Temporal disconnection between pain relief and trigeminal nerve microstructural changes after Gamma Knife radiosurgery for trigeminal neuralgia

Peter Shih-Ping Hung Division of Brain, Imaging & Behaviour–Systems Neuroscience, Krembil Research Institute, and
Institute of Medical Science and

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Sarasa Tohyama Division of Brain, Imaging & Behaviour–Systems Neuroscience, Krembil Research Institute, and
Institute of Medical Science and

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Jia Y. Zhang Division of Brain, Imaging & Behaviour–Systems Neuroscience, Krembil Research Institute, and

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Mojgan Hodaie Division of Brain, Imaging & Behaviour–Systems Neuroscience, Krembil Research Institute, and
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Department of Surgery, Faculty of Medicine, University of Toronto, Ontario, Canada
Division of Neurosurgery, Krembil Neuroscience Centre, Toronto Western Hospital, University Health Network; and

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OBJECTIVE

Gamma Knife radiosurgery (GKRS) is a noninvasive surgical treatment option for patients with medically refractive classic trigeminal neuralgia (TN). The long-term microstructural consequences of radiosurgery and their association with pain relief remain unclear. To better understand this topic, the authors used diffusion tensor imaging (DTI) to characterize the effects of GKRS on trigeminal nerve microstructure over multiple posttreatment time points.

METHODS

Ninety-two sets of 3-T anatomical and diffusion-weighted MR images from 55 patients with TN treated by GKRS were divided within 6-, 12-, and 24-month posttreatment time points into responder and nonresponder subgroups (≥ 75% and < 75% reduction in posttreatment pain intensity, respectively). Within each subgroup, posttreatment pain intensity was then assessed against pretreatment levels and followed by DTI metric analyses, contrasting treated and contralateral control nerves to identify specific biomarkers of successful pain relief.

RESULTS

GKRS resulted in successful pain relief that was accompanied by asynchronous reductions in fractional anisotropy (FA), which maximized 24 months after treatment. While GKRS responders demonstrated significantly reduced FA within the radiosurgery target 12 and 24 months posttreatment (p < 0.05 and p < 0.01, respectively), nonresponders had statistically indistinguishable DTI metrics between nerve types at each time point.

CONCLUSIONS

Ultimately, this study serves as the first step toward an improved understanding of the long-term microstructural effect of radiosurgery on TN. Given that FA reductions remained specific to responders and were absent in nonresponders up to 24 months posttreatment, FA changes have the potential of serving as temporally consistent biomarkers of optimal pain relief following radiosurgical treatment for classic TN.

ABBREVIATIONS

CBZ = carbamazepine; DTI = diffusion tensor imaging; FA = fractional anisotropy; GKRS = Gamma Knife radiosurgery; NRS = numerical rating scale; TN = trigeminal neuralgia.

OBJECTIVE

Gamma Knife radiosurgery (GKRS) is a noninvasive surgical treatment option for patients with medically refractive classic trigeminal neuralgia (TN). The long-term microstructural consequences of radiosurgery and their association with pain relief remain unclear. To better understand this topic, the authors used diffusion tensor imaging (DTI) to characterize the effects of GKRS on trigeminal nerve microstructure over multiple posttreatment time points.

METHODS

Ninety-two sets of 3-T anatomical and diffusion-weighted MR images from 55 patients with TN treated by GKRS were divided within 6-, 12-, and 24-month posttreatment time points into responder and nonresponder subgroups (≥ 75% and < 75% reduction in posttreatment pain intensity, respectively). Within each subgroup, posttreatment pain intensity was then assessed against pretreatment levels and followed by DTI metric analyses, contrasting treated and contralateral control nerves to identify specific biomarkers of successful pain relief.

RESULTS

GKRS resulted in successful pain relief that was accompanied by asynchronous reductions in fractional anisotropy (FA), which maximized 24 months after treatment. While GKRS responders demonstrated significantly reduced FA within the radiosurgery target 12 and 24 months posttreatment (p < 0.05 and p < 0.01, respectively), nonresponders had statistically indistinguishable DTI metrics between nerve types at each time point.

