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 Lars 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

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% 3) 4) 5) 6) but only ≈ 65% become pain free. Median latency to pain relief: 3 months (range: 1 d-13 months) 7).

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

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 8).

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 9).


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 10).

Case reports

A 72-year-old -female presented with trigeminal neuralgia (TN) and radiological evidence of neurovascular compression on the affected side. She had complete resolution of her pain for 7 years after treatment with GKRS. The patient experienced recurrence and underwent repeat GKRS, this time resulting in another 3 years of pain relief. After the second recurrence, repeat intracranial imaging demonstrated resolution of neurovascular compression.

GKRS is an important treatment option for TN, although the mechanisms behind pain relief from this procedure still remain unclear. While prior histological and radiological studies point to ablative mechanisms for pain relief, this case report suggests that GKRS may result in a decompressive effect in TN due to changes in neurovascular architecture. Despite this finding, TN is known to occur and recur in the absence of neurovascular compression; thus, further work is necessary to understand the etiology of TN and its treatments.

In this case, Moosa et al. demonstrated that vessel-nerve relationships may change over time in TN patients treated with GKRS, which raises the possibility that GKRS could release a neurovascular compression 11).

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)

Brisman R. Gamma knife surgery with a dose fo 75 to 76.8 Gray for trigeminal neuralgia. J Neurosurg. 2004; 100:848–854
4)

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
5)

Kondziolka D, Lunsford LD, Flickinger JC. Stereotact ic radiosurgery for the treatment of trigeminal neuralgia. Clin J Pain. 2002; 18:42–47
6)

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
7)

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
8)

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.
9)

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.
10)

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.
11)

Moosa S, Wang TR, Mastorakos P, Sheehan JP, Elias WJ. Gamma Knife Radiosurgery for Trigeminal Neuralgia Reduces Neurovascular Compression: A Case Report after 11 Years. Stereotact Funct Neurosurg. 2019 Sep 5:1-5. doi: 10.1159/000501624. [Epub ahead of print] PubMed PMID: 31487732.

Lactotroph adenoma radiosurgery

Lactotroph adenoma radiosurgery

Lactotroph adenoma radiosurgery also serves as an option for those refractory to medical and surgical therapy 1).

GKRS plays a significant role in the treatment of non-functioning [NFA] and hormonal-active [HAA] pituitary adenoma. It affords high rate of tumor control and offers low risk of collateral neurological or endocrine axis injury. A study showed that control of tumor growth was achieved in 90% patients, shrinkage of tumor in 54% and arrest of progression in 36% cases after GKRS treatment. The biochemical remission rate in GH secreting adenoma was 57%, ACTH adenoma was 67% and prolactinoma was 40%. Age less than 50 years and tumor volume less than 5cm3 were associated with a favourable radiosurgical outcome 2).

Case series

retrospective study included lactotroph adenoma treated with SRS between 1997 and 2016 at ten institutions. Patients’ clinical and treatment parameters were investigated. Patients were considered to be in endocrine remission when they had a normal level of prolactin (PRL) without requiring dopamine agonist medications. Endocrine control was defined as endocrine remission or a controlled PRL level ≤ 30 ng/ml with dopamine agonist therapy. Other outcomes were evaluated including new-onset hormone deficiency, tumor recurrence, and new neurological complications.

The study cohort comprised 289 patients. The endocrine remission rates were 28%, 41%, and 54% at 3, 5, and 8 years after SRS, respectively. Following SRS, 25% of patients (72/289) had new hormone deficiency. Sixty-three percent of the patients (127/201) with available data attained endocrine control. Three percent of patients (9/269) had a new visual complication after SRS. Five percent of the patients (13/285) were recorded as having tumor progression. A pretreatment PRL level ≤ 270 ng/ml was a predictor of endocrine remission (p = 0.005, adjusted HR 0.487). An increasing margin dose resulted in better endocrine control after SRS (p = 0.033, adjusted OR 1.087).

In patients with medically refractory prolactinomas or a residual/recurrent prolactinoma, SRS affords remarkable therapeutic effects in endocrine remission, endocrine control, and tumor control. New-onset hypopituitarism is the most common adverse event 3).

2015

Radiotherapy as an alternative and adjuvant treatment for prolactinomas has been performed at the Department of Radiation Oncology, Prince of Wales Cancer Centre, Sydney, New South Wales, Australia, with the linear accelerator since 1990.

