Impact of a Previous Surgical Procedure.
Previous Versus No Previous Surgery: Retrospective Comparative Studies. Fountas et al.34
compared 2 groups, one without (52 patients) and one with (25 patients) previous surgeries. The 77-patient cohort was followed up over a period of 5 years and was treated with GKS using a median of 1 collimator (range 1–2 collimators), the REZ as the target, and a maximal median dose of 80 Gy (range 80–85 Gy), with the 30% isodose line adjacent to the REZ. In the group with no previous surgery, the initial response rate was 92.4% compared with 84% in the other group (p = 0.16). The excellent outcome rates (FFP without medication) at 1, 2, and 3 years after treatment were 80.8%, 69.2%, and 53.8% compared with 64%, 44%, and 12%, respectively (p = 0.05 at 2 years, p = 0.01 at 3 years). The authors concluded that a previous surgical procedure is a negative predictor for long-term pain control after GKS treatment. The hypesthesia rates were similar, 17.3% in the group with no previous surgery and 16% in the other group (p = 0.48). Two patients (8%) in the group with previous surgery developed bothersome facial tingling.
The same authors conducted a study published the following year,35 which included 106 patients. They compared 2 groups without (57 patients) and with (49 patients) previous surgeries. The mean follow-up period was 34.3 months (range 12–72 months), and they used a median of 1 collimator (range 1–3 collimators), the REZ as the target, and a median maximal dose of 80 Gy (range 70–85 Gy). The initial response rate in those without previous surgery was 92.9% compared with 85.7% in the other group (p = 0.13). At 1 year after treatment, the FFP rates were 82.5% of those without previous surgery compared with 69.4% of those with, and the FFP rates were 78% and 63.5%, respectively, at 2 years after treatment (p = 0.27 and 0.39, respectively). The hypesthesia rate was similar, at 15.8% of patients without previous surgery and 16.3% of those with such surgery (p = 0.73). Four cases (2 in each group) developed facial tingling and numbness.
Although not a comparative study itself, Dhople et al.25 retrospectively analyzed 102 cases, which were separated into 2 groups according to a history of previous surgery or no such history. The difference in terms of actuarial pain relief at 1, 2, 3, 4, 5, 6, and 7 years, respectively, was as follows: 61%, 35%, 20%, 15%, 15%, 7%, and 7% of those with a history of previous surgery compared with 81%, 53%, 50%, 41%, 30%, 23%, and 23% of those with no such history.
Previous surgery is a negative predictor for pain relief after RS; this factor does not, however, contraindicate RS (level II evidence).
GKS After Previous Surgery: Retrospective Noncomparative Studies. Three other studies47,55,75addressed the issue of GKS treatment as salvage therapy following a failed initial surgical procedure. Little et al.75 retrospectively evaluated 79 patients who had received a median dose of 80 Gy (range 70–90 Gy) and had a median follow-up of 5.3 years. The initial FFP response was 91%, which is comparable to rates in general series. The actuarial pain relief rate at 5 years was 50%, with FFP in 20% of patients. Seven patients (10%) reported the development of facial numbness, and 8% described it as “very bothersome.”
Huang et al.47 retrospectively evaluated 65 patients who had been treated with doses ranging between 70 and 90 Gy, a REZ target, and a unique 4-mm shot. The median follow-up was 64 months (range 18–32 months). The authors compared 3 different treatment groups: initial MVD and further GKS, initial GKS and further GKS, and initial percutaneous RFT and further GKS. There was no significant difference in terms of FFP: 74% versus 59% and 50%, respectively (p = 0.342). The overall recurrence rate was 35.4%, and recurrence appeared after a median time of 7 months (range 3–48 months). There was no significant difference in new facial numbness among the 3 treatment groups (p = 0.24). The FFP actuarial rates at 1, 2, and 3 years after treatment were 74%, 71%, and 66% of the patients, respectively.
