Gamma knife radiosurgery for trigeminal neuralgia mechanism

Gamma knife radiosurgery for trigeminal neuralgia mechanism

Gamma Knife radiosurgery for trigeminal neuralgia (GKRS) is a noninvasive surgical treatment option. The long-term microstructural consequences of radiosurgery and their association with pain relief remain unclear.

Studies focusing on the electrophysiology properties of partially demyelinated trigeminal nerves submitted to radiosurgery are vital to truly advance our current knowledge in the field 1).

To better understand this topic, Shih-Ping Hung et al., used diffusion tensor imaging (DTI) to characterize the effects of GKRS on trigeminal nerve microstructure over multiple posttreatment time points.

Ninety-two sets of 3-T anatomical and diffusion weighted MR images from 55 patients with TN treated by GKRS were divided within 6-, 12-, and 24-month posttreatment time points into responder and nonresponder subgroups (≥ 75% and < 75% reduction in posttreatment pain intensity, respectively). Within each subgroup, posttreatment pain intensity was then assessed against pretreatment levels and followed by DTI metric analyses, contrasting treated and contralateral control nerves to identify specific biomarkers of successful pain relief.

GKRS resulted in successful pain relief that was accompanied by asynchronous reductions in fractional anisotropy (FA), which maximized 24 months after treatment. While GKRS responders demonstrated significantly reduced FA within the radiosurgery target 12 and 24 months posttreatment (p < 0.05 and p < 0.01, respectively), nonresponders had statistically indistinguishable DTI metrics between nerve types at each time point.

Ultimately, this study serves as the first step toward an improved understanding of the long-term microstructural effect of radiosurgery on TN. Given that FA reductions remained specific to responders and were absent in nonresponders up to 24 months posttreatment, FA changes have the potential of serving as temporally consistent biomarkers of optimal pain relief following radiosurgical treatment for classic TN 2).


Histopathology examination of the trigeminal nerve in humans after radiosurgery is rarely performed and has produced controversial results.

There is evidence of histological damage of the trigeminal nerve fibers after radiosurgery therapy. Whether or not the presence and degree of nerve damage correlate with the degree of clinical benefit and side effects are not revealed and need to be explored in future studies 3).

Existing studies leave important doubts as to optimal treatment doses or the therapeutic target, long-term recurrence, and do not help identify which subgroups of patients could most benefit from this technique 4).

References

1)

Gorgulho A. Radiation mechanisms of pain control in classical trigeminal neuralgia. Surg Neurol Int. 2012;3(Suppl 1):S17-25. doi: 10.4103/2152-7806.91606. Epub 2012 Jan 14. PubMed PMID: 22826806; PubMed Central PMCID: PMC3400477.
2)

Shih-Ping Hung P, Tohyama S, Zhang JY, Hodaie M. Temporal disconnection between pain relief and trigeminal nerve microstructural changes after Gamma Knife radiosurgery for trigeminal neuralgia. J Neurosurg. 2019 Jul 12:1-9. doi: 10.3171/2019.4.JNS19380. [Epub ahead of print] PubMed PMID: 31299654.
3)

Al-Otaibi F, Alhindi H, Alhebshi A, Albloushi M, Baeesa S, Hodaie M. Histopathological effects of radiosurgery on a human trigeminal nerve. Surg Neurol Int. 2014 Jan 18;4(Suppl 6):S462-7. doi: 10.4103/2152-7806.125463. eCollection 2013. PubMed PMID: 24605252.
4)

Varela-Lema L, Lopez-Garcia M, Maceira-Rozas M, Munoz-Garzon V. Linear Accelerator Stereotactic Radiosurgery for Trigeminal Neuralgia. Pain Physician. 2015 Jan-Feb;18(1):15-27. PubMed PMID: 25675056.

Gamma Knife Radiosurgery for trigeminal neuralgia outcome

Gamma Knife Radiosurgery for trigeminal neuralgia outcome

Significant pain reduction after initial SRS: 80–96% 1) 2) 3) 4) but only ≈ 65% become pain free. Median latency to pain relief: 3 months (range: 1 d-13 months) 5).

Recurrent pain occurs within three years in 10–25%. Patients with TN and multiple sclerosis are less likely to respond to SRS than those without MS. SRS can be repeated, but only after four months following the original procedure.

