Non-isocentric Radiosurgical Rhizotomy for Trigeminal Neuralgia

Non-isocentric Radiosurgical Rhizotomy for Trigeminal Neuralgia

John R. Adler, Jr, Regina Bower, Guarav Gupta, Michael Lim, Allen Efron, Iris C.

Gibbs, Steve D. Chang and Scott G. Soltys

Corresponding author:

John R. Adler, Jr, MD

Department of Neurosurgery

Stanford University Medical Center

300 Pasteur Drive

Stanford, CA 94305

PH: 650 723-5573

FAX: 650 725-1784

EMAIL: [email protected]

Running Title: CyberKnife Rhizotomy for Trigeminal Neuralgia

Keywords: Trigeminal Neuraglia, Radiosurgery, Rhizotomy, Non-isocentric,

CyberKnife

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Abstract

Objective: Although stereotactic radiosurgery is an established procedure for

treating trigeminal neuralgia (TN), the likelihood of a prompt and durable

complete response is not optimal. Moreover, the incidence of facial numbness

remains a challenge. To address these limitations, a new more anatomic

radiosurgical procedure was developed that utilizes the CyberKnife to lesion an

elongated segment of the retrogasserian cisternal portion of the trigeminal

sensory root. Because the initial experience with this approach resulted in an

unacceptably high incidence of facial numbness, a gradual dose and volume de-

escalation was performed over several years. In this single-institution

prospective study, we evaluated clinical outcomes in a group of trigeminal

neuralgia patients who were lesioned with seemingly optimized non-isocentric

radiosurgical parameters.

Methods: Forty-six patients with intractable idiopathic TN were treated between

January 2005 and June 2007. Eligible patients were either poor surgical

candidates or had failed prior microvascular decompression (MVD) or destructive

procedures. During a single radiosurgical session a 6-mm segment of the

affected nerve was treated with a mean marginal prescription dose of 58.3 Gy

and mean maximal dose (Dmax) of 73.5 Gy. Monthly neurosurgical follow-up

was performed until the patient became pain-free. Longer term follow-up was

done both in the clinic and over the phone. Outcomes were graded as excellent

(pain-free and off medication), good (>90% improvement while still on

medication), fair (50-90% improvement) or poor (no change or worse). Facial

numbness was assessed using the Barrow Neurological Institute (BNI) Facial

Numbness score.

Results: Symptoms disappeared completely in 39 (85%) patients after a mean

latency of 5.2 weeks. In most of these patients pain relief began within the first

2

week. TN recurred in a single patient after a pain-free interval of 7 months; all

symptoms abated after a second radiosurgical procedure. Three additional

patients underwent a repeat rhizotomy after failing to respond adequately to the

first operation. After a mean follow-up of 12.4 months, patient-reported

outcomes were excellent in 33 (72%), good in 11 (24%) and poor/no

improvement in 2 (4%) cases. Significant ipsilateral facial numbness (BNI III)

was reported in ten (22%) cases.

Conclusions: Optimized non-isocentric CyberKnife parameters for TN treatment

resulted in high rates of pain relief and a more acceptable incidence of facial

numbness than reported previously. Longer follow-up will be required to

establish whether the durability of symptom relief after lesioning an elongated

segment of the trigeminal root is superior to isocentric radiosurgical rhizotomy.

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Introduction

The treatment of trigeminal neuralgia (TN) by radiosurgical rhizotomy was

conceived by Lars Leksell (9). Over the past several decades radiosurgical

parameters for treating this condition have been optimized, especially for the

Gamma Knife. By investigating a range of maximal doses (Dmax from 60 to 90

Gy)(2, 8, 16) and a variety of lesion locations along the retrogasserian trigeminal

root (from the root entry zone to just proximal to the semilunar ganglion)(3, 5, 8,

12, 15, 16, 21) neurosurgeons are now able to maximize the likelihood of pain

relief while minimizing the risk of facial dysesthesias or numbness. Recent

outcome studies report that complete long-term pain relief can be achieved in

66% to 84% of patients undergoing radiosurgical rhizotomy alone, while varying

degrees of facial numbness are observed in 10% to 54% of cases (13, 14, 16,

18). As a general rule, better pain relief appears to correlate with higher rates of

sensory loss (16, 19, 20).