Kano et al.55 retrospectively reviewed 193 patients with TN treated with GKS after one or more previously failed surgeries. The median dose was 80 Gy (range 60–90 Gy), and the maximum follow-up was 14 years. After GKS, 85% of the patients achieved pain relief or improvement (BNI score I–IIIB). Pain recurrence was observed in 43.5% of the cases after a median of 72 months (range 6–144 months). Eighteen cases (9.3%) developed facial numbness (new or increased) and 1 case (0.5%) developed deafferentation pain.
GKS After Previous MVD. Two retrospective studies address the issue of GKS following MVD.75,133Little et al.75 made an analysis of a subgroup of 24 patients treated with GKS after a previous MVD. The authors stated that at 5 years, only 12% of patients with prior MVD had FFP compared with 25% who had no history of MVD (p = 0.029). Tuleasca et al.133 compared 54 prior-MVD cases with a cohort of 497 cases with more than 1 year of follow-up (range 14.1–144.6 months). The patients were treated at a retrogasserian target with a median dose of 85 Gy (range 70–90 Gy). Although not a case-control study, the authors found that patients with previous MVD had a significantly lower probability of initial pain cessation (77.8% vs 91.75%, p = 0.01). However, the probability of maintaining pain relief without medication was 44.3% at 10 years, similar to the rate in the larger cohort (45.3%, p = 0.85). Toxicity was low, with an actuarial hypesthesia rate of only 9.1% in the patients with prior MVD (BNI score II).
Figure 5 shows a comparison of cases with versus those without prior MVD. When initial efficacy was pooled, there was a statistically significant difference between the two, with an HR = 7.08 (95% CI 3.76, 13.34), p < 0.00001 (Fig. 5A). For the maintenance of pain relief on a long-term basis, there was no statistically significant difference between the cases with and those without prior MVD, with an HR = 1.20 (95% CI 0.65, 2.24), p = 0.56 (Fig. 5B)
FIG. 5.When initial efficacy was pooled (A), there was a statistically significant difference between cases with prior MVD and those without, with an HR = 7.08 (95% CI 3.76, 13.34), p < 0.00001. For the maintenance of pain relief on a long-term basis (B), there was no statistically significant difference, with an HR = 1.20 (95% CI 0.65, 2.24), p = 0.56. Figure is available in color online only.
Particular Follow-Up Aspects: The Risk of Vascular Damage After RS.
Lorenzoni et al.78
prospectively evaluated the maximal dose received by the SCA. In 55 patients treated with GKS for classical TN, who received a dose of 15 Gy or more to the SCA, and who had a minimum follow-up of 1 year, the study end points were SCA occlusion, stenosis, or infarction in the supplied territory. Fifteen patients whose SCA had received a mean maximal dose of 57.5 Gy (range 15–87 Gy) were ultimately analyzed. Neither obstruction nor infarction was demonstrated. In 1 patient, asymptomatic SCA stenosis, which was visualized distant to the irradiation field, was suspected. The authors concluded that the SCA could receive a high dose of radiation during radiosurgical treatment, with no confirmation of any vascular damage induced by RS.
Yatshushiro et al.143 reported a case of SCA occlusion with cerebellar infarction 15 months after GKS in a 55-year-old patient, with a dose between 65 and 75 Gy received by the artery.
Other cases that are not related to targeting of the trigeminal nerve in classical TN are not discussed here.
Quality of Life and Patient Satisfaction.
Petit et al.103
reported a median of 80% improvement in QOL after GKS, as a direct result of pain relief, and 65% of the patients believed that GKS was successful in their case. Patients in whom pain relief was maintained at the time of analysis reported a median 100% improvement in their QOL, with a 100% success rate. Those with temporary treatment responses (pain recurrence after a median of 8.5 months) described a median of 80% improvement in QOL with an associated 60% rate of treatment success. Jawahar et al.51
showed that patients’ self-reported QOL scores improved 90% and that overall patient satisfaction was 80%. Régis et al. studied QOL for 100 patients treated with GKS and followed up prospectively.112
The authors concluded that all QOL parameters were improved after RS (p < 0.001).