Favorable prognosticators: higher radiation doses, previously unoperated patient, absence of atypical pain component, normal pre-treatment sensory function 6).

Side effects: Hypesthesia occurred in 20% after initial SRS, and in 32% of those requiring repeat treatment 7) (higher rates associated with higher radiation doses) 8).


Outcome prediction of this modality is very important for proper case selection. The aim of a study was to create artificial neural networks (ANN) to predict the clinical outcomes after gamma knife radiosurgery (GKRS) in patients with TN, based on preoperative clinical factors.

They used the clinical findings of 155 patients who were underwent GKRS (from March 2000 to march 2015) at Iran Gamma Knife center, TehranIran. Univariate analysis was performed for a long list of risk factors, and those with P-Value < 0.2 were used to create back-propagation ANN models to predict pain reduction and hypoesthesia after GKRS. Pain reduction was defined as BNI score 3a or lower and hypoesthesia was defined as BNI score 3 or 4.

Typical trigeminal neuralgia (TTN) (P-Value = 0.018) and age>65 (P-Value = 0.040) were significantly associated with successful pain reduction and three other variables including radiation dosage >85 (P-Value = 0.098), negative history of diabetes mellitus (P-Value = 0.133) and depression (P-Value = 0.190). On the other hand, radio dosage > 85 (P-Value = 0.008) was significantly associated with hypoesthesia, other related risk factors (with p-Value < 0.2), were history of multiple sclerosis (P-Value = 0.106), pain duration more than 10 years before GKRS (P-Value = 0.115), history of depression (P-Value = 0.139), history of percutaneous ablative procedures (P-Value = 0.148) and history of diabetes mellitus (P-Value = 0.169).ANN models could predict pain reduction and hypoesthesia with the accuracy of 84.5% and 91.5% respectively. By mutual elimination of each factor in this model we could also evaluate the contribution of each factor in the predictive performance of ANN.

The findings show that artificial neural networks can predict post operative outcomes in patients who underwent GKRS with a high level of accuracy. Also the contribution of each factor in the prediction of outcomes can be determined using the trained network 9).

Case series

The long-term results in 130 patients who underwent radiosurgery for classical TN and were subsequently monitored through at least 7 years (median = 9.9, range = 7-14.5) of follow-up.

The median age was 66.5 years. A total of 122 patients (93.8%) became pain free (median delay = 15 days) after the radiosurgery procedure (Barrow Neurological Institute, BNI class I-IIIa). The probability of remaining pain free without medication at 3, 5, 7 and 10 years was 77.9, 73.8, 68 and 51.5%, respectively. Fifty-six patients (45.9%) who were initially pain free experienced recurrent pain (median delay = 73.1 months). However, at 10 years, of the initial 130 patients, 67.7% were free of any recurrence requiring new surgery (BNI class I-IIIa). The new hypesthesia rate was 20.8% (median delay of onset = 12 months), and only 1 patient (0.8%) reported very bothersome hypesthesia.

The long-term results were comparable to those from our general series (recently published), and the high probability of long-lasting pain relief and rarity of consequential complications of radiosurgery may suggest it as a first- and/or second-line treatment for classical, drug-resistant TN 10).


Thirty-six consecutive patients with medically intractable TN received a median radiation dose of 45 Gy applied with a single 4-mm isocenter to the affected trigeminal nerve. Follow-up data were obtained by clinical examination and telephone questionnaire. Outcome results were categorized based on the Barrow Neurological Institute (BNI) pain scale with BNI I-III considered to be good outcomes and BNI IV-V considered as treatment failure. BNI facial numbness score was used to assess treatment complications.

The incidence of early pain relief was high (80.5 %) and relief was noted in an average of 1.6 months after treatment. At minimum follow-up of 3 years, 67 % were pain free (BNI I) and 75 % had good treatment outcome. At a mean last follow-up of 69 months, 32 % were free from any pain and 63 % were free from severe pain. Bothersome posttreatment facial numbness was reported in 11 % of the patients. A statistically significant correlation was found between age and recurrence of any pain with age >70 predicting a more favorable outcome after radiosurgery.

