Radiosurgery for the management of refractory trigeminal neuralgia
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.185393
Source of Support: None, Conflict of Interest: None
Gamma Knife stereotactic radiosurgery (SRS) is a minimally invasive surgical approach for managing medically refractory trigeminal neuralgia (TN). The goal of trigeminal neuralgia SRS is to eliminate or reduce the facial pain in order to improve the quality of life. Over the past 28 years, 1250 patients have undergone gamma knife SRS for TN at our institution. In our retrospective review of 503 patients who underwent SRS for management of refractory TN, 449 patients (89%) experienced initial pain relief at a median latency of 1 month. At the one year mark, 73% patients were pain free (with or without medications) and 80% had pain control. Repeat radiosurgery was performed for 193 patients (43%). At the one year mark, 26% of these patients were completely pain free and 78% were pain free with or without medications. The role of gamma Knife SRS in the management of medically refractory trigeminal neuralgia has evolved over the past two decades. SRS is a minimally invasive procedure and is associated with 60-90% rate of pain relief in patents with medical refractory trigeminal neuralgia. Early intervention with SRS as the initial surgical procedure for management of refractory trigeminal neuralgia is associated with faster, better, and longer pain relief. As SRS is the least invasive procedure for TN, it is a good treatment option for patients with other high-risk medical conditions. SRS is an attractive alternative especially to those who do not want to accept the greater risk associated with other surgical procedures.
Keywords: Gamma knife; outcome; pain-relief; radiosurgery; refractory; trigeminal neuralgia
Trigeminal neuralgia (TN) is a pain syndrome characterized by severe intermittent stabbing or electric shock like unilateral facial pain. The mechanism of pain production remains controversial. One theory suggests that peripheral injury or disease of the trigeminal nerve increases afferent firing in the nerve perhaps by ephaptic transmission between the afferent unmyelinated axons and partially damaged myelinated axons. Compression of the trigeminal root by blood vessels (especially branches of the superior cerebellar arteries or venous channels) is the commonest cause. A magnetic resonance imaging (MRI) scan with and without contrast is essential to rule out the presence of a tumor, arteriovenous malformation, or multiple sclerosis, all of which can cause trigeminal neuralgia in a small number of patients. In addition, basal skull conditions including maxillary sinusitis may mimic symptoms of TN. In some patients, the neuralgic pain is idiopathic in origin.
Surgical management is often required for medically refractory trigeminal neuralgia. Although microvascular decompression (MVD) treats the suspected etiology of trigeminal neuralgia, it is not an appropriate option for poor surgical candidates. Stereotactic Radiosurgery (SRS) is the least invasive surgical procedure which has proven to be safe and effective in the management of trigeminal neuralgia.
The goal of trigeminal neuralgia radiosurgery is to eliminate or reduce the attacks of severe facial pain in order to improve the quality of life. Numerous reports have documented the efficacy and safety of gamma knife stereotactic radiosurgery (GKRS) for TN.,,,,,,,,,,,,,,,,,,,,, Trigeminal neuralgia radiosurgery is a good treatment option for patients with co-morbidities, high-risk medical illnesses, or pain refractory to prior surgical procedures. Radiosurgery is an attractive alternative especially in those patients who do not want to accept the additional risks associated with other surgical procedures.
The ideal patients for trigeminal neuralgia radiosurgery include those with typical trigeminal neuralgia who have had an adequate trial of medical management, and have developed intolerance or ineffectiveness to medical management; patients who have failed other surgical procedures; patients with medical co-morbidities; patients at risk for side effects from percutaneous ablative or vascular decompression procedures; patients in more advanced age groups; and, patients who are unwilling to accept the risk of craniotomy and vascular decompression. Radiosurgery is not offered in an acute setting because it takes 2-4 weeks for patients to experience pain relief.
The procedure starts with the application of a Leksell Model G stereotactic frame (Elekta Instruments) under conscious sedation and local anesthesia. Patients then undergo stereotactic magnetic resonance (MR) imaging to identify the trigeminal nerve. MRI is performed using contrast-enhanced, short repetition time sequences, and axial phase volume acquisitions of 256 × 256 matrices divided into 1-mm slices. In addition, we also obtain three dimensional (3D) T2 images. Computed tomography (CT) scans can be used in patients who are ineligible for MR imaging. In rare cases, if metallic artefacts in the region of trigeminal nerve on a computed tomographic (CT) scan are expected (due to old ferromagnetic clips, etc.), a CT cisternogram can be performed. For CT cisternography, the intrathecal contrast is injected via a lumbar puncture prior to the performance of the CT scan.