CONCLUSIONS

Ultimately, this study serves as the first step toward an improved understanding of the long-term microstructural effect of radiosurgery on TN. Given that FA reductions remained specific to responders and were absent in nonresponders up to 24 months posttreatment, FA changes have the potential of serving as temporally consistent biomarkers of optimal pain relief following radiosurgical treatment for classic TN.

In Brief

The researchers used brain white matter imaging to examine the long-term consequence of Gamma radiation for the treatment of facial pain. Long-term changes in trigeminal nerve white matter may serve as specific biomarkers of successful Gamma radiation treatment for facial pain.

Classic trigeminal neuralgia (TN) is a severe, chronic, neuropathic pain disorder characterized by intermittent lancinating episodes of unilateral facial pain.13 Successful surgical options for this debilitating disorder include Gamma Knife radiosurgery (GKRS), which delivers gamma radiation to the affected trigeminal nerve to result in long-lasting, successful pain relief.10,15,23,24 Diffusion tensor imaging (DTI) is an MRI technique capable of characterizing trigeminal nerve microstructure1,16 and a growing body of work indicates its ability to inform microstructural changes in the CNS and peripheral nervous system that correlate with and prognosticate clinical response to surgical treatments for TN, including GKRS.9,17,29 Moreover, machine-learning models based on trigeminal nerve microstructural diffusivities appear to be able to accurately separate patients with chronic facial pain due to TN from healthy individuals34 and predict long-term pain relief on an individual level following surgical interventions for TN.17

While it has been suggested that GKRS results in pain relief by altering symptomatic trigeminal nerve microstructure,19,33 human evidence for this remains limited. DTI can demonstrate acute focal-nerve white-matter disorganization in radiosurgically treated patients with TN;14 however, the long-term effects of radiosurgery on the trigeminal nerve and how it affects different diffusivities has not been previously studied. This is important, because it can inform us of the effects of radiation on nonneoplastic white matter such as the nerve and provide consequent mechanistic insights into how radiosurgery affects chronic facial pain.

Our retrospective study aims to use DTI to illustrate the effect of radiation on trigeminal nerve microstructure at multiple time points after radiosurgery treatment and identify microstructural biomarkers that separate treatment responders from nonresponders. We hypothesize that DTI will reveal a dynamic pattern of DTI metric (diffusivity) alterations that characterize treated from contralateral control nerves. Furthermore, we expect to find specific posttreatment diffusivity alterations in treated nerves that are consistently associated with successful TN pain relief.

Methods

Patient Population

This study was approved by the University Health Network (Toronto) research ethics board. MR images and medical records from 55 patients with unilateral, classic TN following International Headache Society diagnostic guidelines13 were retrospectively studied. Informed patient consent is not required by our research ethics board for retrospective brain imaging studies. Briefly, these patients must exhibit attacks of unilateral facial pain that occur solely in one or more divisions of the trigeminal nerve with severe, recurrent, and electric shock–like attacks triggered by innocuous stimuli to the affected side of the face. All patients underwent GKRS as their first surgical intervention for TN. This facilitated detailed retrospective analysis of trigeminal nerve microstructure associated with successful posttreatment pain relief and lack thereof at multiple time points. Patients who underwent prior surgical procedures such as microvascular decompression and trigeminal rhizotomies for facial pain, and patients with TN secondary to skull base tumors, vertebrobasilar dolichoectasia, and multiple sclerosis, were excluded. GKRS was performed using either Elekta 4C or Elekta Perfexion systems (Elekta) with 4-mm collimators. The symptomatic trigeminal nerve in each patient was irradiated with 80 Gy of radiation to the 100% isodose line. Brainstem radiation was restricted to 15 Gy/mm3 to minimize adverse effects.

