Novel theory about radiosurgery’s action mechanisms on trigeminal ganglion for idiopathic trigeminal neuralgia: Role of the satellite glial cells
- Department of Neurosurgery, Centro Diagnostico Docente Las Mercedes, Hospital de Clinicas Caracas,
- Department of Radiation Oncologist Radiation Oncology, Centro Diagnostico Docente Las Mercedes, Caracas, Miranda, Venezuela.
Department of Radiation Oncologist Radiation Oncology, Centro Diagnostico Docente Las Mercedes, Caracas, Miranda, Venezuela.
DOI:10.25259/SNI_484_2019Copyright: © 2020 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 Somaza1, Eglee M. Montilla2. Novel theory about radiosurgery’s action mechanisms on trigeminal ganglion for idiopathic trigeminal neuralgia: Role of the satellite glial cells. 04-Dec-2020;11:412
How to cite this URL: Salvador Somaza1, Eglee M. Montilla2. Novel theory about radiosurgery’s action mechanisms on trigeminal ganglion for idiopathic trigeminal neuralgia: Role of the satellite glial cells. 04-Dec-2020;11:412. Available from: https://surgicalneurologyint.com/surgicalint-articles/10433/
Background: There are many theories about the cause of trigeminal neuralgia (TN). None of them satisfactorily explains how demyelination alone through the ephaptic mechanism can contribute to the development of the TN crisis. The main characteristic of TN pain is its dynamic nature, which is difficult to explain based only on anatomical findings. With these antecedents, the exact mechanism by which radiosurgery produces pain relief in TN is unknown.
Methods: It is based on the trigeminal ganglion (TG) cytoarchitecture and the pathophysiological findings observed after an injury to a trigeminal branch. TG seems to have a predominant role given its cellular structure. The neuronal component in sensory ganglia is generally surrounded by a single layer of satellite glial cells (SGC), which forms a sheath around each body cell. There is increasing evidence that SGCs play a key role in nociception. This depends on their ability to influence the neuronal excitability that occurs in conditions of neuropathic and inflammatory pain; contributing to both the generation and maintenance of pain.
Results: We have already published the beneficial effects of radiosurgery on the TG for the treatment of idiopathic TN and secondary to vertebrobasilar ectasia. Now, we are investigating the functioning of the TG and how radiosurgery could act on the SGC, deactivating them, and contributing to the decrease or disappearance of the painful condition.
Conclusion: We are postulating a theory on how radiosurgery in TG produces changes in the SGC, with implications in the pathological mechanisms initiated by the alteration caused in the neuron after a nerve injury.
Keywords: Gamma knife, Radiosurgery, Satellite glial cells, Theory, Trigeminal ganglion, Trigeminal neuralgia
At present, the pathogenesis of trigeminal neuralgia (TN) and the exact mechanism by which radiosurgery produces pain relief is unknown.[
In the past decades, many investigations show the role that glial cells of the trigeminal ganglion (TG) play in the origin and maintenance of the painful status in TN, which gives a new perspective.[
We investigate the anatomical, cellular, and functional characteristics of the TG. The results of our research allow us, on the one hand, to postulate the implication of cellular architecture and physiological aspects of TG, which provides a new, more coherent approach to the causes of TN and, second, to present a theory on how radiosurgery works in TG to relieve pain in TN.
We analyzed the findings obtained in our patients, which were previously published.[
In 2014, we reported a case of a patient with NT secondary to vertebrobasilar ectasia. We treated TG for the painful condition because the TN could not be visualized adequately in the neuroimaging studies. Three days after the procedure, the pain intensity had decreased and 15 days after the procedure, the patient was pain-free. During the 48 months of follow-up, the patient remained without pain and any alteration in facial sensation.[
Based on the good results obtained, we decided to prospectively evaluate the technique in 30 patients with idiopathic TN that was reported in 2019.[
The primary outcome after radiosurgery was based on pain intensity, which was defined and assessed using the pain intensity scoring criteria of the Barrow Neurological Institute (BNI). Before undergoing GKS, all patients classified their pain as BNI IV or V. At the last follow-up, significant pain relief was observed in 86.6% of patients. The adverse effects of radiosurgery were presented in 13.3%. Patients with a long history of TN had good responses as those with a short history; the history of the previous surgery did not influence the results.[
These findings led us to investigate two important aspects: the current theories about the cause of the TN and the implication of the TG with its anatomic and functional characteristics.
