Long-Term Efficacy and Complications of Radiofrequency Thermocoagulation at Different Temperatures for the Treatment of Trigeminal Neuralgia

Trigeminal neuralgia (TN) is a common neuropathic pain that seriously affects the daily life of patients. Many invasive treatments are currently available for patients who respond poorly to oral carbamazepine or oxcarbazepine. Among them, radiofrequency (RF) treatment is a viable option with reliable initial and long-term clinical efficacy. The long-term analgesic effects of radiofrequency thermocoagulation (RFT) at high temperatures (≥80°C) are not superior to those at relatively low temperatures (60–75°C). In contrast, the higher the temperature, the greater the risk of complications, especially facial numbness, masticatory muscles weakness, and corneal hypoesthesia. Some patients even experience irreversible lethal complications. Therefore, we recommend low-temperature RFT (60–75°C) for treatment of TN. The therapeutic effects of pulsed radiofrequency (PRF) are controversial, whereas PRF (≤75°C) combined with RFT can improve long-term effects and decrease the incidence of complications. However, large-scale clinical trials are needed to verify the efficacy of the combination of PRF and RFT.


Introduction
Trigeminal neuralgia (TN) is a common neuropathic pain disorder with symptoms of transient, electric-shock-like pain affecting one or more branches of the trigeminal nerve. Talking, eating, brushing teeth, and slight touching of trigger point located in the oral or perioral region can induce severe and brief pain. Severe pain can affect the daily activities of patients. ose who experienced long-term pain often experience emotional changes, such as anxiety and depression. Epidemiological studies have shown that elderly women have a higher incidence than men (1.5-2.1 times more than men), and the annual prevalence of the disease is 12.6-28.9 cases per 10 million people [1][2][3][4]. Patients with severe TN who cannot be completely controlled by oral carbamazepine or oxcarbazepine or who are intolerant to the adverse effect of drugs can benefit from invasive surgery. Common surgical interventions include percutaneous balloon compression [5], microvascular decompression (MVD) [6], gamma knife radiosurgery [7], RFT [8,9], PRF [10,11], and intradermal and/or subcutaneous injections of Botox [12], intragasserian phenol glycerite [13], and peripheral alcohol [14].
Although there are some serious complications reported in prior studies [9,[15][16][17][18][19][20], RFT is still an effective treatment for TN that can instantly relieve pain in 90%-100% of cases [15,[17][18][19][21][22][23][24]. Kanpolat et al. have observed 1561 patients who underwent single-procedure RFT [21]. e proportion of patients who were painless for 5 years and did not require oral medication was as high as 57.7%. By 15 years, 42.2% of patients still had no recurrence of pain. Fouad observed 312 patients with TN [25]. e rate of pain relief after 2 years of RFT was as high as 97.2%, and the rate of pain recurrence tracking to 8.8 years was only 7.6%. Tang et al. have observed 1161 patients who underwent RFT via the Hartel anterior approach, and the pain relief rate was as high as 52% after 11 years [9]. e purpose of this review is to summarize the different temperatures utilizing RFT treatment for TN. us, we hope to reveal the optimal temperature suitable in RFT operation with best outcome.

Principles of RF
e main principle of RF treatment of TN is blockage pain signal conduction by high temperature up to 90°C to destroy the nerve (RFT) or modulation of the nociceptive nerve function of trigeminal nerve with temperature not exceeding 42°C (PRF). Two sets of technology can reduce the transmission of peripheral stimuli to the central nervous system, thereby preventing the disastrous pain. Although the pathogenesis of idiopathic trigeminal neuralgia is not completely clear, most scholars tend to believe that TN was associated with arterial or venous vascular compression, strategically located at the root entry zone. ey recommended that MVD was the gold standard treatment for refractory TN and did not consider RF treatment to be involved in this pathogen [26,27]. Prior clinical reports indicated that MVD can achieve similar or better results than RFT of the gasserian ganglion or trigeminal rootlets [19,28,29]. However, RFT is an alternative treatment for patients with recurrent TN after MVD, and it achieved good pain relief condition [23]. erefore, by interfering with the function of the trigeminal nerve or destroying the integrity of its anatomical structure, therapeutic effects can be achieved.

