Gamma knife radiosurgery on the trigeminal ganglion for idiopathic trigeminal neuralgia: Results and review of the literature
- Departments of Neurosurgery, Centro Diagnostico Docente Las Mercedes, Hospital de Clinicas Caracas, Caracas, Venezuela,
- Departments of Radiation Oncology, Centro Diagnostico Docente Las Mercedes, Hospital de Clinicas Caracas, Caracas, Venezuela,
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, United States.
Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, United States.
DOI:10.25259/SNI-134-2019Copyright: © 2019 Surgical Neurology International This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
How to cite this article: Salvador Somaza, Eglee M. Montilla, Maria C. Mora. Gamma knife radiosurgery on the trigeminal ganglion for idiopathic trigeminal neuralgia: Results and review of the literature. 07-Jun-2019;10:89
How to cite this URL: Salvador Somaza, Eglee M. Montilla, Maria C. Mora. Gamma knife radiosurgery on the trigeminal ganglion for idiopathic trigeminal neuralgia: Results and review of the literature. 07-Jun-2019;10:89. Available from: https://surgicalneurologyint.com/?post_type=surgicalint_articles&p=9359
Background: In the present study, we evaluate the results of gamma knife surgery (GKS) for the treatment of trigeminal neuralgia (TN) using the trigeminal ganglion (TG’) and the adjacent fibers of trigeminal nerve as a target.
Methods: From February 2013 to July 2017, we treated 30 cases of TN with GKS. In this group, all patients had an idiopathic typical TN. The radiosurgical target was conformed through two isocenters, 8 and 4 mm at the cavum de Meckel. The maximum dose was 86 Gy using the isodose line of 50%. The median age of the patients was 58.5 (range 28–94) years old, and the median time from diagnosis to GKS was 94 months (range 13–480 months). The median follow-up was 28.5 (range 12–49) months. Clinical outcomes were analyzed. Univariate and multivariate analyses were performed to evaluate factors that correlated with a favorable, pain-free outcome.
Results: The mean time to relief of pain was 7 (range 1–40) days. The percentage of patients with significant pain relief was 93.3%. Relapse in pain was noted in four patients at 3, 16, 19, and 36 months. Nine patients were treated in acute status. Fourteen patients had intense pain between 1 and 7 days before the procedure. Among those with the recurrence of their symptoms, one patient had a microvascular decompression. Multivariate regression adjusted for age and sex suggests that, by 40 months, 70% of the patients treated with radiosurgery will remain pain free. At the last follow-up, GKS resulted in pain relief in 86.6% of patients. Our analysis suggests that, using this technique, we can expect that approximately 70% of patients with TN will have some degree of pain improvement at 3 years’ post radiosurgery.
Conclusions: GKS on TG appears to be a reasonable treatment option with short latency period, minor collateral effects, and high percentage of pain control. The mechanism of action of radiosurgery could be related to the inactivation of the satellite glial cells in the TG.
Keywords: Facial pain, Gamma knife, Gasser ganglion, Radiosurgery, Satellite glial cells, Trigeminal ganglion, Trigeminal neuralgia
Trigeminal neuralgia (TN) is clinically characterized by severe paroxysmal facial pain and brief, sharp, or stabbing unilateral electric shock-like sensations often triggered by facial movements or cutaneous stimulation.[
Although many reports have documented the efficacy of radiosurgery in the treatment of TN, controversy remains regarding the optimal treatment dose, target site, and brainstem dose.[
In 1971, Leksell[
In 2014, we reported[
Due to the excellent results obtained, we decided to prospectively evaluate the technique in 30 patients with idiopathic TN. The results are presented and discussed.
Between February 2013 and July 2017, a prospective study was conducted to analyze the responses of 30 consecutive patients with typical TN refractory to therapy that treated with gamma knife surgery (GKS) at the gamma knife center las mercedes (CDD) in Caracas, Venezuela. The median age of the patients was 58.5 years (range, 28–94 years) and the mean duration pain was 94 months (range, 13–480 months.). In the distribution of pain, a combination of branches was more frequently involved in all patients. The right side of the face was more frequently involved (71.8%). Numbness was noted in nine patients (28.1%), eight of which had previous local or invasive therapeutic procedures.