The TG, also known as the Gasserian or lunate ganglion, is a large, flattened ganglion found in the middle cranial fossa in the Meckel cave, which is a rigid structure. It is an easy target and there are many fewer possibilities of movement during the radiosurgical treatment.[
TG had been considered as a simple transition site for sensory information from the periphery to the central nervous system (CNS). Now, it is very well known that it can act as an integrating structure located in the peripheral nervous system regulating the intracellular modulating mechanisms as well as intercellular and autocrine signaling. It is a key component in the nociception of craniofacial pain that contributes to the peripheral modulation of pain pathways in TN.[
In the TG, the regions V1, V2, and V3 are interconnected and stimulation of V3 neurons could cause an increase in the levels of active signaling proteins in neuronal and satellite glial cells (SGC) in other regions of the ganglion, which contributes to signal propagation and chronic pain.[
The cytoarchitecture of the TG
As in the CNS, the sensory ganglia contains neurons, glia, and fibroblasts that form collagen fibers, small capillary-type blood vessels, and several types of immune cells, such as microglia-like resident macrophages and peripheral support cells.[
The neuronal component and the proximal portion of its axon in the sensory ganglia are usually surrounded by a single layer of SGC, forming a sheath around each cell body. They are organized in discrete bands or groups within each region of the TG and are connected by gap junctions, a space of approximately 20 nm, forming a path between the connective tissue and the neuronal surface.[
Physiology and the physiopathological responses of the TG. Role of SGC
Under physiological conditions, each cell body surrounded by an SGC sheath forms a morphological and functional differentiation that allows a close bidirectional interaction through paracrine signaling between the neuronal body and the SGC that facilitates the maintenance of neuronal homeostasis.[
In DSG, the excitation of neurons leads to the development of an action potential in neighboring neurons, a property called cross-excitation. In vitro studies have shown that repeated stimulation of these neurons induced a transient depolarization of neighboring neurons in the ganglion, probably mediated by chemical messengers. ATP seems to be the main mediator in the interaction between neurons and SGC in the sensory ganglia.[
In pathological conditions, those molecules initiate and maintain neurogenic inflammation, whose results are peripheral sensitization of trigeminal nociceptors. This will cause the excitation of second-order neurons within the brainstem and spinal cord involved in the transmission of nociceptive information that leads to pain, central sensitization, hyperalgesia, and allodynia.[
These cells undergo profound changes in response to nerve injury. There is an increase in intracellular Ca2 + in both cell types and, consequently, the release of ATP from neurons and the SGCs. In this way, there is a growth of bidirectional communication between the neurons and the SGC which will activate P2 receptors around SGCs and in the neuron itself. The increase in the ATP, together with the multiplication of the number of gaps between the SGCs of neighboring perineural sheaths, will allow the propagation of Ca2 + waves to these SGCs and neighboring neurons, which influences the excitability of the neurons that are not directly affected by the injury, as shown in [
Schematic of trigeminal ganglion neurons and surrounding satellite glial cells. Glial cells play a primary role in the processes of nervous system dysfunction, such as the generation and/or maintenance pain. After a nerve injury, there is a release of some neurotransmitters as CGPR, substance P and ATP, which activate satellite glial cells (SGC), increasing the intracellular calcium concentration in those cells. Through the gap junctions, the SGC communicate with others SGC using the wave propagation of Ca2+, affecting those neurons in the same manner as the first neuron was affected. Thus, the excitability process of the last neurons was not directly affected by the injury. Concomitantly, there is an increasing number of gap junctions and alterations with a rapid redistribution which increases K+ and Ca2+ in neurons as well as in SGC.
Those ultrastructural and biochemical changes in the axon and myelin are seen not only in the TG but also in the root or both structures.[
Demyelination and other factors may delay the restoration of membrane potentials and excitability after an episode of TN. The appearance of a refractory period from seconds to minutes after a TN attack is well known, during which no further attacks can be triggered. Devor et al.[
Theories about the cause of TN
Dandy proposed compression of the TN in the entry zone into the pons by an arterial vessel as a possible cause of TN.[
For many years, the most popular theory of the peripheral mechanism of the disease was the “short connection” theory proposed by Dott in 1951.[
The knowledge that clinical improvement occurs after microvascular decompression (MVD) supports the concept that the development of TN involves two different and concurrent processes in the same pathological condition. The rapid clinical and electrophysiological recovery that often follows MVD has led to questioning the central role of demyelination in the development of NT. The process of myelination does not occur immediately after the MVD, so it cannot explain the rapid relief of neuralgia. In the long-term, however, remyelination can help ensure sustained symptomatic relief.[
Thus, the main feature of the pain of TN is its dynamic nature, which is difficult to explain based only on the anatomical findings. The TG seems to have a predominant role given its cellular architecture.[
How does radiosurgery work in trigeminal pain?