The Pain Relief Rate of RFT at Different
Temperatures for TN Treatment ere is no specific standard for temperature selection in RFT. A review of the published English literature indicated that the temperature for RFT varied widely among studies (60°C to 95°C). e theoretical basis for choosing hightemperature RFT is the hypothesis that the recurrence rate of TN is correlated with the degree of postoperative sensory deficit [9,22,30]. In support of this possibility, Taha et al. [22] have reported that the recurrence rate within 4 years was 100% among patients with mild postoperative facial numbness, whereas the rate was only 10% over a period of 10 years among patients with dense hypalgesia. Notably, those with analgesia had the lowest recurrence rate within 15 years. In addition, previous animal experiments have reported that temperatures below 80°C can selectively damage the Ab and C unmyelinated nerve fibers without damaging the Aα and Aβ nerve fibers, thereby blocking pain transmission without affecting facial tactile sensation [31].
Some studies use the recurrence rate as an indicator to assess the efficiency of high-temperature RFT for TN. e percentage of patients with recurrent pain ranged from 7.8% to 42.7% with tracking from 11.6 to 15 years [15,21]. However, there were some limitations to the studies. e studies did not provide a detailed definition of "pain relief" or specify whether the patients used medication to control pain after the procedure. In addition, they included patients with secondary trigeminal neuralgia (STN) who had received other invasive interventions without success. Nonetheless, high-temperature RFT was not superior to low-temperature RFT in terms of the longterm pain relief rate. Tang et al. have analyzed a total of 1161 patients retrospectively and divided them into 65-70°C, 75°C, and 80-85°C groups according to the temperature used in the procedure [9]. Notably, there was no significant difference in the long-term pain relief rate among the three groups, thus suggesting that a higher temperature for RFT would not further increase long-term pain relief, and a temperature >65°C can generate satisfactory analgesic effects.
To explore the optimal temperature for achieving efficacious treatment of RFT, we conducted a multicenter clinical observational study to evaluate the long-term efficacy of low-temperature RFT, including temperatures of 62°C, 65°C, 68°C, 70°C, and 75°C for RFT [16,34]. Patients with STN or V1 division of TN were excluded, as well as those who did not respond to other invasive procedures. e probability of experiencing no pain and requiring no drugs (BNI I) was 94.2%, 98.3%, 98.8%, 98.4%, and 98.9% at discharge; 83.8%, 90.1%, 91.4%, 94.3%, and 94.4% at 1 year after the procedure; and 66.7%, 80.5%, 88.2%, 84.3%, and 87.9% at 3 years after the procedure. ese data suggest that the pain relief rates at discharge were similar at temperatures from 62°C to 75°C. With a prolonged follow-up time, the pain relief rate in the 62°C and 65°C groups decreased more significantly than that in the 68-75°C groups. However, up to 5 years after procedure, 59% and 64.3% of patients were pain-free in the 62°C and 65°C groups, confirming that 62-65°C in RFT is an efficacious temperature. Yang et al. have achieved a satisfactory pain reduction rate with RFT at 60°C; the proportion of patients whose pain reduction was >90% during 3-month-3.6-year follow-up period was as high as 80%, thus further supporting the efficacy and feasibility of low-temperature RFT [35]. In long-term followup, patients in the 75°C group appeared to have higher painfree rates than those in the 68°C and 70°C groups, but this difference was not statistically significant. Zhao et al. have also compared the effectiveness of RFT at 70°C and 75°C and have found no significant differences in the rates of excellent relief in the Kaplan-Meier actuarial curve [32].
In summary, no significant differences were observed in the rates of pain relief after RFT at ≥80°C and ≤75°C. e probability of excellent pain relief at temperatures of 60-65°C was inferior to that at 68-75°C, whereas the analgesic effects were similar at 70°C and 75°C in some studies. Hence, we recommend RFT at 68-75°C.
Anatomically, the V1 division of the TN is adjacent to the oculomotor nerve, trochlear nerve, and abducens nerve. When higher temperatures are used in RFT, the coagulum size due to the radiofrequency probe increases in both length and diameter [43], thus potentially damaging the nerves near TN and causing severe complications, such as ptosis, limited eye movement, diplopia, and corneal ulceration. erefore, the temperatures associated with V1 division should be selected with caution. Several studies have observed the specific temperature delivered to the V1 division. e incidence of decreased corneal reflex has been found to be 3.57%-17.5% at temperatures of 62-68°C [34,38]. However, there are no reports of the disappearance of corneal reflexes. When the V1 division combined with V2 or/and V3, a higher stepped temperature from 70°C to 85°C was delivered to the V2 or/and V3. Decreased corneal reflexes were observed in a greater proportion of individuals, at 15.69%-26.47% [20,34,38]. Moreover, ptosis, limited eye movement, diplopia, and corneal ulceration have been reported in the literature with temperatures of 70-90°C [9,21,23,44].
In summary, the incidence of adverse effects gradually increases with increasing RFT temperature. As the observation time increases, the degree of these adverse effects gradually lessens, but the recovery times vary with the temperature used for RFT. e incidence and severity of complications are lower at temperatures <70°C, and the recovery time is within 6 months. Severe facial numbness, permanent masticatory atonia, and corneal hypoesthesia are associated with using temperatures at ≥70°C, and some patients had not recovered by the end of the 5-year followup. Notably, irreversible and severe complications have low occurrence rates at temperatures ≤65°C for RFT. e probability of complications at 75°C is three-to eightfold greater than that at 70°C. ese data suggest that inappropriately increasing the temperature for RFT can damage not only the Ab and C unmyelinated nerve fibers but also the Aα and Aβ fibers in a nonselective manner, thereby inducing severe complications [31], such as abducens nerve injury, diplopia, and vision loss at 95°C [15], as well as diplopia, hearing loss, and ptosis at 85°C [9].