All patients received pharmacotherapy which included gabapentin, pregabalin, carbamazepine, and combinations. Ten patients had a history of previous surgical intervention, including local blocks of trigeminal branches (n = 8), cryotherapy (n = 2), radiofrequency (n = 4), peripheral neurectomy (n = 3), maxillofacial surgeries (n = 5), balloon compression (n = 1), and previous radiosurgery (n = 1). No patients had anesthesia Dolorosa. Clinical characteristics are shown in
Associated pathologies were arterial hypertension (n = 17), obesity (n = 2), diabetes mellitus (n = 1), hypothyroidism (n = 1), and hemochromatosis (n = 1).
As part of our protocol for TN radiosurgery, all patients underwent clinical examination and neuroimaging with computed tomography (CT) or magnetic resonance imaging (MRI) to exclude other pathologies that could produce TN (tumors, compression by the complex of vertebrobasilar arteries and other vascular malformations, and multiple sclerosis). All patients fulfilled the criteria of the International Headache Society and had a TN1.
Criteria for using GKS
The decision to use GKS was based on criteria such as the medical condition of the patients, pain refractory to pharmacologic treatment, significant adverse effects from medication, previous unsuccessful surgical procedures, the absence of vascular or tumor compression of the involved trigeminal nerve on the MR images, and the patients’ willingness to undergo radiosurgery instead of other techniques.
All patients underwent SRS using a gamma knife (Leksell Gamma Knife, Elekta Instruments, Atlanta, Ga), model C. Under mild sedation and local anesthesia, the Leksell Model G stereotactic frame (Elekta Instruments) was applied. Stereotactic MRI was performed on each patient to identify the trigeminal nerve and its course from the pons, using contrast enhancement. A three-dimensional time-of-flight (3D-TOF) sequence was performed using a 1.5-Tesla MRI scanner (General Electric Signa HD). Fast imaging, employing steady-state acquisition sequence, provides images included in the MR protocol. A treatment plan was implemented using the Leksell Gamma Plan treatment planning system (Elekta AB).
Stereotactic coordinates were calculated for two isocenters; one 8-mm isocenter was placed on the Meckel’s Cavum and a 4 mm was placed at the adjacent fibers of the trigeminal nerve from the TG. The maximum dose was 86 Gy (43 Gy prescribed to the 50% isodose) [
Patient outcomes and follow-up evaluation
All patients were discharged the same day after radiosurgery. They were instructed to continue their preoperative medications after the radiosurgical procedure and to gradually taper their medications over 16-week intervals.
The primary outcome after radiosurgery was based on pain intensity which was defined and assessed using the barrow neurological institute (BNI) pain intensity scoring criteria. The mean follow-up time after radiosurgery was 28.5 months (range, 12–49 months). An assessment of outcomes was performed by a blinded evaluator, trained to complete telephone follow-ups and clinical examinations as part of our protocol. It was then followed by a clinical consultation in our center, every 4 months; all of which allowed to keep updated patients’ records. Clinical evaluation included facial sensory testing, corneal reflex, and jaw motility. We evaluated the degree of pain relief, latency interval to pain relief, drugs used, development of new signs or symptoms, and the need for and response to additional surgical procedures.
Categorical variables were compared through Chi-square testing. For continuous variables, Student’s t-test was used for normally distributed variables (e.g., age); Kruskal–Wallis tests were used for non normally distributed variables (e.g., length of stay). P < 0.05 was considered to be statistically significant. Cox proportional regression was used to generate a predicted pain-free survival curve, adjusting for age and sex of patients. All statistical analyses were performed in SAS 9.4 (SAS Institute Inc., Cary, NC).
Before undergoing GKS, all patients categorized their pain as BNI IV or V. The BNI pain score at baseline and last follow-up is shown in
The mean latency period was 7 days (range, 1–40 days); all patients were pain free. The initial response rate in the patients was 100%, including patients with previous local and ablative procedures. In 18 patients (60%), pain relief was obtained before 8 days.
At last follow-up, significant pain relief was noted by 86.6% of patients (good plus excellent results). Relapse in pain was noted in four patients at 3, 16, 19, and 36 months. In two of them, the pain was similar to the pain before the radiosurgery procedure. One patient returned to the pain-free state with medication; although his pain presents occasionally, it is not as intense as previously recorded. One patient decided to undergo surgery; therefore, the case was considered a treatment failure.
Univariate analysis did not identify any factors associated with pain-free survival.
Of the 30 patients, seven patients continue under medication at the last follow-up. One of them, an 83-year-old patient suffering from TN for 19 years, does not want to leave the medication even in the absence of pain.