MRI Acquisition

Ninety-two MRI sessions were completed by our cohort at various time points, ranging from 6- to 24-month posttreatment time points. All images were acquired on a 3-T GE Signa HDx scanner (General Electric) equipped with an 8-channel head coil and included both T1 fast-spoiled gradient echo anatomical and high-resolution 60-direction diffusion-weighted MRI scans. Anatomical MRI scan parameters were: voxel size 0.86 mm × 0.86 mm × 1.00 mm, matrix 256 × 256, TE 5.1 msec, TR 12.0 msec, field of view 22 cm, 146 slices, and flip angle 20°. Diffusion-weighted imaging parameters were: voxel size 0.94 mm × 0.94 mm × 3.00 mm, matrix 256 × 256, TE 86.4 msec, TR 12,000 msec, field of view 24 cm, 62 slices, flip angle 90°, 1 baseline, 60 noncollinear diffusion directions with 1000 s/mm2 gradient, spin-echo echo planar imaging sequence, 1 excitation, and array spatial sensitivity encoding technique.

Image Registration, Region of Interest Definition, and Diffusivity Extractions

Advanced Normalization Tools2 (stnava.github.io/ANTs) was used to linearly rigid transform subject-specific GKRS-planning MR images to anatomical T1-weighted MR and diffusion-weighted MR images for each imaging session. This facilitated consequent transformations of the GKRS treatment target from subject-specific planning space to session-specific diffusion space. In each subject, 2 × 2 voxel axial-planar regions of interest were then placed at the center of the GKRS target zone and root entry zone along the symptomatic, treated trigeminal nerve. The isodoses received by these regions were approximately 80% and 20%, respectively. Spatially equivalent 2 × 2 axial-planar regions were also defined along the contralateral nerve as within-subject controls. Diffusion tensor images were then estimated from diffusion-weighted MR images using the FSL25 software package (http://fsl.fmrib.ox.ac.uk/fsl/fslwiki) to facilitate bilateral extraction of region-specific axial diffusivity, radial diffusivity, mean diffusivity, and fractional anisotropy (FA), which provided microstructural insights into axonal integrity, degree of myelination, neuro-edema, and white matter organization, respectively.1

Study Groups and Statistical Analyses

MRI sessions and associated pain intensities were divided into multiple time-point groups at 6, 12, and 24 months posttreatment. Based on percentage change on an 11-point numerical rating scale (NRS) of TN pain intensity compared to pretreatment levels, individuals at each time point were then separated into treatment responder and nonresponder subgroups, with responders achieving 75% or greater reduction in posttreatment pain intensity as per prior work.9 This led to responder subgroups of 28, 11, and 14 imaging sessions, alongside nonresponder subgroups of 21, 11, and 7 imaging sessions, respectively. Posttreatment pain levels in each subgroup were then compared against pretreatment levels using Wilcoxon signed-rank tests. Subsequently, regional diffusivities were contrasted between treated and contralateral side trigeminal nerves within each posttreatment subgroup using Wilcoxon signed-rank tests. All statistical analyses were implemented in Python with statistical significance set at p < 0.05 after false discovery rate correction for multiple comparisons.3

Results

Patient Demographics

Our patient cohort comprised 55 patients with classic TN (36 women and 19 men) treated with GKRS as their first surgical intervention for chronic facial pain. TN-induced chronic neuropathic facial pain was unilateral in all cases (localized to the left in 24 patients and right in 31 patients). Mean (± SD) patient age at the time of GKRS treatment for TN was 65.1 ± 13.2 years. Detailed patient demographics with pain medication used are provided in Table 1.

TABLE 1.

