should be able to: (1) summarize the management options for patients with trigeminal neuralgia; (2) discuss the technical aspects of trigeminal neuralgia radiosurgery; and (3) summarize the treatment expectations that follow this procedure. Medical therapy is the initial approach for most patients with trigeminal neuralgia. However, many pa- tients fail or cannot tolerate medical therapy and even- tually require surgical intervention. Although often associated with initial pain relief, all surgical procedures are associated with variable but definite rates of recur- rence and morbidity. Gamma knife radiosurgery has been advocated as a minimally invasive alternative sur- gical approach to microvascular decompression (MVD) or percutaneous surgeries. Stereotactic irradiation of the trigeminal ganglion was first reported by Leksell.1 More recently, numerous authors have reported their initial results with radiosurgery using high-resolution image guidance.2–9 These data testified to the accuracy of radiosurgical targeting and the initial safety of the technique and provided dose-response information. In this article, we review clinical outcomes following radio- surgery and discuss indications and technical issues of the procedure. TECHNIQUE OF RADIOSURGERY We use the model U or C gamma knife units inter- changeably for radiosurgery at our center. Patients undergo the entire procedure during a 23-hour hospital- ization. First, the Leksell model G stereotactic frame (Elekta Instruments, Atlanta, GA) is attached to the head under local anesthesia. Second, the patient under- goes stereotactic magnetic resonance (MR) imaging to identify the trigeminal nerve. Rarely, patients have computed tomography (CT) imaging for targeting if they cannot undergo MR imaging. MR imaging is performed using contrast-enhanced, short repetition time (TR) sequences and axial volume acquisitions of 512 Â 216 matrices divided into 1-mm slices. When the trigeminal nerve is difficult to identify on imaging (usually because of prior MVD), additional axial long relaxation time MR images were used. A single 4-mm isocenter is used for targeting, although in the past some patients have been treated with two-isocenter plans. Pain Management for the Neurosurgeon: Part 2; Editor in Chief, Winfield S. Fisher III, M.D.; Guest Editor, Kim J. Burchiel, M.D., F.A.C.S. Seminars in Neurosurgery, volume 15, numbers 2/3, 2004. Address for correspondence and reprint requests: Douglas Kondziolka, M.D., Ste. B-400, UPMC Presbyterian, 200 Lothrop St., Pittsburgh, PA 15213. E-mail: kondziolkads@msx.upmc.edu. Departments of 1 Neurological Surgery, and 2 Radiation Oncology, University of Pittsburgh, and 3 the Center for Image-Guided Neurosurgery, Pittsburgh, Pennsylvania. Copyright # 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. 1526-8012,p;2004,15,02/03, 135,141,ftx,en;sns00195x. 135
  2. 2. With a single isocenter, the target is 2 to 4 mm anterior from the junction of the trigeminal nerve and pons (Fig. 1). The isocenter is usually located so that brain- stem surface is irradiated at the 30% isodose line. Past patients received maximum doses of 60, 70, 80, 85, or 90 Gy, although 80 Gy is our usual dose (Fig. 2). METHOD OF PATIENT EVALUATION Following radiosurgery, we evaluate patients for the degree of pain relief, latency interval to pain relief, need for further surgical procedures, use of medication, and complications. In addition, up-to-date clinical in- formation is obtained by telephone interview at periodic intervals.10 To evaluate effectiveness over time (besides the typical measure of the proportion of patients with pain relief at initial or last follow-up), we calculate the time to initial response from radiosurgery and the dura- tion of pain relief using the product limit method of Kaplan and Meier.11 The time to onset of complications after radiosurgery (new or increased sensory disturbance) is also calculated using the same methods. Pain relief duration is calculated from the time when the level of pain relief being studied (complete or > 50%) was achieved. To identify any correlation of outcomes (time to initial response, duration of benefit, and complica- tions) with treatment parameters that include sex, age, duration of symptoms, presence or absence of preopera- tive paresthesia or additional atypical features, number of prior surgeries, maximum dose, and number of iso- centers, stepwise (forward conditional) multivariate analyses using the Cox proportional hazards model are performed. UNIVERSITY OF PITTSBURGH EXPERIENCE Our current experience included 513 patients. There were 305 (60%) women and 208 men. The mean age was 68 years (range, 16–92). The mean duration of symptoms was 8 years. Our last detailed review studied patients managed between December 1992 and December 1998 (n ¼ 264 consecutive radiosurgery procedures for trigeminal neu- ralgia).10 Of these 264 procedures, 25 were performed for nonidiopathic trigeminal neuralgia (19 were associated Figure 1 Magnetic resonance images at gamma knife radiosurgery for an 80-year-old woman with right trigeminal neuralgia. A maximum dose of 75 Gy was delivered to the nerve using a single 4-mm isocenter. Coronal and sagittal views are shown on the right. 136 SEMINARS IN NEUROSURGERY/VOLUME 15, NUMBERS 2/3 2004