Given the straightforward objective of radiosurgical rhizotomy in patients with TN,

it is unclear why outcomes vary so much between patients. The long latency to

pain relief and its poor durability in some patients are lingering shortcomings of

the procedure. In contrast, immediate, long-lasting symptom relief is routinely

achieved in similar patients who undergo less expensive percutaneous

radiofrequency (RF) rhizotomy (22). Perhaps with these limitations in mind,

some neurosurgeons have sought to improve the outcome after radiosurgery by

increasing the length of the irradiated nerve (1, 6, 11). However, this concept

was discredited in a small randomized study by Flickinger and colleagues (6). In

a multi-institutional study that utilized the Gamma Knife, two adjacent 4-mm

shots served to lengthen the segment of lesioned trigeminal nerve. Because of a

trend towards increased “complications” in the experimental group (albeit not

statistically significant), the study was stopped short of complete patient accrual;

the investigators concluded “Increasing the treatment volume to include a longer

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nerve length for trigeminal neuralgia radiosurgery does not significantly improve

pain relief but may increase complications”. Although Flickinger et al. did not

provide much qualitative detail, facial numbness and dysesthesias were central

to the early termination of this study. The outcomes of this study are surprising

because they violate the direct relation between target dose, target volume, and

clinical response that underlies much of radiosurgery. One would have

anticipated that any increase in facial numbness would have been accompanied

by an improved rate and durability of pain relief. It seems possible that chance

may have contributed to the paradoxical findings observed in the small Flickinger

et al series.

With the goal of enhancing the clinical response to radiosurgery, the first author

began in 2002 to lesion a longer segment of the trigeminal sensory root using a

relatively homogeneous radiation dose. Because of the CyberKnife’s capacity

for non-isocentric irradiation, it is a straightforward process to conformally lesion

an elongated non-spherical target with greater dose uniformity, as opposed to

instruments that treat only iso-centrically. In the initial report detailing the results

of 41 patients treated in this manner, 92.7% of patients experienced initial pain

relief after only a median of 7 days post radiosurgery; pain relief was maintained

in 78% of patients at 11 months. However, facial numbness developed in 73% of

patients (11). To address this shortcoming, dose and volume were gradually de-

escalated. Since January 2005, appropriately selected TN patients at Stanford

have been managed with a relatively consistent radiosurgical lesion. In this

study we analyze the outcomes in this cohort of patients and compare it to

published radiosurgery series.

Materials and Methods

Patients

Patient data was reviewed under an IRB-approved protocol. All cases had

idiopathic TN of several years duration; pain symptoms were either refractory to

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standard anti-convulsants or the patient suffered from severe drug-induced side

effects. Cases involving either multiple sclerosis or tumors were excluded from

this analysis as was any patient with atypical facial pain. A total of 46

consecutive TN patients who met these criteria were lesioned at Stanford

University Medical Center by CyberKnife rhizotomy between January 2005 and

June of 2007 (see Table 1). In this group were 17 males and 29 females with a

median age of 78 years (range 40-94 years). The average time from the earliest

onset of TN symptoms to stereotactic radiosurgery was 8.6 years (range 8

months to 20 years). Eleven patients (24%) had failed prior surgical procedures

(averaging 1.8 procedures per patient) directed towards their trigeminal

symptoms, which included microvascular decompression (MVD) (14 cases) and

rhizotomy by means of an open (3), glycerol (5) or gamma knife (3) technique.

Eleven patients (24%) reported either a moderate or significant degree of facial

numbness prior to CyberKnife rhizotomy, which unfortunately was not

prospectively scored on the BNI scale.