Azar et al.9 compared QOL before and after GKS, stating that statistically significant positive changes were encountered in all domains, except in physical function and in role limitation due to a physical problem. Pan et al.95 evaluated QOL in 52 patients who were severely ill (BNI score IV or V) at baseline and were subsequently treated with GKS. The mean physical function score was 55.9 ± 7.7 before GKS and improved to a mean of 66.3 ± 8.1 at 3 months after GKS. The mean score for role limitation due to an emotional problem changed from 4.8 ± 9.9 at the time of GKS to 86.5 ± 12.6 at 3 months after GKS. The mean social functioning score changed from 32.0 ± 5.7 to 80.3 ± 8.7.
In the series by Régis et al.,115 93.1% of the patients had no regrets and said they would undergo RS again without hesitation, whereas 4.6% regretted having undergone the procedure and would not undergo it again.
The cost-effectiveness analysis of TN surgery in general has been addressed in 5 studies.37,46,105,123,131
Pollock et al.105
included 126 patients who underwent 153 interventions (33 MVD, 51 glycerol injection [GLR], 69 RS) and had a mean follow-up of 20.6 months. A higher percentage of patients who underwent MVD obtained and maintained excellent outcomes, compared with the patients who underwent GLR and RS (78% vs 55% and 52%, respectively, at 2 years; p = 0.01 for both). The authors concluded that the use of percutaneous procedures in older patients is supported by the results. Additionally, if the risk of general anesthesia is acceptable, MVD should be the preferred operation.
Tarricone et al.131 evaluated 20 patients undergoing CKR and 20 undergoing MVD, both groups including only patients with a BNI score of IV or V at baseline. The 2 procedures were equally effective at 6 months’ follow-up but had different resources consumption: CKR reduced hospital costs by an average of 34% per patient. The authors concluded that CKR is the cost-saving alternative to MVD.
Fransen37 compared MVD to RFT, BMC, and GKS. This author concluded that percutaneous techniques are more cost-effective than GKS.
Sivakanthan et al.123 evaluated the use and cost-effectiveness of 3 different surgical procedures by using the Medicare Claims database. A total number of 1582 claims were collected. In patients undergoing surgery, 51.1% underwent MVD, 41.5% RS, and 7.4% RFT. These authors concluded that the most frequently used surgical treatment was MVD, followed closely by stereotactic RS, and that RFT, despite being the most cost-effective, is the least used treatment modality.
Holland et al.46 retrospectively analyzed a cohort of 89 patients who had undergone MVD (27 patients), RFT (23 patients), and RS (39 patients). At baseline, the patients significantly differed by age (mean 53.9 years vs 76.2 and 74.5 years, p < 0.001, MVD vs RFT and RS groups). Facial numbness significantly differed between the groups: 11%, 52%, and 28%, respectively (p < 0.01). At 2 years, the rates of recurrence requiring a new procedure were 22% compared with 74% and 31% (p < 0.01) in a mean time of 26 ± 29, 59 ± 76, and 35 ± 25 months, respectively. The authors concluded that MVD was the most expensive procedure, was performed in younger patients, and had the lowest rate of facial numbness and recurrence. Radiosurgery was slightly less costly, was more likely to be performed in older patients, and had a short-term recurrence rate similar to that for MVD. Radiofrequency rhizotomy was the least expensive with immediate pain relief but the highest rates of facial numbness and recurrence.