The success rate of GKRS for treatment of medically intractable TN declines over time with 32 % reporting ideal outcome and 63 % reporting good outcome. Patients older than age 70 are good candidates for radiosurgery. This data should help in setting realistic expectations for weighing the various available treatment options 11).


From 1994 to 2009, 40 consecutive patients with typical, intractable TN received GKRS. Among these, 22 patients were followed for >60 months. The mean maximum radiation dose was 77.1 Gy (65.2-83.6 Gy), and the 4 mm collimator was used to target the radiation to the root entry zone.

The mean age was 61.5 years (25-84 years). The mean follow-up period was 92.2 months (60-144 months). According to the pain intensity scale in the last follow-up, 6 cases were grades I-II (pain-free with or without medication; 27.3%) and 7 cases were grade IV-V (<50% pain relief with medication or no pain relief; 31.8%). There was 1 case (facial dysesthesia) with post-operative complications (4.54%).

The long-term results of GKRS for TN are not as satisfactory as those of microvascular decompression and other conventional modalities, but GKRS is a safe, effective and minimally invasive technique which might be considered a first-line therapy for a limited group of patients for whom a more invasive kind of treatment is unsuitable 12).


Kondziolka et al., evaluated pain relief and treatment morbidity after trigeminal neuralgia radiosurgery.

All evaluable patients (n = 106) had medically or surgically refractory trigeminal neuralgia. A single 4-mm isocenter of radiation was focused on the proximal trigeminal nerve just anterior to the pons. For follow-up an independent physician who was unaware of treatment parameters contacted all patients.

After radiosurgery, 64 patients (60%) became free of pain and required no medical therapy (excellent result), 18 (17%) had a 50% to 90% reduction (good result) in pain severity or frequency (some still used medications), and 9 (9%) had slight improvement. At last follow-up (median, 18 months; range, 6-48 months), 77% of patients maintained significant relief (good plus excellent results). Only 6 (10%) of 64 patients who initially attained complete relief had some recurrent pain. Radiosurgery dose (70-90 Gy), age, surgical history, or facial sensory loss did not correlate with pain relief. Poorer results were found in patients with multiple sclerosis. Twelve patients developed new or increased facial paresthesias after radiosurgery (10%). No patient developed anesthesia dolorosa. There was no other procedural morbidity.

Gamma knife radiosurgery is a minimally invasive technique to treat trigeminal neuralgia. It is associated with a low risk of facial paresthesias, an approximate 80% rate of significant pain relief, and a low recurrence rate in patients who initially attain complete relief. Longer-term evaluations are warranted 13).

References

1)

Brisman R. Gamma knife surgery with a dose fo 75 to 76.8 Gray for trigeminal neuralgia. J Neurosurg. 2004; 100:848–854
2) , 8)

Pollock BE, Phuong LK, Foote RL, Sta ord SL, Gor- man DA. High-dose trigeminal neuralgia radiosur- gery associated with increased risk of trigeminal nerve dysfunction. Neurosurgery. 2001; 49:58–62; discussion 62-4
3)

Kondziolka D, Lunsford LD, Flickinger JC. Stereotactic radiosurgery for the treatment of trigeminal neuralgia. Clin J Pain. 2002; 18:42–47
4)

Massager N, Lorenzoni J, Devriendt D, Desmedt F, Brotchi J, Levivier M. Gamma knife surgery for idi- opathic trigeminal neuralgia performed using a far-anterior cisternal target and a high dose of radiation. J Neurosurg. 2004; 100:597–605
5) , 7)

Urgosik D, Liscak R, Novotny J, Jr, Vymazal J, Vlady- 1982 ka V. Treatment of essential trigeminal neuralgia with gamma knife surgery.JNeurosurg.2005; 102 Suppl:29–33
6)

Maesawa S, Salame C, Flickinger JC, Pirris S, Kond- ziolka D, Lunsford LD. Clinical outcomes after ster- eotactic radiosurgery for idiopathic trigeminal neuralgia. J Neurosurg. 2001; 94:14–20
9)

Ertiaei A, Ataeinezhad Z, Bitaraf M, Sheikhrezaei A, Saberi H. Application of an artificial neural network model for early outcome prediction of gamma knife radiosurgery in patients with trigeminal neuralgia and determining the relative importance of risk factors. Clin Neurol Neurosurg. 2019 Feb 12;179:47-52. doi: 10.1016/j.clineuro.2018.11.007. [Epub ahead of print] PubMed PMID: 30825722.
10)