TABLE 1: Patient Characteristics (N=46)

Male/Female 17/29

Age (median, range) 78 years, (40-94 years)

Time from TN onset to radiosurgery (mean, range) 8.6 years (8-20 years)

Right side/Left side 29/17

Prior surgical procedures (24% of patients total)

Microvascular decompression 14 cases

Open rhizotomy 3 cases

Glycerol rhizotomy 5 cases

Gamma Knife 3 cases

Pre-CyberKnife facial numbness 11 patients (26%)

Radiosurgical Procedure

Radiosurgical trigeminal rhizotomy was performed with the CyberKnife

Radiosurgical System (Accuray Inc., Sunnyvale, CA) utilizing the technique

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reported previously (11). Both the 400 monitor units (MU)/min CyberKnife G3

and 600 MU/min CyberKnife G4 models were used over the course of this study.

To summarize, a customized Aquaplast mask (Medtech, Des Moines, Iowa) was

fashioned for each patient. While immobilized in the mask, the entire head was

imaged with thin section (1.25 mm slice thickness) contrast computerized

tomography (CT); the first 15 cases in this series underwent a lumbar intrathecal

injection of iodinated contrast (8 cc of Iohexal) prior to CT. Patients were then

imaged with a fast imaging employing steady-state acquisition (FIESTA)

sequence magnetic resonance (MR) imaging using 3D volumetric acquisition and

1 mm slice thickness. These CT and MR techniques reliably demonstrated the

trigeminal nerve in negative relief as it transited the pre-pontine cistern (4).

Midway through the current series we documented the reliability and spatial

fidelity of radiosurgical targeting performed only with T2-weighted MR scanning.

(4) Once confident in the accuracy of MRI-based targeting, the use of CT

cisternography for this purpose was largely abandoned.

On the CyberKnife treatment planning workstation, the MRI and CT scans were

fused. Standard segmentation tools were used to delineate on the fused data

sets a 6-mm length of the retrogasserian trigeminal sensory root as defined in the

reconstructed sagittal plane of the nerve. This target volume deliberately spared

the proximal 2 to 3 mm of trigeminal dorsal root at the brainstem. Dose to the

brainstem and semilunar ganglia was restricted to the maximal extent possible.

The earlier patients in the current investigation were treated with the 65 cm

source to axis distance (SAD) “trigeminal node set” which provides a nominal

collimator diameter at isocenter of 6 mm. After the higher-output CyberKnife G4

model was installed at Stanford, patients were treated using a 5-mm collimator

and an 80 cm SAD. A mean marginal prescription dose of 58.3 Gy (range 56-62

Gy) and Dmax of 73.5 Gy (range 71.4-86.2 Gy) were used over the course of this

series. The average prescription isodose line was 79%. Figure 1 depicts a

representative radiosurgical plan for trigeminal neuralgia. Note the relatively

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homogeneous dose within the target volume that is achievable with a non-

isocentric technique.

Radiosurgery was performed as an outpatient procedure. Treatment sessions

lasted approximately one hour. At the end of the procedure patients were given 4

mg of dexamethasone.

Follow-up

Patients were followed at one-month intervals until they were pain-free, at which

point anticonvulsants were tapered. Subsequent follow-up occurred at monthly

intervals to insure a stable clinical status. Any relapse of pain or the

development of facial numbness was clinically re-evaluated in person. At each

point of contact, patients were grouped into one of four categories; 1) excellent

(pain-free and off medication), good (>90% improvement while still on

medication), fair (50-90% improvement) or poor (no change or worsening pain).

The presence and timing of facial numbness was also recorded and classified by

BNI Facial Numbness Score (see Table 2) (19). Five patients (11%) underwent

repeat CyberKnife rhizotomy more than 6 months after the initial procedure; in

four of these cases there was inadequate clinical response to the first

radiosurgical procedure while in one patient there was a relapse in TN symptoms

seven months after the initial operation. Longer term follow-up was done by mail

and telephone. Follow-up data was maintained in a prospective database

approved by the Stanford IRB.