MVD Versus RS: Comparative Studies
The only prospective, nonrandomized cohort trial comparing MVD and GKS (dose 80–90 Gy, target REZ, brainstem receiving a maximum of 16 Gy at the 20% isodose line) was performed by Linskey et al.,73
with outcomes reported for 80 patients (36 treated with MVD, 44 with GKS). Over a mean follow-up of 3.4 ± 2.14 years (range 0.17–8.5 years), the initial and last follow-up FFP rates were 100% and 80.6% for the MVD group and 77.3% and 45.5% for the GKS group, respectively. The respective actuarial FFP rates initially and at 2 and 5 years’ follow-up were 100%, 88%, and 80% for the MVD group compared with 78%, 50%, and 33% for the GKS group (p = 0.0002). The permanent mild and severe sensory loss rates were 5.6% and 0% in the MVD group compared with 6.8% and 2.3% in the GKS group. Complications such as CSF leakage, hearing loss, and persistent diplopia (1 case each) were found only in the MVD group. The authors concluded that MVD should be preferred as the first-line surgical therapy in young and healthy patients, whereas GKS should be performed in those who are older, have significant medical problems, or refuse the recommended intervention of MVD.
In the framework of a retrospective study, Pollock compared patients (age < 70 years) who had undergone posterior fossa exploration (PFE; 55 patients) with those who had undergone GKS (28 patients).104 At a mean follow-up of 25.5 months, PFE cases more commonly had FFP without medication (75% at 1 year and 72% at 3 years vs 59% at both 1 and 3 years, p = 0.01). New facial numbness or dysesthesias appeared in 15% of the patients after PPE compared with 43% after GKS (REZ target and mean maximum dose of 89.1 Gy, p = 0.02).
Oh et al.94 retrospectively evaluated older patients (age > 65 years) treated with MVD (27 patients) versus GKS (18 patients, target REZ, mean dose 77.8 Gy [range 70–84.3 Gy], one 4-mm collimator). At a mean follow-up of 35.9 months for the MVD group and 33.1 months for the GKS group, according to the BNI pain intensity scale, a better prognosis (63% vs 55.6% with score I or II) and an earlier response was found in the MVD group, with an identical recurrence rate in the 2 groups. Lower complication rates were seen in the GKS group, with only 1 case of dysesthesia (5.6%) compared with 2 cases of facial numbness and 1 case each of herpes zoster, CSF leakage, hearing disturbance, and subdural hematoma in the MVD group.
Nanda et al.92 retrospectively reviewed 20 patients treated with MVD and 49 treated with GKS, with no prior or further intervention and a median follow-up of 5.3 years. The authors concluded that there was no significant difference in terms of initial pain relief (100% MVD and 84% GKS, p = 0.055) or in recurrence (20% MVD and 39% GKS, p = 0.133). At the last follow-up, 85% of MVD cases had a BNI score of I compared with 45% of the GKS cases (p = 0.002). Patient satisfaction was the same in the 2 groups. However, this study lacks details about the technical nuances regarding GKS.
Figure 6 shows results of a comparison of MVD versus GKS. For the maintenance of pain relief on a long-term basis, there was a statistically significant difference, with an HR = −0.29 (95% CI −0.49, −0.10), p = 0.003.
FIG. 6.When the maintenance of pain relief on a long-term basis was compared between MVD and GKS, there was a statistically significant difference, with an HR = −0.29 (95% CI −0.49, −0.10), p = 0.003. Figure is available in color online only.
However, the results previously described should be balanced with several factors, including the overall risk of complications. Microvascular decompression yields more risks than RS, including severe facial numbness (1.8%) or major complications such as chemical meningitis (19%), cerebrospinal fluid leakage (1.7%), ipsilateral hearing loss (1.3%), extraocular muscle palsy (1.2%), facial palsy (1%), and a very low postoperative death rate (0.2%).11
Microvascular decompression is the reference technique, whereas SRS can be recommended as an alternative (level III evidence).