The radiosurgery team consists of a neurosurgeon, radiation oncologist, and medical physicist, who together perform dose selection and treatment planning. The nerve on the affected side is identified first. Typically, a single 4-mm beam diameter collimator is used for radiosurgery planning and delivery. With a single isocenter, the radiosurgery target is 3–8 mm anterior from the junction of the trigeminal nerve and the pons. After placing a single isocenter, the 50% and 20% isodose lines are projected. The isocenter is usually located on the trigeminal nerve so that 20% isodose line touches the brainstem surface. A median maximum target dose of 80 Gy (range, 70 – 85 Gy) is prescribed. The brainstem and nearby temporal lobe are also outlined to evaluate the radiation dose distribution within them [Figure 1].
At our institution, we prefer a trigeminal target which is not too anterior, but does not include the brain stem. This target location is associated with a reduced risk of trigeminal dysfunction (due to exclusion of the brain stem). This segment of the nerve can be seen well in the cisterns as it enters the brain stem and all the three divisions (V1, V2 and V3) are located within the nerve. The posterior segment of the nerve possesses central myelin, which is more radiosensitive compared to Schwann cell myelin seen more distally in the nerve.
Over the past 28 years, 1250 patients have undergone gamma knife radiosurgery for trigeminal neuralgia at our institution. We reviewed prospectively collected data on 503 patients who underwent trigeminal neuralgia radiosurgery for management of refractory trigeminal neuralgia. A single 4-mm isocenter was used in 498 patients (99%) and two 4-mm isocenters were used in 5 patients (1%). A median maximum dose of 80 Gy (range 60-90Gy) was administered. Four hundred and forty-nine patients (89%) responded to GKS after the procedure at a median latency of 1 month. Major pain relief (Barrow Neurological Institute [BNI] scores I-IIIa) was achieved in 73% patients at 1 year, 65% at 2 years, and 41% at 5 years. Eighty-nine percent of patients achieved initial pain relief with or without medications (BNI Scores I-IIIb). A BNI score of I-IIIb was reported by 80% patients at 1 year, 71% at 3 years, 46% at 5 years, and 30% at 10 years. A faster initial pain response (including those patients with adequate and some pain relief) was noted in TN patients who had no additional symptoms, in those who had no prior surgery, and in those whose symptom duration was 3 years or less. One hundred and ninety three (43%) of 450 patients who achieved initial pain relief, reported some recurrence at a median of 50 months after the initial relief. Factors associated with earlier pain recurrence that failed to maintain adequate or some pain relief were trigeminal neuralgia with additional symptoms, and 3 or more prior failed surgical procedures. Fifty-three patients (10.5%) developed new numbness in the trigeminal nerve distribution and one developed deafferentation pain. Sensory loss resolved in 17 patients. Patients who developed sensory loss had better long-term pain control (78% at 5 years).
In a recent study of 121 patients, we evaluated factors associated with better outcomes after stereotactic radiosurgery (SRS) when it was performed as the first surgical procedure for medically refractory trigeminal neuralgia. BNI score I-IIIa pain relief was achieved in 107 (88%) patients at a median time of one month. Patients who underwent earlier SRS (within 3 years of pain onset) had a shorter interval until pain relief, had a longer interval of pain relief off medication (BNI-I) and a longer duration of adequate pain control (BNI I-IIIa). Median pain free intervals for patients who underwent SRS at 1, 2, 3 and more than 3 years after the diagnosis of trigeminal neuralgia had been made were 68, 37, 36 and 10 months, respectively. Fifteen patients (12%) reported new sensory dysfunction after SRS. In this study, we found that early SRS (within 3 years of pain onset) as the initial surgical procedure for management of refractory trigeminal neuralgia was associated with faster, better, and longer pain relief when compared to late SRS.