Régis J, Tuleasca C, Resseguier N, Carron R, Donnet A, Yomo S, Gaudart J, Levivier M. The Very Long-Term Outcome of Radiosurgery for Classical Trigeminal Neuralgia. Stereotact Funct Neurosurg. 2016;94(1):24-32. doi: 10.1159/000443529. Epub 2016 Feb 17. PubMed PMID: 26882097.
11)

Karam SD, Tai A, Wooster M, Rashid A, Chen R, Baig N, Jay A, Harter KW, Randolph-Jackson P, Omogbehin A, Aulisi EF, Jacobson J. Trigeminal neuralgia treatment outcomes following Gamma Knife radiosurgery with a minimum 3-year follow-up. J Radiat Oncol. 2014;3:125-130. Epub 2013 Nov 20. PubMed PMID: 24955219; PubMed Central PMCID: PMC4052001.
12)

Lee JK, Choi HJ, Ko HC, Choi SK, Lim YJ. Long term outcomes of gamma knife radiosurgery for typical trigeminal neuralgia-minimum 5-year follow-up. J Korean Neurosurg Soc. 2012 May;51(5):276-80. doi: 10.3340/jkns.2012.51.5.276. Epub 2012 May 31. PubMed PMID: 22792424; PubMed Central PMCID: PMC3393862.
13)

Kondziolka D, Perez B, Flickinger JC, Habeck M, Lunsford LD. Gamma knife radiosurgery for trigeminal neuralgia: results and expectations. Arch Neurol. 1998 Dec;55(12):1524-9. PubMed PMID: 9865796.

Gamma Knife radiosurgery for trigeminal neuralgia

Gamma Knife radiosurgery for trigeminal neuralgia

Gamma knife radiosurgery (GKRS) is one of the alternatives for treatment for classical trigeminal neuralgia (TN).

The first use of SRS by Leksell was for the treatment of trigeminal neuralgia. Initially, this was reserved for refractory cases following multiple operations 1).

The Leksell Gamma Knife and the Accuray CyberKnife systems have been used in the radiosurgical treatment of trigeminal neuralgia. The 2 techniques use different delivery methods and different treatment parameters. In the past, CyberKnife treatments have been associated with an increased incidence of treatment-related complications, such as facial numbness.

CyberKnife radiosurgical parameters can be optimized to mimic the dose distribution of Gamma Knife plans. However, Gamma Knife plans result in superior sparing of critical structures (brainstem, temporal lobe,and cranial nerves VII and VIII) and in steeper dose fall off away from the target. The clinical significance of these effects is unknown 2).

Indications

Generally recommended for patients with co-morbidities, high-risk medical illness, pain refractory to prior surgical procedures, or those on anticoagulants (anticoagulation does not have to be reversed to have SRS).

Mechanism

The exact mechanism of pain relief after radiosurgery is not clearly understood. Histopathology examination of the trigeminal nerve in humans after radiosurgery is rarely performed and has produced controversial results.

There is evidence of histological damage of the trigeminal nerve fibers after radiosurgery therapy. Whether or not the presence and degree of nerve damage correlate with the degree of clinical benefit and side effects are not revealed and need to be explored in future studies 3).

Existing studies leave important doubts as to optimal treatment doses or the therapeutic target, long-term recurrence, and do not help identify which subgroups of patients could most benefit from this technique 4).

Treatment plan

4 -5 mm isocenter in the trigeminal nerve root entry zone identified on MRI. Use 70–80 Gy at the center, keeping the 80% isodose curve outside of the brainstem.

Results: Significant pain reduction after initial SRS: 80–96% 5) 6) 7) 8) but only ≈ 65% become pain free. Median latency to pain relief: 3 months (range: 1 d-13 months) 9).

Recurrent pain occurs with in three years in 10–25%. Patients with TN and multiple sclerosis are less likely to respond to SRS than those without MS. SRS can be repeated, but only after four months following the original procedure.

Outcome

Favorable prognosticators: higher radiation doses, previously unoperated patient, absence of atypical pain component, normal pre-treatment sensory function 10).