Results

Thirty-nine patients (85%) in this study had complete disappearance of their

trigeminal neuralgia and were off medications at some point over the course of

follow-up. At a mean follow-up of 12.4 months (range 6-29 months), 34

(72%) patients graded their pain relief as excellent and 11 (24%)

described it as good. Consequently, 96% of patients obtained

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meaningful relief of TN symptoms after CyberKnife rhizotomy. Within

this group were 5 patients who at 6 months continued to have severe

TN and were retreated; the eventual outcome for these five salvage

cases was generally excellent (2) or good (2). However, one of the 5

retreated patients had a poor outcome. Although across the entire series

an improvement in symptoms was typically experienced within a few days or

weeks of radiosurgery, the full benefits were obtained after a mean latency of 5.2

weeks (ranging from immediately to 6 months after the procedure).

Trigeminal neuralgia recurred in only a single patient, 7 months post

radiosurgery; repeat CyberKnife radiosurgical rhizotomy subsequently rendered

this patient pain-free. At last follow-up, 11 patients (24%) reported a significant

improvement (3 cases) or even complete abatement (8 cases) in TN symptoms

but required, or elected to continue, anticonvulsants for controlling their pain;

three patients refused to give up their medication due only to concern that their

pain might return. Meanwhile, after rhizotomy TN symptoms were deemed to be

worse in only one case.

Among the 41 patients who had only a single radiosurgical rhizotomy,

significant new ipsilateral facial numbness was reported in 7 cases (17%).

New onset sensory loss typically involved the hemicranium and occurred on

average 7 months after the procedure. Interestingly, only one of five patients

who underwent repeat radiosurgery (after a prior Gamma Knife or

CyberKnife rhizotomy) developed significant subsequent facial

numbness. At the time of most recent follow-up, facial sensation and

dyesthesia were categorized in all patients according to BNI score as

follows: BNI I: 28, BNI II: 11 and BNI III: 7 (Table 2). It is important to

note that eleven patients had some measure of numbness prior to

CyberKnife rhizotomy and at last follow-up there were no cases of

anaesthesia dolorosa.

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Table 2 – Barrow Neurological Institute Facial Numbness Score and outcomes

Grade Description No. Patients (Total=46)

I No facial numbness 28

II Mild facial numbness, not bothersome 11

III Facial numbness, somewhat bothersome 7

IV Facial numbness, very bothersome 0

Twenty-eight patients (61%) reported the optimal result of being pain-

free and off anti-convulsants, while retaining pretreatment facial

sensation. Six additional patients were pain-free but elected to either

remain on reduced doses of anti-convulsants or were unable to taper

off such drugs completely without experiencing some recurrent

symptoms. Consequently, CyberKnife rhizotomy resulted in 74% of all

cases experiencing good to excellent pain relief without significant

facial numbness; if one includes 9 additional patients who developed

significant facial numbness, then 96% of all patients experienced complete or

near complete relief of trigeminal neuralgia. It is especially noteworthy that

among the 31 TN patients who had never undergone any prior surgical

procedure, 100% had either a good or excellent response to

CyberKnife rhizotomy.

Discussion

The benefits of radiosurgical rhizotomy for TN using the standard isocentric

technique are, for many patients, insufficient. Because of the latency of pain

relief, overall rate of response, and recurrence of TN symptoms, radiosurgical

rhizotomy has limited appeal in the eyes of some neurosurgeons. In an attempt

to address the shortcomings of the standard isocentric technique, our group has

sought to refine over several years a procedure that utilizes non-isocentric

radiosurgery to lesion an elongated segment of the retrogasserian portion of the

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trigeminal sensory root. Over time treatment parameters have been optimized to

enhance the pain response and reduce facial numbness. The primary objective

of the current prospective single-institution study was to characterize short-term

outcomes with this technique.