Classic TN patient demographics

IDPain LateralitySexTx Age (yrs)Pain DistributionMedications
RS01LtF39V2/3PGB, OXC, BCF
RS02LtF42V2/3HMO
RS03LtF49V1/2/3PGB
RS04LtF54V3GBP
RS05LtF62V2/3CBZ
RS06LtF63V2/3None
RS07LtF65V3GBP, OXC, LMT
RS08LtF67V3CBZ, GBP
RS09LtF70V2/3PGB
RS10LtF71V2/3None
RS11LtF76V3CBZ, PGB
RS12LtF77V3CBZ
RS13LtF80V2/3GBP
RS14LtF87V1/2GBP
RS15LtM32V1/2CBZ, BCF
RS16LtM38V1/2PGB
RS17LtM43V2CBZ
RS18LtM64V2/3PGB
RS19LtM64V3CBZ
RS20LtM66V3CBZ
RS21LtM66V1/2/3CBZ
RS22LtM66V3CBZ, PGB, OXC
RS23LtM71V2/3CBZ
RS24LtM79V2/3CBZ, ASA
RS25RtF44V3PGB, HMO
RS26RtF47V1/2/3CBZ, PGB
RS27RtF52V1/2CBZ
RS28RtF56V1/2/3CBZ
RS29RtF60V2/3GBP
RS30RtF61V1/2/3None
RS31RtF61V2/3CBZ, PGB
RS32RtF63V3PGB
RS33RtF65V2CBZ, GBP
RS34RtF68V2/3CBZ, GBP
RS35RtF69V1/2CBZ
RS36RtF70V2CBZ
RS37RtF71V1CBZ
RS38RtF71V2/3PGB
RS39RtF74V2/3CBZ, GBP
RS40RtF75V3GBP
RS41RtF76V2/3CBZ
RS42RtF77V1/2/3GBP
RS43RtF79V3CBZ
RS44RtF80V3PGB
RS45RtF81V2/3CBZ
RS46RtF82V2/3CBZ, GBP
RS47RtM41V2/3CBZ, PGB
RS48RtM59V3CBZ
RS49RtM60V1/2CBZ
RS50RtM64V3BCF
RS51RtM71V2/3CBZ, GBP
RS52RtM73V1/2CBZ
RS53RtM76V2/3CBZ, GBP
RS54RtM82V1/2CBZ, PGB
RS55RtM84V1/2/3CBZ

ASA = aspirin, BCF = baclofen, GBP = gabapentin, HMO = hydromorphone, LMT = lamotrigine, OXC = oxcarbazepine, PGB = pregabalin, Tx = treatment, V1 = ophthalmic branch of the trigeminal nerve, V2 = maxillary branch of the trigeminal nerve, V3 = mandibular branch of the trigeminal nerve.

GKRS and Relief of TN Pain

TN pain intensity was assessed based on an NRS of pain (from 0 to 10, with 10 = the worst pain imaginable). On average, before radiosurgery, responders reported 9.0 ± 1.7 intensity while nonresponders reported 9.3 ± 1.2 intensity. After radiosurgery, numerical rating of facial pain intensity was greatly reduced at all posttreatment time points compared to pretreatment levels for responders, with 97.2%, 97.7%, and 98.4% reduction from baseline pain intensity observed at 6-, 12-, and 24-month posttreatment time points, respectively (p < 0.001, p = 0.002, and p < 0.001; Fig. 1A–C). Conversely, facial pain intensity was only slightly decreased for nonresponders with 50.0%, 31.1%, and 28.8% reduction from baseline pain intensity observed at 6-, 12-, and 24-month posttreatment time points, respectively (p < 0.001, p = 0.005, and p = 0.06; Fig. 1D–F).

FIG. 1.
FIG. 1.

Temporal profiles of TN pain intensities after GKRS. Responders to GKRS had significantly reduced numerical rating of pain intensity (NRS) at all posttreatment time points compared to pretreatment levels (A–C, Wilcoxon signed-rank tests). Nonresponders to GKRS had significantly reduced NRS at 6- and 12-month time points (D and E). Pain intensity for nonresponders to GKRS at the 24-month posttreatment time point was statistically indistinguishable from pretreatment levels (F). Black whiskers indicate standard errors of the mean, gray dots indicate individual pain intensity ratings. Blue lines depict individual posttreatment decreases in NRS. ** p < 0.01, *** p < 0.001 (false discovery rate corrected). Figure is available in color online only.