The Pain Relief Rate of RFT Combined with
PRF for the Temperature of TN e magnetic field generated by PRF plays a therapeutic role by modulating the release of immune inflammatory mediators or inhibiting C-fiber activation and synaptic transmission [45]. PRF is effective for the treatment of neuropathic pain. erefore, some researchers believe that PRF can produce good analgesic effects [20,32,36,39,40,[46][47][48][49]. However, the effectiveness of PRF for the treatment of TN remains controversial. e painlessness rate of the treatment is 0%-85.7% for 6 months and 0%-78.6% for 2 years. Luo et al. have explored the causes of the poor effects of PRF and have found that a higher output voltage and electrical field intensity result in better outcomes [50]. Chua et al. have suggested that shortening the pulsed width to 10 ms, enhancing the frequency to 4 Hz, and prolonging the treatment duration to 6 min can improve the long-term analgesic effect, at least to some extent [51].
RFT combined with PRF is a relatively new method for the treatment of TN, especially for the V1 branch. is procedure (RFT at 62-75°C combined with PRF at 42°C) can increase long-term efficacy (85%-92% effective rate for 1 year and 70%-92% for 2 years), while simultaneously minimizing the incidence of adverse effects [32,36,39], although there are some opposing opinions [20]. Nonetheless, large-scale clinical trials are needed to evaluate the effectiveness of RFT combined with PRF for the treatment of TN.

Improving the Effectiveness and Feasibility of RFT
Increasing the temperature is not the only effective way to improve the efficacy of RFT treatment. Regulating the distance between the tip of the needle and the target nerves is crucial. e target location should be in the junction between the third division and the trigeminal ganglion, which can effectively improve the postoperative effects [15]. In addition, three-dimensional computed tomography (CT) or neuronavigator-guided control can be used to improve the accuracy of the puncture by monitoring the direction and angle of the needle in real time [52,53]. is technology simplifies the puncture process and avoids severe intraoperative or postoperative side effects, such as damage to the Biochemistry Research International  optic nerve, auditory nerve, internal carotid artery, and cavernous sinus. It is especially important to select the parameters of RFT. For example, at <0.1 V, an abnormal sensation or muscle contraction is induced in the areas controlled by the target nerves, suggesting that the needle tip is located in the nerve sheath. When RFT is performed, Aα and Aβ fibers are destroyed nonselectively, rather than just the Ab and C unmyelinated nerve fibers. erefore, we recommended refraining from using high temperatures for RFT. If the above signs appear at 0.1-0.3 V, the needle tip should be directed to the nerve root, and the temperature should be controlled to ≤70°C. At >0.3 V, we suggest that the needle tip be at a certain distance from the nerve and be located near the ganglion. Consequently, only the small nerves (i.e., the Ab and C unmyelinated nerve fibers) will be heated, and the location of the needle tip should be adjusted to enhance efficiency [9,37].

Conclusion
In summary, RF treatment is a safe, effective, and minimally invasive procedure of TN. An optimal temperature should be selected according to the branches of the trigeminal nerves involved in the RFT procedure. If V1 is involved, in order to decrease the risk of corneal reflex weakness or disappearing, a temperature of ≤65°C is recommended. If V2 and/or V3 are involved, 65-70°C temperatures are more suitable to effectively control pain and decrease the probability of adverse reactions. Too high temperature (≥80°C) should be avoided because it could seriously damage the tissue and is associated with irreversible complications. In order to improve the accuracy of the puncture and decrease the complications of injuring crucial blood vessels and nerves caused by repeated punctures, it is better to use threedimensional CT or neuronavigator as guidance. Although the value of PRF for the treatment of TN remains controversial, RFTat ≤75°C combined with PRF is a feasible option, and further clinical trials are required to evaluate efficacy.

Conflicts of Interest
e authors declare no conflicts of interest regarding the publication of this paper.