The overall response rate observed in the current CyberKnife series appears

satisfactory. In fact 100% of the patients that had not previously undergone a

surgical procedure reported their outcome as either good (13%) or excellent

(87%); one of these patients needed to be treated twice to achieve this outcome.

It is reasonable to propose that this high rate of response is attributable, at least

in part, to the longer length of trigeminal nerve lesioned with the CyberKnife.

Although the methods used to score the response of TN to trigeminal rhizotomy

are relatively consistent among most clinical series, patient inclusion criteria,

length of follow-up and measures of facial numbness and/or dysesthesia vary

widely. Consequently it is difficult to directly compare those outcomes with the

current study, and as a result, it cannot be determined at present whether or not

irradiating a longer nerve segment is clinically beneficial. Nevertheless, crude

comparisons with published radiosurgical rhizotomy series that have utilized

isocentric Gamma Knife (16, 18) and Linac-based (21) procedures, suggest that

the outcome with non-isocentric radiosurgical rhizotomy is at least competitive in

terms of overall rate of response. Ideally, the current experience could provide a

reasonable substrate for a randomized trial which compared the two procedures.

The rate of numbness observed in the present series appears to be greater than

first reported by several groups using an isocentric Gamma Knife technique (12,

17, 19). However, higher rates of facial numbness after Gamma Knife rhizotomy

have also been reported, especially with larger and more effective dosing

regimens (14, 16). Consequently, the overall incidence and characteristics of

sensory loss experienced by some of the patients in the current CyberKnife study

seem comparable to what has been reported previously with more conventional

isocentric procedures.

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While there are important technical differences, the relatively unremarkable

incidence of facial sensory changes we observed in the present series may

challenge one of the key findings reported in Flickinger et al. (6). This

randomized trial, which examined the utility of two adjacent 4-mm Gamma Knife

shots when lesioning the trigeminal nerve, needed to be terminated prematurely

when patients in the experimental arm developed severe dysesthesias. The

investigators concluded that a longer radiosurgical lesion merely increased the

likelihood of “complications” without altering the pain response. What remains

unclear is why Flickinger et al. did not encounter an increased rate of response

among patients treated with a longer lesion of the trigeminal sensory root. The

failure to find such a response would appear to run counter to the experience

described by our group (10, 23) and perhaps the reports of other Gamma Knife

series that found a direct correlation between integral dose to the trigeminal

nerve and the likelihood of pain relief (16). Moreover the Flickinger et al. findings

would seem to be at odds with the widely observed dose-volume-response

phenomenon seen throughout most of radiosurgery. Of note, the Flickinger et al.

study compared the standard one-isocenter treatment to a solitary experimental

group in which the longer rhizotomy consisted of 2 adjacent isocenters. By

comparison, our group required several years to slowly titrate a radiosurgical

dose and volume for lesioning the trigeminal nerve which is proving in our

experience to be more optimal in terms of pain relief and avoidance of facial

numbness. Perhaps a wider investigation of volumes and doses delivered with a

2-isocenter Gamma Knife technique might reveal a combination that improves

pain relief without further risk of unpleasant facial numbness. Only further study,

and most probably a randomized trial, can determine whether or not a longer

trigeminal rhizotomy ultimately has any clinical advantages.

One of the primary rationales for modifying the standard radiosurgical rhizotomy

technique was to increase the durability of pain relief. Because only one patient

(1/39) suffered relapse in their trigeminal neuralgia (7 months post SRS), the

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current experience is encouraging. Nevertheless, much longer follow-up will be

required to prove that lesioning a longer segment of nerve can significantly

increase the durability of the radiosurgical rhizotomy.