  3. 3. with multiple sclerosis, three were secondary to tumors, and three were secondary to other pathological condi- tions such as a herpetic infection, Lyme disease, or Wallenberg’s syndrome). These 25 procedures were excluded from this study. Of the 239 procedures per- formed for idiopathic trigeminal neuralgia, 19 were a repeated radiosurgery after an initially successful procedure. For these 19 patients, the outcome after initial radiosurgery was included in this study as a poor result (subsequent outcomes of the repeated procedure were excluded). Thus, 220 procedures in 220 patients were available for analysis. All 220 patients had trigem- inal neuralgia that was idiopathic, long standing, and refractory to medication therapy such as carbamazepine, phenytoin, baclofen, or gabapentin as well as a variety of analgesic medications. Of these 220 patients, 94 were male and 126 were female. The median age of the patients was 70 years (range 26–92). Most of the patients had long history of medical treatment with a median symptom duration of 96 months (range 3–564 months). Pain was predomi- nantly distributed in the V2 and V3 distributions of the trigeminal nerve (29.5%), followed by V2 alone (22.3%) and V3 alone (13.2%). Patients with first-division pain often had radiosurgery as an alternative to other procedures. Although all patients complained of the typical trigeminal neuralgia features of a sharp, lancinat- ing, or shooting electric shock type of pain triggered by a variety of events, 16 (7.3%) complained of additional features such as a more constant dull, aching, or burning pain. Eighty patients (36.4%) had some sensory disturb- ance (usually paresthesias) preoperatively, and three patients (1.4%) had partial deafferentation pain caused by prior ablative procedures. Prior surgery was performed in 135 patients (61.4%), including MVD, glycerol rhizotomy, radio- frequency rhizotomy, balloon microcompression, pe- ripheral neurectomy, or ethanol injections. Of these 135 patients, 86 (39.1%) had one, 39 (17.7%) had two, and 10 (4.5%) had three or more procedures prior to radiosurgery. Thus, the majority of patients represented both medical and surgical failures. In the remaining 85 patients (38.6%), radiosurgery was the first surgical procedure performed. Figure 2 Magnetic resonance images at gamma knife radiosurgery for a 78-year-old woman with right trigeminal neuralgia. Note the prominent arteries surrounding the nerve. A maximum dose of 80 Gy was delivered using a single 4-mm isocenter. She had relief of pain and tapered her medications. TRIGEMINAL NEURALGIA RADIOSURGERY/KONDZIOLKA ET AL 137
  4. 4. Pain Relief The outcome of the intervention was graded in four categories: excellent, good, fair, and poor. Complete pain relief without the use of any medication was defined as an excellent outcome. We recommended that all patients with complete pain relief taper off their medications, and some patients were in the process of tapering at the time of evaluation (or refused to taper because of fear of a recurrence). The patients with complete pain relief who were still using some medication were considered as having good outcomes. Patients with partial pain relief (more than 50% pain relief) were considered to have a fair outcome.2 No pain relief or less than 50% pain relief was considered as poor. Placement within a category was decided by the patient rather than by the physician. Criteria for improvement included a reduction in both the frequency and severity of pain attacks. Of the 220 patients, 47 (25.1%) required further additional surgical procedures because of poor pain control. These patients were considered as treatment failures (poor outcome), and the results after the additional procedure were excluded from this analysis. Most of the patients responded to radiosurgery within 6 months of the procedure (median 2 months). The first evaluation was performed for all patients within 6 months after radiosurgery. At the initial follow-up assessment, excellent results were obtained in 105 pa- tients (47.7%), and excellent