For patients with recurrent pain after an initial good response, a second GK procedure can be performed. For a second radiosurgical procedure, the target is usually placed anterior to the first target for an overlap of the two radiosurgical volumes by approximately 50%. The median maximum target dose for the second radiosurgery is 70 Gy (range, 40 – 80 Gy). One hundred and ninety-three (43%) patients underwent repeat radiosurgery at our institution. One-year complete (BNI grade I), significant (BNI grade I-IIIa), and adequate (BNI grade I-IIIb) pain relief rates were 26%, 78%, and 81%, respectively. The median interval to achieve significant pain relief (BNI grade I-IIIa) was 45 days and adequate pain relief (BNI grade I to IIIb) was 30 days. Patients with fewer than 3 previous surgical procedures had a better chance of complete or adequate pain relief. The probability of maintaining adequate pain relief (BNI grade I-IIIb) was 80% at 1 year, 74% at 2 years, 66% at 3 years, and 55% at 5 years. Eighteen patients (9.3%) developed increased trigeminal sensory loss or paresthesia during the first 2 years after radiosurgery. The 1-, 3-, and 5-year rates for maintenance of adequate pain relief (BNI grade I-IIIb) in patients who observed new sensory dysfunction were 94%, 86%, and 86%, respectively, whereas the 1-, 3-, and 5-year rates for maintenance of adequate pain relief in patients without new sensory loss were 78%, 64%, and 51%, respectively.
It is very rare for a patient to undergo a third radiosurgery procedure. In selected cases of elderly patients with recurrent pain, a third gamma knife procedure can be performed. The target for the third radiosurgical procedure is typically distal to the first and second targets but their overlap varies and depends on the total pons-to- Gasserian ganglion More Details distance in each patient. This process ensures less radiation to the brainstem at each subsequent radiosurgical procedure, while providing additional dose along the trigeminal nerve more proximal to the Gasserian ganglion. We recently reviewed the results of a third radiosurgery procedure performed on 17 patients who were drawn from four different centers across North America. Eight patients (47.1%) reported an initial complete pain relief (BNI Score I) following their third GKRS; and, 8 others (47.1%) experienced at least partial relief (BNI scores II-IIIb). No patient sustained additional sensory disturbances after the third procedure. At a mean follow-up of 22.9 months after the third GKRS, 6 patients (35.3%) reported continued BNI I complete pain relief, while 7 others (41.2%) reported pain improvement (BNI Scores II-IIIb). Four patients (23.5%) suffered recurrent pain following the third procedure at a mean interval of 19.1 months. In patients unsuitable for other microsurgical or percutaneous strategies, especially those receiving long-term oral anticoagulation or antiplatelet agents, GKRS repeated for a third time was a satisfactory, low risk option.
Factors affecting pain relief after radiosurgery
Till date, the largest reported series are still characterized by a wide spectrum of success rates after radiosurgery, with BNI Grade I outcome in 21% to 76.8% of the patients, and Grade II in 65% to 88% of them.,,,,,,, Better radiosurgical outcomes have been associated with several factors which include: Typical pain features, absence of multiple sclerosis, no previous surgery, greater radiation dose, and proximity of the isocenters to the brainstem edge., In a population of 54 patients, Rogers et al., found a higher rate of BNI Grade I outcome in patients with idiopathic typical TN in comparison with those with atypical features (49% as opposed to 9%). In a study of 179 patients, Brisman et al., noted that 41% of their patients achieved a Grade I outcome and 17%, a Grade II outcome. Better results were reported by patients with no history of previous surgery (60%). Young et al., and Maesawa et al., reported similar results and noted that the presence of atypical pain was the most important factor yielding a poor response to radiosurgery (84.4 versus 43.8%)., Several authors have reported similar results using linear accelerator based radiosurgery for trigeminal neuralgia.
Several recent reports suggest that post-GKRS sensory loss is the dominant factor that predicts improved and a long-term pain relief. Previous studies had also highlighted the positive association of pain relief with post radiosurgery numbness both for the first radiosurgical procedure., and after a second application of GKRS for recurrent TN., Pollock et al., reported that patients treated with the higher dose (90Gy) experienced a higher rate of post-GKRS trigeminal nerve dysfunction. These patients also had an improved rate of pain relief. Similarly, Aubuchon et al., found that the most significant factor predicting pain relief after a second GKRS procedure was the development of post-procedural numbness.