In a retrospective review of 13 patients managed with stereotactic radiosurgery (SRS) and 5 managed with fractionated stereotactic radiotherapy (FSRT), as well as 5 managed with conventional radiotherapy, at the Prince of Wales Hospital. Patients with a histopathologically diagnosed prolactinoma were eligible. Those patients who had a confirmed pathological diagnosis of prolactinoma following surgical intervention, a prolactin level elevated above 500 μg/L, or a prolactin level persistently elevated above 200 μg/L with exclusion of other causes were represented in this review.

At the end of documented follow-up (SRS median 6 years, FSRT median 2 years), no SRS patients showed an increase in tumour volume. After FSRT, 1 patient showed an increase in size, 2 showed a decrease in size and 2 patients showed no change. Prolactin levels trended towards improvement after SRS and FSRT, but no patients achieved the remission level of <20 μg/L. Seven of 13 patients in the SRS group achieved a level of <500 μg/L, whereas no patients reached this target after FSRT.

A reduction in prolactin level is frequent after SRS and FSRT for prolactinomas; however, true biochemical remission is uncommon. Tumour volume control in this series was excellent, but this may be related to the natural history of the disease. Morbidity and mortality after stereotactic radiation were very low in this series 4).


Cohen-Inbar et al., reviewed the outcome of patients with medically and surgically refractory prolactinomas treated with Gamma Knife radiosurgery (GKRS) during a 22 years follow-up period.

They reviewed the patient database at the University of Virginia Gamma Knife center during a 25-year period (1989-2014), identifying 38 patients having neurosurgical, radiological and endocrine follow-up.

Median age at GKRS treatment was 43 years. Median follow-up was 42.3 months (range 6-207.9). 55.3 % (n = 21) were taking a dopamine agonist at time of GKRS. 63.2 % (n = 24) had cavernous sinus tumor invasion. Endocrine remission (normal serum prolactin off of a dopamine agonist) was achieved in 50 % (n = 19). GKRS induced hypopituitarism occurred in 30.3 % (n = 10). Cavernous sinus involvement was shown to be a significant negative prognosticator of endocrine remission. Taking a dopamine agonist drug at the time of GKRS showed a tendency to decrease the probability for endocrine remission.

GKRS for refractory prolactinomas can lead to endocrine remission in many patients. Hypopituitarism is the most common side effect of GKRS 5).

2013

evaluated the efficacy of Gamma knife stereotactic radiosurgery (GKSR) as an adjunctive management modality for patients with drug resistant or intolerant cavernous sinus invasive prolactinomas. Twenty-two patients with cavernous sinus invasive prolactinoma underwent GKSR between 1994 and 2009. Thirteen patients were dopamine agonist (DA) resistant. Six patients were intolerant to DA. Three patients chose GKSR as their initial treatment modality in hopes they might avoid life long suppression medication. The median tumor volume was 3.0 cm3 (range 0.3–11.6). The marginal tumor dose (median= 15 Gy, range 12–25 Gy) prescribed was based on the dose delivered to the optic apparatus. The median follow-up interval was 36 months (range, 12–185). Endocrine normalization was defined as a normal serum prolactin level off DA (cure) or on DA. Endocrine improvement was defined asa decreased but still elevated serum prolactin level. Endocrine deterioration was defined as an increased serum prolactin level. Endocrine normalization was achieved in six(27.3%) patients. Twelve (54.5%) patients had endocrine improvement. Four patients (18.2%) developed delayed increased prolactin. Imaging-defined local tumor control was achieved in 19 (86.4%) patients, 12 of whom had tumor regression. Three patients had a delayed tumor progression and required additional management. One patient developed a new pituitary axis deficiency after GKSR. Invasive prolactinomas continue to pose management challenges. GKSR is a non invasive adjunctive option that may reduce prolactin levels in patients who are resistant to or intolerant of suppression medication. In a minority of cases, patients may no longer require long term suppression therapy 6).

2006

Twenty-three patients were included in analysis of endocrine outcomes (median and average follow-up of 55 and 58 mo, respectively) and 28 patients were included in analysis of imaging outcomes (median and average follow-up of 48 and 52 mo, respectively). Twenty-six percent of patients achieved a normal serum prolactin (remission) with an average time of 24.5 months. Remission was significantly associated with being off of a dopamine agonist at the time of GKRS and a tumor volume less than 3.0 cm3 (P < 0.05 for both). Long-term image-based volumetric control was achieved in 89% of patients. Complications included new pituitary hormone deficiencies in 28% of patients and cranial nerve palsy in two patients (7%).