Side effects: Hypesthesia occurred in 20% after initial SRS, and in 32% of those requiring repeat treatment 11) (higher rates associated with higher radiation doses) 12).

Repeat Radiosurgery for Trigeminal Neuralgia

Case series

A total of 263 patients contributed by 9 member tertiary referral Gamma Knife centers (2 in Canada and 7 in USA) of the International Gamma Knife Research Consortium (IGKRF) constituted this study.

The median latency period of Facial pain response (PR) after SRS was 1 mo. Reasonable pain control (Barrow Neurological Institute Pain Scale I-IIIb) was achieved in 232 patients (88.2%). The median maintenance period from SRS was 14.1 months (range, 10 days to 10 years). The actuarial reasonable pain control maintenance rates at 1 yr, 2 yr, and 4 yr were 54%, 35%, and 24%, respectively. There was a correlation between the status of achieving BNI-I and the maintenance of facial pain recurrence-free rate. The median recurrence-free rate was 36 mo and 12.2 mo in patients achieving BNI-I and BNI > I, respectively (P = .046). Among 210 patients with known status of post-SRS complications, the new-onset of facial numbness (BNI-I or II) after SRS occurred in 21 patients (10%).

In this largest series SRS offers a reasonable benefit to risk profile for patients who have exhausted medical management. More favorable initial response to SRS may predict a long-lasting pain control 13).

2016

One hundred seventeen patients with medically refractory TN treated by GKRS at the Department of Functional Neurosurgery and Gamma Knife Radiosurgery, and Department of Neurology, Ruber International Hospital, Madrid, Spain were followed up between 1993 and 2011. Mean maximum dose was 86.5 Gy (range: 80-90 Gy; median: 90 Gy). Clinical response was defined based on the Burchiel classification. They considered classes I and II as a complete response. For toxicity, they use the Barrow Neurological Institute Pain Scale. Mean duration of follow-up was 66 months (range: 24-171 months).

Complete response at last follow-up in our patients was 81%, with an excellent response while off medication in 52%. Pain-free rates without medication (class I) were 85% at 3 years (confidence interval [CI]: 78%-94%), 81% at 5 years (CI: 72%-91%), and 76% at 7 years (CI: 65%-90%). Complete response rates (classes I-II) were 91% at 3 years (CI: 86%-97%), 86% at 5 years (CI: 79%-93%), and 82% at 7 years (CI: 72%-93%). Poor treatment response rates differed significantly between patients who had undergone previous surgery and were refractory to management with medication prior to GKRS. New or worsening facial numbness was reported in 32.5% (30% score II and 2.5% score III). No anesthesia dolorosa was reported. Permanent recurrence pain rate was 12%.

GKRS achieved favorable outcomes compared with surgery in terms of pain relief and complication rates in our cohort of patients, notwithstanding decreasing pain-free survival rates over time. They consider GKRS to be an initial treatment in the management of medically intractable TN in selected patients 14).


In a single-center, retrospective comparative study, 202 patients with MS and concomitant TN were evaluated. A minimum follow-up of 24 months was required. Patients with a history of microvascular decompression or previous intervention were excluded. There were 78 PBC procedures performed and 124 first-dosage GKRS procedures for a total of 202 patients between February 2009 and December 2013. The PBC procedures were successfully completed in all cases. The two groups were compared with regards to initial effect, duration of effect, and rate of complication(s), including the type and severity of the complication(s).

Immediate pain relief resulted in 87% of patients treated with PBC and in 23% of patients treated with GKRS. The Kaplan-Meier plots for the two treatment modalities were similar. The 50% recurrence rate was at 12 months for the PBC and 18 months for the GKRS. The rates of complication (excluding numbness) were 3% for GKRS and 21% for PBC. The difference was statistically significant (Chi-square test, p = 0.03).

PBC and GKRS are effective techniques for the treatment of TN in patients with MS, with GKRS presenting fewer complications and superior long-term relief. For these reasons, we consider GKRS as the first option for the treatment of TN in MS patients, reserving PBC for patients with acute, intractable pain 15).