Role of target selection in pain relief
Despite the widespread use of GKRS for TN, there is no consensus on target selection. Some centers prefer a more posterior target closer to the root entry zone while others advocate a more anterior target closer to the Gasserian ganglion. Kondziolka et al., used the posterior target (proximal trigeminal nerve and root entry zone as an anatomical target) for GKRS. Kondziolka et al., reported that 58% of patients had an excellent control and 94% reported pain relief, when targeting the dorsal root entry zone (DREZ). In a study by Sheehan et al., 34% patients were pain free and 70% had pain relief with the DREZ target. Brisman et al., studied the dose volume histogram analysis on the nerve and brainstem and suggested that the target of radiation effect was in close proximity to the brainstem. In this series, patients who received a dose of at least 15 Gy to nearby brain stem volume experienced improved pain relief [Figure 1]. Marshall et al., analyzed the effects of target location on pain relief. These authors noted that improved pain relief occured when the SRS isocenter was placed closer to the brainstem. Their analysis disclosed a statistically significant difference between the dose delivered to the DREZ in patients who benefited from GKRS compared with those who did not benefit. The DREZ has been described in the literature as a potential target of radiation effect after GKRS because of the change in radiosensitivity at this location based on the transition from Schwann cells distally to oligodendrocytes centrally.
In a study by Mastuda et al., 50 patients received 80 Gy at the proximal trigeminal nerve, including the DREZ (posterior group), and 49 were treated using the anterior target. Their analysis of initial pain control showed that patients with the posterior target were more likely to have an excellent result. The total complication rate, as well as the bothersome complication rate, were significantly higher in the anterior target group.
Regis et al., in a series of studies targeted the retrogasserian zone (RGZ), which is just posterior to the Gasserian ganglion, and documented the efficacy and safety of the RGZ target., These investigators reported an 87% pain free rate in their series of 57 patients treated with a maximum dose of 75 to 90 Gy., In most patients, they used the higher maximum dose of 90 Gy, and their target was placed at a more anterior site (closer to the Gasserian ganglion). Massager et al., performed GKRS using a far-anterior cisternal target and a higher dose. In their study, excellent pain control (excellent or good pain relief) was achieved in 68% of patients, while pain relief was satisfactory in 83%. These authors noted a lower rate of complications using the RGZ target. Massager et al., recommended targeting the nerve at a distance of 5 to 8 mm from the brainstem for an optimal balance between better pain control using a higher dose and the limitation of adverse effects such as trigeminal dysfunction.
Park et al., retrospectively analyzed 39 patients who had GKRS for TN to determine the role of anterior versus posterior target in pain relief. Radiosurgery was performed using the DREZ target in 23 patients and the RGZ target in 16 patients. Fifteen (93.8%) RGZ and 20 (87.0%) DREZ cases achieved a BNI I-IIIb pain score. However, this difference was not statistically significant (P = 0.631). The time to a response after the GKRS was significantly shorter in the RGZ group (mean 4.1 weeks) than in the DREZ group [mean 6.4 weeks] (P = 0.044). The complication rate (about 25.0%) was similar for both the groups. The frequency of bothersome facial numbness and dry eye syndrome was lower in the RGZ group (8.7% compared to 13.1% with the DREZ target), however, it was not significant. (P = 0.255 and 0.503). The trend towards a better outcome in the RGZ group could be due to a higher prescription dose (85.6 Gy vs. 82.6 Gy) compared to the DREG group. In any case, the argument over target selection has little merit, since the pons-to-Gasserian ganglion nerve length varies considerably.
The role of radiosurgery in the management of trigeminal neuralgia has evolved over the past two decades. It has become an important minimally invasive strategy for patients with medically refractory trigeminal neuralgia. The current recommended central dose of 80 Gy is associated with 60-90% rate of pain relief in patents with medical refractory trigeminal neuralgia. Early SRS as the initial surgical procedure for management of refractory trigeminal neuralgia is associated with faster, better, and longer pain relief when compared to late SRS. Radiosurgery can be repeated for recurrent trigeminal neuralgia.
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Conflicts of interest
Dr. Lunsford is a consultant and stockholder with AB Elekta.