Nine patients were treated in acute status, with pain the same day of the procedure and between 1 and 10 days before the procedure in 21 patients.
Regarding the adverse effects of radiosurgery, one patient reported moderate hypoesthesia in all three divisions, two patients had tickling sensations, and one patient reported hypoesthesia in V2, although in this case, the patient presented dysesthesias in the same region before treatment with radiosurgery.
Radiosurgery has become an excellent treatment choice for patients who do not respond to medical therapy or other surgical procedures. In the management of the typical TN, most patients are suitable candidates for GKS which was demonstrated to be an effective and safe option.[
The concept of SRS was introduced by Lars Leksell, who in 1951 began performing clinical radiosurgery with a stereotactic X-ray beam in patients with essential TN. Leksell was the first to use radiosurgery for the treatment of functional disorders such as TN. Using a conventional stereotactic frame, he directed the radiation beam produced by an orthovoltage X-ray tube at the TG.[
After treating a series of 40 patients, the Leksell team abandoned this approach because Leksell discovered the efficacy of the glycerol injection. This injection was first used for the visualization of the Meckel cave but turned out to be sufficient to stop the pain in a significant percentage of patients.[
Lindquist et al.[
Many years after Leksell’s report, Rand et al.[
Chen et al.[
Target location, accuracy, and treatment dose
Since the duration of pain relief tends to lessen over time, various modifications of the radiosurgical technique for TN have been devised to improve outcomes such as the duration of pain relief.[
Many authors have reported that higher the applied dose of the trigeminal nerve, the better the pain control, as well as greater benefits with the use of two isocenters.[
Accuracy is a critical aspect when placing isocenters on the trigeminal nerve. However, there are inaccuracies that depend on the images, the selection of nerve target site, mechanical errors of the stereotactic frame, and mechanical errors of the radiation equipment used.[
In our study, we applied the same doses used in the trigeminal nerve to the TG and we used two isocenters which were determined by the semioval shape of the ganglion and the adjacent fibers of the nerve similar to what was previously described to completely cover the TG.[
The dose is one of the most important factors that improve outcomes following GKS for TN. GKS is associated with high rates of pain control. Patients report excellent or good pain relief in more than 70% of cases.[
Pollock et al.,[
There is no dose established to be used on the TG. Chen et al.[
On the other hand, vascular injury has been reported in vessels adjacent to the entry zone. Pollock et al.[
More recently, Chen et al.[
It has been established that radiosurgery should not be performed on patients under acute attacks of pain, due to the known latency necessary to produce pain relief with radiosurgery and the fact that it often takes several weeks or months to reach the optimal therapeutic peak. Thus, radiosurgery is considered a second option for patients with severe pain, with difficulty speaking or maintaining adequate hydration, who need an immediate method of pain control through percutaneous procedures.[
Complications, recurrence, and latency period
For excellent results, radiosurgery and other ablative techniques must find a balance between the production of an injury to trigeminal fibers that are sufficient to provide adequate pain relief without causing so much damage that it produces complications such as facial numbness, paresthesias, bothersome dysesthesia, masseter weakness, or disagreeable numbness that could transform into anesthesia Dolorosa.[
With radiosurgery targeting the trigeminal nerve, sensory dysfunction is less common than with ablative techniques, ranging between 6% and 66%,[
In our series, the percentage of complications during the follow-up period was very low, even taking into account that the maximum dose used can be considered within the high range.
Another important aspect to consider is the recurrence of attacks of facial pain which is contrary to the goal of obtaining a pain-free status.[
The effect of the latency period after SRS is reported in most series as an interval of 1–2 months.[
It has been suggested that this parameter should be seriously considered for radiosurgical planning. Patients with previous surgery seem to be more frequently late responders to GKS than patients with no history of previous surgery.[
In our cases, we observed a short latency period with a median of 7 days (range, 1–40). In 18 patients, the pain relief was obtained before 7 days. Patients with a long history of TN had similar responses to those with a short history; history of previous surgery did not have any influence on the results.