Successful Pain Relief and Delayed Reductions in FA

Comparisons of treated and contralateral control nerves in treatment responders (Fig. 2)—who had 75% or greater reduction in pain intensity posttreatment compared to pretreatment levels—at each time point demonstrated significant reduction in FA at the treatment target 12 and 24 months after GKRS (p = 0.023, p = 0.017; Fig. 2E and I). The peak radiation effect on FA was noted at 24 months posttreatment with a 32.3% reduction from contralateral control, in contrast to 9.9% and 29.7% reductions observed at the 6- and 12-month posttreatment time points.

FIG. 2.
FIG. 2.

Posttreatment patterns of target microstructural diffusivities in responders. Microstructural diffusivities were contrasted between treatment target and contralateral controls within 6- (A–D), 12- (E–H), and 24-month posttreatment (I–L) time points. Successful TN pain relief was associated with significantly reduced treatment target FA at 12- (E) and 24-month (I) posttreatment time points compared to contralateral, untreated trigeminal nerve controls (Wilcoxon signed-rank tests). Black whiskers indicate 1.5 interquartile range, gray dots are individual diffusivity measurements. Blue lines depict individual decreases in diffusivity measurements in the treatment target compared to contralateral control. Red lines depict individual increases in diffusivity measurements in the treatment target compared to contralateral control. * p < 0.05 (false discovery rate corrected). 1e-3 = 1 × 10−3. Figure is available in color online only.

Conversely, axial, radial, and mean diffusivities remained statistically similar for treatment responders at the target compared with contralateral controls across all posttreatment time points. Furthermore, nonresponders did not exhibit statistically significant alterations in microstructural diffusivity metrics between treated and contralateral control nerves (Fig. 3). Given this finding, reductions in FA appeared to be solely present in responders and uniquely associated with pain relief after GKRS.

FIG. 3.
FIG. 3.

Posttreatment patterns of target microstructural diffusivities in nonresponders. Microstructural diffusivities were contrasted between treatment target and contralateral controls within 6- (A–D), 12- (E–H), and 24-month posttreatment (I–L) time points. Bilateral diffusivities remained statistically indistinguishable between treated and contralateral control nerves across all posttreatment time points (Wilcoxon signed-rank tests). Black whiskers indicate 1.5 interquartile range, gray dots are individual diffusivity measurements. Blue lines depict individual decreases in diffusivity measurements in the treatment target compared to contralateral control. Red lines depict individual increases in diffusivity measurements in the treatment target compared to contralateral control. Figure is available in color online only.

Radiosurgery-Induced Focal Diffusivity Changes

While bilateral diffusivities were similarly assessed at the root entry zone within each time point, diffusivities within the treated root entry zone remained statistically indistinguishable from contralateral controls for both responders and nonresponders. Consequently, GKRS appeared to exert a focal posttreatment effect on trigeminal nerve microstructure that is isolated to the treatment target.

Discussion

In this study, we used retrospective DTI to identify a dynamic pattern of diffusivity changes consistently associated with pain relief following GKRS for TN, drawing upon growing evidence demonstrating that DTI metrics are sensitive to focal changes in trigeminal nerve microstructure.9,14,17 Our results demonstrated that a microstructural pattern involving reduced treatment target FA is specifically associated with successful posttreatment pain relief. Furthermore, an important temporal disconnect exists between this microstructural pattern and successful clinical expression of pain relief. While significant pain relief was initially observed 6 months after treatment, significant target FA reduction occurred much later at 12- and 24-month posttreatment time points. Ultimately, this pattern extends our current understanding of the long-term effects of ionizing radiation on nonneoplastic peripheral white matter and may help delineate optimal treatment response to radiosurgery for TN pain.

GKRS and Long-Term Changes in Trigeminal Nerve Microstructure

Single-time-point studies have highlighted a variety of microstructural changes within treated trigeminal nerves compared to contralateral controls.9,14,17 More specifically, at 6 months posttreatment, nerves treated with GKRS demonstrated possible changes in myelination, suggested by increased radial diffusivity within the radiation treatment target.5,14 Similar acute effects of radiosurgery have also been shown through electron microscopy and histological studies on nonhuman primates, which demonstrated focal axonal damage, demyelination, and general white matter disorganization within the treatment target.19,33 Nevertheless, microstructural changes across a longer time span in the human trigeminal nerve following GKRS and their temporal relationships to pain relief have not been adequately documented.