There are interesting animal research studies evaluating the effect of radiosurgery. Kondziolka et al.[
The authors concluded that through partial axonal (focal) degeneration, radiosurgery probably relieves the pain of TN by affecting a population of axons large enough to relieve pain. They assumed that the low incidence of loss of facial sensation indicated that the remaining intact axonal population was sufficient to maintain neurological function in the majority of patients. This balance between pain relief and preservation of sensation, as well as the histological effect, was related to the dose.
Unlike what happens in the TN where there are studies of pathological anatomy after radiosurgical treatment, there are no such studies at the level of the TG that allow us to expand our knowledge on the effects of radiosurgery. Nevertheless, recently Goldschmidt et al.[
The animals were assessed to detect motor and sensory deficiencies every 2 weeks and were sacrificed at 3 and 6 months after the SRS. No detectable deficit was observed in any of the animals at any time. They verified the hypothesis that 80 Gy administered in a single fraction would induce changes similar to those described for the TN without compromising the sensory or motor function of the nerve root.
These findings mimic those observed after SRS in the TN in experimental animals. Using the same dose as for TN, similar histological changes were obtained without clinical toxicity. These results suggest that radiosurgery may be a possible option in the treatment of chronic spinal radicular pain. It can be inferred, based on these findings, that similar doses to the TG could have a beneficial clinical effect with low clinical toxicity.
The similarity found between astrocytes and SGCs, both anatomically and functionally, is also reflected in the response obtained at high doses of radiation such as those commonly used in radiosurgery for TN. This, together with the results obtained in radiosurgery in the DRG for chronic radicular pain; coincide in many aspects with the clinical results obtained in the treatment of the TG in patients with idiopathic TN.
Kamiryo et al.[
The results obtained with GKS on TG are also based on precision, which is a critical aspect when it comes to TN where a shot with a 4 mm isocenter is placed. In addition to the neurosurgeon’s experience in determining the correct area to place the shot, there are other variables related to precision such as the quality of the images, the mechanical errors of the stereotactic frame, and the mechanical errors of the radiation equipment used. The sum of errors can be superior to 2 mm. Moreover, there is a minimal submillimetric respiratory movement of the cranial nerves while crossing cerebrospinal fluid space within the skull. Minimal variations of the nerve position during prolonged radiation delivery time may negatively impact the amount of clinically relevant fibers of the TN receiving the minimal radiation dose necessary to produce pain relief in conjunction with the previously mentioned aspects and help explain why some patients fail radiosurgery and some patients respond sooner than others.[
In summary, once a nerve injury occurs, it induces changes in the SGC, with an increase in GAP junctions and the formation of bridges that interconnect the perineuronal sheaths, all of which increase the sensitivity of nociception receptors to a variety of chemical mediators and ionic changes. These alterations can occur not only in the TG but also in the TN.
The results suggest that radiosurgery on the TG produces elimination of pain or the reduction of its intensity in a short period. Concomitantly, there is a disruption of ephaptic transmission, secondary to demyelination. It remains to be determined whether the dose of radiosurgical treatment used is adequate or whether it is possible to decrease it. The same consideration could be made concerning the use of a single collimator located at the level of the Meckel’s cave.
Our follow-up is short to assess long-term pain relief. However, the results are very promising regarding the short term to obtain pain relief, and the long duration of this status over time. This maintained condition could further improve the results when compared with those where the target is the TN. To answer this assumption, we must have a longer follow-up.
We postulate that radiosurgery in the TG produces an injury to the SGC that leads to the cessation of the pathological mechanisms initiated by the alteration in the neuron after a nerve injury. Reducing the gaps and functionality of the SGCs would produce a prolonged extracellular hyperpolarization. Clinically, there is a decrease in pain discharges and the maintenance of this state for a long time. In addition, there is a short latency period, minor side effects, and a high percentage of pain control.
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