The TG role of the satellite glial cells (SGC)
Although the vascular compression theory is popular, it cannot account for all phenomena associated with TN.[
It seems that the main feature of TN pain is its dynamic nature which is difficult to explain in purely anatomical terms. The fact that the pain is not continuous, but paroxysmal speaks against the fact that a simple compression is an ectopic generator of pain at the level of the lesion. Moreover, pain must not only occur spontaneously but must also be produced, as often happens, by innocuous tactile stimuli. Therefore, demyelination alone does not provide clear evidence of the characteristic symptoms of the disease. It has been assumed that the pain is the result of hyperactivity or abnormal discharges. These arise from the gasserian ganglion, the “injured” nerve root, and the trigeminal nucleus within the brainstem.[
TG seems to have a predominant role given its cellular architecture. The crescent-shaped TG lies on Meckel’s cave, which is a rigid structure. The TG has dimensions ranging from 14 to 22 mm in length and 4–5 mm in thickness and is easily identified on CT or MRI.[
The fine structure of the TG contains cells that give rise to the three divisions of the trigeminal nerve. The cell bodies of neurons are completely surrounded by specialized glial cells known as SGC that together form distinct, functional units.[
Neurons and SGCs extend processes that are thought to facilitate the exchange of chemicals between neurons and glia and can communicate directly through gap junctions that allow for the direct transfer of small molecular weight molecules, such as ions, that regulate cellular excitability, metabolic precursors, and second messengers.[
V1, V2, and V3 regions are interconnected. Stimulation of V3 neurons could cause increased levels of active signaling proteins in neuronal and SGCs in other regions of the ganglion which could explain why a pain originating in V2, for example, is propagated to V1 and/or V3, contributing to signal propagation and chronic pain.[
SGCs divide after an insult to the peripheral nerve including nerve damage.[
Therefore, the glial cells have the ability to communicate with neurons and modulate their activity, particularly in TG where SGCs establish a privileged relationship with the surrounding neuronal bodies. The increased neuron-glial interactions are thought to play an important role in the induction and maintenance of peripheral sensitization of trigeminal nociceptors.[
TG may become the first level of the pathophysiological changes of modulation of afferent signaling, as it allows the interaction between different types of information and seems to be a trigger of the central sensitization mechanism as observed also in the spinal cord dorsal horn neurons in relation to the spinal ganglion.[
Thus, knowledge about the SGC and its mechanisms of interaction with the neuronal body assumes a growing importance in the search for new targets for chronic pain treatment, which includes TN.[
The occurrence of a refractory period of seconds to minutes after an attack of TN is well known, during which further attacks cannot be provoked. Besides demyelination, other factors could delay the restoration of membrane potentials and excitability after an episode of TN.[
The refractoriness period could be explained by the release of potassium ions due to the activation of potassium channels by calcium, leading to neuronal hyperpolarization and the trigger stop.[
Our findings suggest that there is a longer refractory period as a consequence of the treatment of the ganglion and nerve adjacent fibers, probably affecting primarily the SGCs and, as a consequence, the repolarization process which would produce a delay of a possible new attack.
How does radiosurgery act on trigeminal pain?
At present, from a pathological point of view, the exact mechanism of pain relief is unknown. There is the assumption that there exists a critical region in which the central myelin (oligodendrocyte) becomes peripheral (Schwann cell) myelin. The oligodendrocytes are more sensitive to irradiation than Schwann cells, and consequently, a stronger radiobiological effect would occur on the root entry zone.[
However, Régis et al. treated the trigeminal nerve at the pontine cistern where the myelin is peripheral (Schwan cells) obtaining the same results.[
In any case, after the treatment, it is observed that patients report an immediate decrease in the intensity of pain even if the attacks still occur. This is postulated to be the result of an immediate interruption of ephaptic transmission. Several weeks later, there is a complete cessation of the attacks. This is probably secondary to delayed demyelination injury to the nerve. The compact union of fibers from different divisions would facilitate the irradiation of the entire nerve with the smallest volume of energy (4-mm collimator).[
There is a growing body of evidence that glial satellite cells undergo structural and biochemical changes after nerve injury which influence neuronal excitability and consequently the development and/or maintenance of pain in different animal models of chronic pain.[
Radiosurgery on TG for the treatment of TN has several positive aspects: short latency period, minor collateral effects, a high percentage of pain control, and the pain relief which is not related to the time of the diagnosis of TN. In general, a better understanding of the radiobiology and pathophysiology of NT is important to explain the mechanism of action of radiosurgery.
The current series investigates the use of TG to treat NT using GK with commonly used doses and high-resolution images. A comparative prospective randomized trial is necessary for the use of GKR on the TG for idiopathic TN.
There are no conflicts of interest.
We thank Dr. Roman Liscak who provided insight and expertise for reviewing and for his comments that greatly improved the manuscript, although he may not agree with all of the interpretations/conclusions of this paper.
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