plus good results were found in 139 patients (63.2%). More than 50% pain relief (excellent, good, or fair) was noted in 181 patients (82.3%). At the last follow-up evaluation, 88 patients (40%) had excellent outcomes, 121 patients (55.9%) had excellent plus good outcomes, and 152 were fair or better (69.1%). Thirty patients (13.6%) had recurrence of pain after the initial achievement of pain relief (25 patients after complete relief, 5 patients after more than 50% relief) between 2 and 58 months after radiosurgery. Recurrences occurred at a mean of 15.4 months from irradiation. Time to the Initial Response The time to response after radiosurgery was analyzed using the product limit method of Kaplan and Meier. The median time to achieving more than 50% pain relief (excellent, good, or fair) was 2 months (2.0 Æ 0.05), and median time to achieving complete pain relief (good or excellent) was also 2 months (2.0 Æ 5.1). At 6 months after treatment, 81.4 Æ 2.6% of patients had achieved more than 50% pain relief, and by 12 months, 85.6 Æ 2.47% of patients had (actuarial statistics). Complete pain relief (good or excellent) was achieved in 64.9 Æ 3.2% of the patients at 6 months, 70.3 Æ 3.16% by 1 year, and 75.4 Æ 3.49% of patients by 33 months. Prior authors including our group noted a latency interval to pain relief of approximately 1 to 2 months.2,4,9 However, about 15% of patients had no improvement in their pain even after 12 months. Because no patient achieved complete or even more than 50% pain relief after 12 months follow-up, we believe that patients with unchanged pain at 1 year cannot expect any improve- ment afterward. In reality, this is an uncommon situation because most patients would not wait so long to attain pain relief. Patients who have continued disabling pain after radiosurgery are managed with other surgical procedures. We advocate repeated radiosurgery only if complete pain relief had been achieved with subsequent recurrence. Complete pain relief was achieved at a median time of 2 months, with most patients achieving this level of relief within 6 months. Interestingly, a further 10% of patients achieved complete pain relief 6 to 33 months after radiosurgery. All of these patients obtained partial pain relief within 6 months and then had complete re- solution of pain afterward. Thus, it appears that patients with partial pain relief may go on to complete relief over time. This finding provides some ideas regarding the mechanism of response to radiosurgery. Because most patients responded in the initial months, electrophysio- logic blocking of ephaptic transmission after nerve irradiation, which has been discussed as a possible mechanism by some authors,4,9 is possible. On the other hand, because some patients responded or improved in a later phase (more than 6 months after radiosurgery), a later radiation effect with axonal degeneration may be present. Maintenance of Pain Relief The duration of pain relief after the initial response in all patients was also analyzed. Patients who never re- sponded to radiosurgery were recorded as having a relief duration of zero months. More than 50% pain relief (excellent, good, or fair) was achieved and maintained in 75.8 Æ 2.9% of patients at 1 year, 71.3 Æ 3.3% of patients at 2 years, 67.2 Æ 3.9% of patients at 3 years, 65.1 Æ 4.3% of patients at 3.5 years, and 55.8 Æ 9.3% of patients at 5 years. Complete pain relief (excellent or good) was achieved and maintained in 63.6 Æ 3.3% of patients at 1 year, 59.2 Æ 3.5% of patients at 2 years, and 56.6 Æ 3.8% of patients at 3 years. A history of no prior surgery was the only factor significantly associated (p ¼ .01) with achieving and maintaining complete pain relief. Side Effects of Radiosurgery No patient sustained an early complication after any radiosurgery procedure. Seventeen patients (7.7%) de- veloped increased facial paresthesia and/or facial numb- ness that lasted more than 6 months. The median time to developing paresthesia was 8 months (range 138 SEMINARS IN NEUROSURGERY/VOLUME 15, NUMBERS 2/3 2004