References

1)

Lunsford LD. Comment on Taha J M and Tew J M: Comparison of Surgical Treatmen ts for Trigemin al Neuralgia: Reevaluation of Radiofrequency Rhizotomy. Neurosurgery. 1996; 38
2)

Descovich M, Sneed PK, Barbaro NM, McDermott MW, Chuang CF, Barani IJ, Nakamura JL, Lijun M. A dosimetric comparison between Gamma Knife and CyberKnife treatment plans for trigeminal neuralgia. J Neurosurg. 2010 Dec;113 Suppl:199-206. PubMed PMID: 21222296.
3)

Al-Otaibi F, Alhindi H, Alhebshi A, Albloushi M, Baeesa S, Hodaie M. Histopathological effects of radiosurgery on a human trigeminal nerve. Surg Neurol Int. 2014 Jan 18;4(Suppl 6):S462-7. doi: 10.4103/2152-7806.125463. eCollection 2013. PubMed PMID: 24605252.
4)

Varela-Lema L, Lopez-Garcia M, Maceira-Rozas M, Munoz-Garzon V. Linear Accelerator Stereotactic Radiosurgery for Trigeminal Neuralgia. Pain Physician. 2015 Jan-Feb;18(1):15-27. PubMed PMID: 25675056.
5)

Brisman R. Gamma knife surgery with a dose fo 75 to 76.8 Gray for trigeminal neuralgia. J Neurosurg. 2004; 100:848–854
6)

Pollock BE, Phuong LK, Foote RL, Sta ord SL, Gorman DA. High-dose trigeminal neuralgia radiosurgery associated with increased risk of trigeminal nerve dysfunction. Neurosurgery. 2001; 49:58–62; discussion 62-4
7) , 12)

Kondziolka D, Lunsford LD, Flickinger JC. Stereotact ic radiosurgery for the treatment of trigeminal neuralgia. Clin J Pain. 2002; 18:42–47
8)

Massager N, Lorenzoni J, Devriendt D, Desmedt F, Brotch i J, Levivier M. Gamma kn ife surgery for idiopathic trigeminal neuralgia performed using a far-anterior cisternal target and a high dose of radiation. J Neurosurg. 2004; 100:597–605
9) , 11)

Urgosik D, Liscak R, Novotny J, Jr, Vymazal J, Vladyka V. Treatment of essential trigeminal neuralgia with gamma knife surgery. J Neurosurg. 2005; 102 Suppl:29–33
10)

Maesawa S, Salame C, Flickinger JC, Pirris S, Kondziolka D, Lunsford LD. Clinical outcomes after stereotactic radiosurgery for idiopathic trigeminal neuralgia. J Neurosurg. 2001; 94:14–20
13)

Xu Z, Mathieu D, Heroux F, Abbassy M, Barnett G, Mohammadi AM, Kano H, Caruso J, Shih HH, Grills IS, Lee K, Krishnan S, Kaufmann AM, Lee JYK, Alonso-Basanta M, Kerr M, Pierce J, Kondziolka D, Hess JA, Gerrard J, Chiang V, Lunsford LD, Sheehan JP. Stereotactic Radiosurgery for Trigeminal Neuralgia in Patients With Multiple Sclerosis: A Multicenter Study. Neurosurgery. 2019 Feb 1;84(2):499-505. doi: 10.1093/neuros/nyy142. PubMed PMID: 29688562.
14)

Martínez Moreno NE, Gutiérrez-Sárraga J, Rey-Portolés G, Jiménez-Huete A, Martínez Álvarez R. Long-Term Outcomes in the Treatment of Classical Trigeminal Neuralgia by Gamma Knife Radiosurgery: A Retrospective Study in Patients With Minimum 2-Year Follow-up. Neurosurgery. 2016 Dec;79(6):879-888. PubMed PMID: 27560193.
15)

Alvarez-Pinzon AM, Wolf AL, Swedberg HN, Barkley KA, Cucalon J, Curia L, Valerio JE. Comparison of Percutaneous Retrograsserian Balloon Compression and Gamma Knife Radiosurgery for the Treatment of Trigeminal Neuralgia in Multiple Sclerosis: A Clinical Research Study Article. World Neurosurg. 2016 Oct 15. pii: S1878-8750(16)31016-6. doi: 10.1016/j.wneu.2016.10.028. PubMed PMID: 27756676.
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