The incidence and intensity of delayed numbness observed in the current series

represents a substantial improvement over what was previously reported for

CyberKnife rhizotomy (11, 23), and, importantly, there were no instances of

anesthesia dolorosa. As a consequence, it appears that the dose-volume

parameters being used with the present non-isocentric technique make for a

better clinical outcome. Given the reported latency between radiosurgery and

the onset facial numbness, it is quite possible that with further follow-up

additional patients will develop sensory symptoms. However, because in the

present study the mean overall follow-up is 12.6 months, while the mean time to

occurrence of numbness of 7 months, it seems unlikely that loss of facial

sensation will occur in enough additional patients to alter this primary finding.

Ultimately, it seems clear that numbness is significantly less likely using the

optimized treatment parameters of the present study than it was during the

development stages of CyberKnife rhizotomy for TN.

It is worth pointing out that TN is somewhat unique among pain syndromes in

that pain is usually either present or absent. As a consequence the large

majority of patients with complete relief were easy to categorize as such. In

contrast the nature of symptoms and outcome among patients with only partial

pain relief was more complex and less conducive to the relatively simplistic

measuring tools used in this investigation. Moreover several of the patients in

this series had co-existing facial pain syndromes that were not trigeminal

neuralgia-like and were precipitated in part by previous failed ablative procedures

or microvascular decompression. Because some of these same patients also

eventually developed post-rhizotomy delayed facial numbness, it was often

difficult to distinguish new sensory symptoms from their pre-existing pain

condition. Therefore, one of the limitations of the current investigation is that

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unlike the recent Regis et al study there is not a more detailed analysis of our

patients' ultimate facial sensation. (18). Despite this shortcoming, the current

investigation should provide a useful starting point for future investigation.

The biologic mechanism underlying the cessation of TN symptoms after

radiosurgical rhizotomy remains poorly defined. Some investigators have

concluded that the likelihood of a clinical response to radiosurgery correlates with

the development of facial numbness (16, 19). This suggests that a common

mechanism underlies these two phenomena. However, their very different time

course implies distinct mechanisms underlie pain relief and facial numbness; TN

pain abates relatively rapidly after a radiosurgical rhizotomy, while facial

numbness is clearly a delayed event (6-9 months or more post-radiosurgery).

Meanwhile, both the latency of sensory changes and the appearance of

enhancement on contrast MR at the root entry zone (REZ), the later being

consistent with breakdown in the blood-brain barrier, strongly suggest that facial

numbness stems from injury to the microvasculature of the trigeminal nerve and

adjacent brainstem (7). If so, such a phenomenon raises some intriguing

possibilities for intervention. In particular, the use of an intravascular free radical

scavenger, like Ethyol, at the time of radiosurgery might provide relative

radioprotection to endothelium and limit the incidence of delayed microvascular

injury. Theoretically, such an agent would not alter the biologic mechanism

underlying the therapeutic benefits of radiosurgery. A randomized trial is being

planned to investigate such a possibility.

Conclusion

Compared to previous reports that describe the clinical outcome after non-

isocentric radiosurgical rhizotomy in patients with trigeminal neuralgia, the

present investigation demonstrates both high rates of pain relief and an

acceptable incidence of facial numbness. We are not able to determine whether

this technique can ultimately improve upon either the rate of response or

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durability of symptom relief that can be achieved with the standard isocentric

radiosurgical rhizotomy. Further study is warranted, and ideally a randomized

trial comparing isocentric and non-isocentric techniques.

Disclosure

John R. Adler is a shareholder and a member of the board of directors of

Accuray, Inc., the manufacturer of the CyberKnife Radiosurgical System. The

other authors have no personal financial interest in Accuray, Inc or the

CyberKnife System and have received no financial support in conjunction with

the generation of this article.

Acknowledgement

The authors would like to acknowledge the helpful suggestions and diligent edits

made by David Schaal PhD during the preparation of this manuscript.

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Figure 1

Legend

This screen shot taken from the CyberKnife treatment planning workstation, depicts a representative radiosurgical plan for trigeminal neuralgia. Note the relatively homogeneous dose within the target volume that is achievable with a non-isocentric technique.

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