  5. 5. 1–19 months). After 19 months, no patient developed any new sensory symptoms. No patient developed a mastication deficit after radiosurgery or noted problems in facial motor function. One patient (0.4%) developed deafferentation pain after radiosurgery. This patient had recurrent trigeminal neuralgia previously treated by MVD. Following her MVD she had some decrease in facial sensation, and her recurrent pain had some addi- tional atypical features such as constant burning. Eight years after initial surgery, radiosurgery was performed to a maximum dose of 75 Gy using two isocenters. Eight months later, she developed increased constant burning pain with numbness consistent with deafferentation pain. Comparing Radiosurgery with Other Procedures The results of radiosurgery do not appear to be as good as those observed after a first MVD but appear to be as good or better as a second procedure. Barker et al, in reporting on Jannetta’s series of 1185 patients, found that complete pain relief was maintained in 70% of patients at 10 years.12,13 Thus, we continue to advocate MVD for appropriate younger patients with trigeminal neuralgia because of the potential for longer duration pain relief. Nevertheless, the possible risks of MVD make it unsuitable for some patients. In addition, the benefit of MVD is less when performed a second time or for recurrent trigeminal neuralgia. We consider radio- surgery a good choice for patients with recurrent pain after MVD or percutaneous surgery has failed, even though prior surgical failure reduces the radiosurgical success rate. Other investigators have reported long-term re- sults following different percutaneous techniques for trigeminal neuralgia. Percutaneous retrogasserian ther- mal rhizotomy, first described in 1974 by Sweet and Wepsic, has been widely performed.14 In Broggi and Flanzini’s series of 1000 patients with 9.3 years of mean follow-up, they found an initial pain relief rate of 95%, with recurrence in 18.1%.15 Scrivani et al reported their series of 215 patients and found that 83% maintained pain relief at a mean interval of 32 months.16 Percuta- neous retrogasserian glycerol rhizotomy, first reported by Ha˚kanson, is also widely used.17 Jho and Lunsford reported that 90% of 523 patients achieved complete pain relief initially and that 77% maintained longer term pain control, sometimes requiring multiple procedures.18 The pain recurrence rate was estimated to be between 30 and 50% over 2 to 10 years. Others reported a longer term pain control rate of 50 to 90%.14,19,20 Results following percutaneous trigeminal nerve balloon com- pression indicated a high rate of initial pain relief, but that pain recurred in 26% (50 patients with average 3-year follow-up).21 The low incidence of complications is the greatest advantage of stereotactic radiosurgery compared with all other surgeries. Paresthesia or numbness of varying magnitude is observed in 20 to 70% of patients after percutaneous thermorhizotomy, glycerol rhizotomy, or balloon nerve compression.12,14–21 In this study, 17 patients (10.2 Æ 2.35% at 2 years) developed increased facial paresthesia and/or facial numbness. The majority of our patients described their numbness or paresthesia as minor and not bothersome. Some authors advocated percutaneous balloon nerve compression as advanta- geous for management of first-division trigeminal neu- ralgia because of the lower risk for postoperative corneal analgesia. In the present radiosurgery study, no patient developed this complication. The reduced rate of facial sensory deficits or symptoms indicates that the effects on nerve tissue may be less than after other ablative surgeries. Thus, the mechanistic effect of radiosurgery is probably a combination of both histologic and electro- physiologic responses. Radiosurgery can be repeated if pain returns after initial relief. We advocate a maximum dose of 50 to 60 Gy at a second procedure and usually target a more anterior section of the nerve. Doing so has led to a pain response similar to that after primary radiosurgery in properly selected patients.22 Effect of Radiation on Nerves: A Primate Model of Radiosurgery Peripheral nerves are considered highly radioresistant. A dose that produces delayed radiation necrosis of spinal cord may have no effect on peripheral nerves. To study the effects of radiosurgery on trigeminal nerve fibers, we used a baboon radiosurgery model and delivered either 80 or 100 Gy to the nerve using a single 4-mm isocenter.23 Trigeminal nerves that received 80 Gy radiosurgery had no inflammation. Focal myelin pallor and vacuolation without fibrosis was noted with Masson trichrome in the preganglionic nerve segments. Immunoreactivity for neurofilament revealed sub- stantial axonal loss, fragmentation, and some swellings. Plastic sections and ultrastructural studies revealed a focal region near the center of the nerve exhibiting acutely degenerating axons with preservation of some identifiable myelinated axons admixed with small foci of tissue necrosis (Fig. 3). Schwann cell nuclei were also necrotic. The surrounding region contained only rare degenerating axons in which the trigeminal ganglia appeared normal, as did the distal nerve beyond the radiosurgery target. Trigeminal nerves that received 100 Gy exhibited axonal degeneration with myelin vacuolation and expan- sion of the endoneurial intercellular matrix consistent with edema. In one specimen, nearly the entire nerve width was necrotic. The ganglion remained normal. TRIGEMINAL NEURALGIA RADIOSURGERY/KONDZIOLKA ET AL 139