Clinical remission in 26% of treated patients is a modest result. However, because the GKRS treated tumors were refractory to other therapies and because complication rates were low, GKRS should be part of the armamentarium for treating refractory prolactinomas. Patients with tumors smaller than 3.0 cm3 and who are not receiving dopamine agonist at the time of treatment will likely benefit most 7).

2000

Twenty patients with prolactinomas were followed after GKS. Five patients were treated successfully; their prolactin (PRL) levels dropped into the normal range and dopaminergic drugs could be discontinued. Two spontaneous pregnancies were observed and 11 patients experienced improvement. Improvement was defined as normal PRL levels with the continued possibility of reduced medical treatment or a substantially reduced medical treatment dose with some degree of hyperprolactinemia maintained. The treatment failed in three patients who experienced no improvement. Patients treated with dopaminergic drugs during GKS did significantly less well in comparison with the untreated group when a cumulative distribution function (Kaplan-Meier estimate) was used. CONCLUSIONS:

The results of GKS for prolactinomas in this investigation are better than the results published by others. This may be an effect of case selection because there were no “salvage cases” in our group of patients. Because a dopamine agonist seemed to induce radioprotection in this series, it is suggested that GKS be performed during an intermission in drug therapy when the dopamine agonist is discontinued 8).

References

1)

Wong A, Eloy JA, Couldwell WT, Liu JK. Update on prolactinomas. Part 2: Treatment and management strategies. J Clin Neurosci. 2015 Oct;22(10):1568-74. doi: 10.1016/j.jocn.2015.03.059. Epub 2015 Aug 1. Review. PubMed PMID: 26243714.
2)

Narayan V, Mohammed N, Bir SC, Savardekar AR, Patra DP, Bollam P, Nanda A. Long term Outcome of Non-functioning and Hormonal-active Pituitary Adenoma after Gamma Knife Radio Surgery. World Neurosurg. 2018 Mar 21. pii: S1878-8750(18)30576-X. doi: 10.1016/j.wneu.2018.03.094. [Epub ahead of print] PubMed PMID: 29574220.
3)

Hung YC, Lee CC, Yang HC, Mohammed N, Kearns KN, Nabeel AM, Abdel Karim K, Emad Eldin RM, El-Shehaby AMN, Reda WA, Tawadros SR, Liscak R, Jezkova J, Lunsford LD, Kano H, Sisterson ND, Martínez Álvarez R, Martínez Moreno NE, Kondziolka D, Golfinos JG, Grills I, Thompson A, Borghei-Razavi H, Maiti TK, Barnett GH, McInerney J, Zacharia BE, Xu Z, Sheehan JP. The benefit and risk of stereotactic radiosurgery for prolactinomas: an international multicenter cohort study. J Neurosurg. 2019 Aug 2:1-10. doi: 10.3171/2019.4.JNS183443. [Epub ahead of print] PubMed PMID: 31374549.
4)

Wilson PJ, Williams JR, Smee RI. Single-centre experience of stereotactic radiosurgery and fractionated stereotactic radiotherapy for prolactinomas with the linear accelerator. J Med Imaging Radiat Oncol. 2015 Jun;59(3):371-8. doi: 10.1111/1754-9485.12257. Epub 2014 Nov 20. PubMed PMID: 25410143.
5)

Cohen-Inbar O, Xu Z, Schlesinger D, Vance ML, Sheehan JP. Gamma Knife radiosurgery for medically and surgically refractory prolactinomas: long-term results. Pituitary. 2015 Dec;18(6):820-30. doi: 10.1007/s11102-015-0658-1. PubMed PMID: 25962347.
6)

Liu X, Kano H, Kondziolka D, Park KJ, Iyer A, Shin S, Niranjan A, Flickinger JC, Lunsford LD. Gamma knife stereotactic radiosurgery for drug resistant or intolerant invasive prolactinomas. Pituitary. 2013 Mar;16(1):68-75. PubMed PMID: 22302560.
7)

Pouratian N, Sheehan J, Jagannathan J, Laws ER Jr, Steiner L, Vance ML. Gamma knife radiosurgery for medically and surgically refractory prolactinomas. Neurosurgery. 2006 Aug;59(2):255-66; discussion 255-66. PubMed PMID: 16883166.
8)

Landolt AM, Lomax N. Gamma knife radiosurgery for prolactinomas. J Neurosurg. 2000 Dec;93 Suppl 3:14-8. PubMed PMID: 11143231.

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.
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