Percutaneous techniques are ablative as they act by causing destruction of the nerve fibers via thermal energy (RFT), chemical damage (glycerol rhizotomy), or mechanical damage (BMC). Within this framework, they frequently cause facial numbness of variable grades as a condition of complete and sustained efficacy. Initial pain relief rates range between 90% and 97.6% for all of these techniques, and at 3 years the pain relief rate falls to between 53% and 69%, with severe numbness occurring in up to 20%–23% of patients. These procedures are notable for high recurrence rates (as high as 26% at a very short mean time of 18 months).16,20,56,93 Additionally, other procedure-related complications include exposure keratitis (0%–2%), anesthesia dolorosa (0%–2.5%), troublesome dysesthesias (4%–10%), and masticatory weakness (0–12%).16,20,56,93
Quality of Reporting
Since 2003, Zakrzewska et al. have proposed a protocol for collecting data and reporting on surgical treatment for TN.22,147 The only RS paper that completely (with the exception of the follow-up period) fulfills such a practice remains the one written by Régis et al.112 We believe that in future papers, for easier and more standardized comparison of the results, one should follow such recommendations.
Radiosurgery for TN is currently considered a minimally invasive alternative to the standard MVD. Technical refinements over time have aimed at improving the safety and efficacy of RS. The availability of MRI at the beginning of the 1990s largely contributed to the appraisal of this indication due to the direct and better visualization of the trigeminal nerve. Upfront radiosurgical treatment should be performed in cases with pharmacoresistance during the first 3 years after diagnosis. Although RS has lower pain relief rates on a long-term basis, careful and individual analysis should be made and the risks of both interventions should be balanced with a patient’s age, anatomical condition, and potential benefit. While most analyzed series use the posterior target, comparative studies have demonstrated that the anterior retrogasserian target yields similar initial pain relief rates with a lower probability of toxicity (as well as a lower probability of bothersome and very bothersome hypesthesia) and higher maintenance of the FFP response on a long-term basis.
Although there is only one level I study (Flickinger et al.32) and the rest of the studies comprise level II evidence, to help guide the management of patients with classical TN and given the limitations of the retrospective series, a number of consensus statements have been made (Table 5).
TABLE 5.Final recommendations
||Single-fraction RS is better than hypofractionated RS
||Previous surgery is a negative predictor for pain relief after RS; this factor does not, however, contraindicate RS
||A neurovascular conflict is not a negative predictor for RS
||The minimal effective dose is 70 Gy
|I & II
||Do not increase the length of the treated nerve: use only one 4-mm isocenter; using 2 isocenters (either continuously or concentrically) yields similar rates of initial efficacy but w/ increased toxicity (so-called Flickinger effect); do not use beam channel blocking at 90 Gy
||An anterior target & a posterior target have similar initial efficacy
||An anterior target has lower hypesthesia & bothersome hypesthesia rates than the posterior target
|II & III
||Additional complications, including dry eye syndrome, are seen only w/ a posterior target
|II & III
||An anterior target, as compared to the posterior one, has higher pain relief rates on a long-term basis (7 & 10 yrs’ FU)
||SRS is recommended as an alternative to the reference technique, which is MVD for classical trigeminal neuralgia
||SRS yields a better initial freedom from pain response if performed in the first 3 years after pain onset
||The maximal effective dose is 90 Gy
||Beyond 90 Gy, the efficacy rate remains similar but w/ a higher complication rate
||LINAC & CKR result in higher bothersome hypesthesia rates
Mr. Paddick has been a consultant for Elekta AB. Dr. Régis has been a consultant for Medtronic and has received support from Elekta for non–study-related clinical or research effort. Dr. Sahgal has received honoraria for past educational seminars from Medtronic, Elekta AB, Accuray Inc., and Varian Medical Systems and research grants from Elekta AB and belongs to the Elekta MR LINAC Research Consortium.
Conception and design: Tuleasca, Régis, Sahgal, De Salles, Levivier. Acquisition of data: Tuleasca, Régis, Levivier. Analysis and interpretation of data: Tuleasca, Régis, Sahgal, Ma, Martínez-Álvarez, Paddick, Ryu, Slotman, Levivier. Drafting the article: Tuleasca. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Tuleasca. Statistical analysis: Tuleasca, Levivier. Administrative/technical/material support: all authors. Study supervision: Régis, Sahgal, Levivier.