  6. 6. On plastic sections, axonal degeneration was noted out- side the necrotic zone, but the histology normalized toward the ganglion (Fig. 3). Ultrastructural studies revealed that the axonal degeneration around the irra- diated targets affected large and small myelinated axons similarly at both radiosurgery doses. Only rare primary demyelination (vesicular demyelination) was noted out- side the necrotic zones. Only rare intact unmyelinated axons were identified within and surrounding the major foci of nerve injury in both the 80 and 100 Gy groups.23 We know from rat brain parenchymal experi- ments that doses of 100 Gy or more will lead to tissue necrosis after a 3-month time interval.24 In an attempt to avoid nerve necrosis and maintain facial sensation, we have chosen doses below 100 Gy in patients. As this study showed, the histologic effect was dose related. Radiosurgery at 100 Gy was followed by nerve necrosis in each animal and with a more pronounced axonal effect than radiosurgery at 80 Gy. The hypothesis that radio- surgery might affect different fiber types selectively (i.e., those conducting pain rather than light touch) was not substantiated by the findings of our experiments. We could not detect a substantial difference in axonal injury among small myelinated, large myelinated, and unmye- linated fibers. Through partial (focal) axonal degenera- tion, radiosurgery probably relieves trigeminal neuralgia pain by affecting an axon population large enough to result in pain relief. On the other hand, the low incidence of lost facial sensation indicates that the remaining intact axonal population is enough to main- tain neurologic function in the majority of patients. This balance between pain relief and preservation of sensation is dose related. Improving Radiosurgery Technique We compared radiosurgery using two 4-mm isocenters with that using one isocenter with a maximum dose of 75 Gy. Our hypothesis was that irradiation of a longer nerve segment may have led to an improved rate of pain relief. This randomized, blinded trial found no pain benefit to two-isocenter radiosurgery but a higher rate Figure 3 Electron micrograph of a baboon trigem- inal nerve 6 months following 80 Gy radiosurgery (top). Note the partial nerve degeneration. Distal to the target, the nerve appeared normal (bottom). 140 SEMINARS IN NEUROSURGERY/VOLUME 15, NUMBERS 2/3 2004
  7. 7. of facial sensory loss.25 Regis et al advocate a maximum dose of 90 Gy and a more anterior radiosurgery target.26 With this approach, they have reported a low rate of facial sensory loss despite using a higher dose. Reports from Pollock et al found a higher rate of sensory loss at 90 Gy, although they used the more traditional posterior nerve target.27,28 These questions, dose and target, are appropriate considerations for randomized clinical trials. REFERENCES 1. Leksell L. Stereotaxic radiosurgery in trigeminal neuralgia. Acta Chir Scand 1971;137:311–314 2. Kondziolka D, Lunsford L, Flickinger JC, et al. Stereotactic radiosurgery for trigeminal neuralgia. A multiinstitutional study using gamma knife unit. J Neurosurg 1996;84:940–945 3. Kondziolka D, Lunsford L, Flickinger JC. Gamma knife radiosurgery as the first surgery for trigeminal neuralgia. Stereotact Funct Neurosurg 1998;70(suppl 1):187–191 4. Kondziolka D, Perez B, Flickinger JC, et al. 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Percutaneous trigeminal nerve compression for treatment of trigeminal neuralgia: results in 50 patients. Neurosurgery 1993;32:570– 573 22. Hasegawa T, Spiro R, Flickinger JC, Kondziolka D, Lunsford LD. Repeat radiosurgery for trigeminal neuralgia. Neuro- surgery 2002;50:494–502 23. Kondziolka D, Lacomis D, Niranjan A, et al. Histologic effects of trigeminal nerve radiosurgery in a primate model: implications for trigeminal neuralgia radiosurgery. Neuro- surgery 2000;46:971–977 24. Kondziolka D, Lunsford LD, Flickinger JC. The radiobiology of radiosurgery. Neurosurg Clin N Am 1999;10:157–166 25. Flickinger JC, Pollock BE, Kondziolka D, et al. Does increased nerve length within the treatment volume improve trigeminal neuralgia radiosurgery? A prospective, blinded, randomized study. Int J Radiat Oncol Biol Phys 2001;51:449– 454 26. Regis J, Bartolomei F, Metellus P, et al. Radiosurgery for trigeminal neuralgia and epilepsy. Neurosurg Clin N Am 1999;10:359–377 27. 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