Our study fills this gap by revealing a novel long-term consequence of GKRS on peripheral white matter. In addition to short-term radiation effects, in patients who exhibited successful posttreatment pain relief (responders), but not nonresponders, we demonstrated delayed and consistent reduction in target FA 12 and 24 months posttreatment (Fig. 3). As FA has been biologically linked with white matter myelination,6,27 a novel link appeared to exist over time between altered myelination that peaked at 24 months posttreatment and successful pain relief after GKRS (Fig. 4). Because the observed link between FA reduction and successful pain relief occurred within a critical period from 12 to 24 months posttreatment, additional studies are needed to determine if this relationship remains salient beyond 24 months and whether there are reversals of FA reductions with recurrences of pain.

FIG. 4.
FIG. 4.

A biomarker of successful pain relief after GKRS. Microstructural diffusivity analyses revealed that delayed reductions in FA may uniquely indicate treatment success as it coincides with successful pain relief (defined as 75% or greater reduction in pain intensity after radiosurgery) at 12- and 24-month posttreatment time points. Furthermore, given that FA is a measure of myelination, this suggests that a unique association exists between altered myelination and successful pain relief. Figure is available in color online only.

Disconnection Between Radiosurgery-Induced Diffusivity Changes and Onset of Pain Relief

Our study indicates a disconnected temporal relationship or “temporal disconnect” between diffusivity alterations and the clinical onset of pain relief. Because the earliest MR time point after GKRS in our study is at 6 months, it is difficult to capture immediate, acute trigeminal nerve diffusivity changes after treatment. However, the fact that FA reduction peaks at 24 months suggests that while diffusivity changes are associated with long-term pain relief after surgical treatment for TN,9,17 the magnitude of specific posttreatment diffusivity change cannot be directly correlated to the amount of pain relief. As we have shown, maximal FA reduction is clearly not required for maximal or optimal pain relief. Nevertheless, the present study provides an avenue for the investigation of long-term effects of radiation on peripheral nerves. To what degree microstructural diffusivity changes may be required to achieve initial effective pain relief after GKRS will necessitate additional analyses of early and very early posttreatment time points.

Radiosurgery and Focal Microstructural Alterations Within Treated Nerves

We found that GKRS-induced FA reductions remain limited to the target even after prolonged, 24-month-long assessment. Given the paucity of tools that allow the study of the effect of radiation on the nerve, the availability of a noninvasive, in-vivo imaging technique that can detect dynamic changes in the nerve after radiation holds promise for a better understanding of the effect of radiation on pain. This is particularly important because FA changes suggest a significant effect of radiation on nerve myelination, which may, in turn, affect nociception. Our microstructural findings agree with prior literature using trigeminal nerve phantoms4 and further affirm that GKRS on humans has a successful in-vivo spatial specificity. As the transition zone between central and peripheral myelin is, on average, 1.13 mm away from the root entry zone,12,22 GKRS appears to impact peripheral as opposed to central neural microstructure.

Microstructural Insight Into GKRS’s Mechanism of Pain Relief

Nociceptive fibers within the trigeminal nerve, consisting of Aδ and c fibers, are known to be poorly myelinated,8 and therefore presumably more susceptible to radiation injury.19,31,32 Mechanistically speaking, given our observation of FA reductions in the treatment target, it is thus possible that GKRS exerts pain relief by disrupting the neural microstructure/myelination in these poorly insulated peripheral nociceptors, preventing them from efficiently transmitting signals toward higher-order pain neurons. Sensory discriminative fibers, on the other hand, have a higher degree of myelination and are consequently less impacted by radiation, potentially explaining why facial numbness is infrequently encountered after radiosurgery for TN. Taking these findings together, it is thus possible that GKRS selectively dampens peripheral nociceptive input to consequently reduce TN-related chronic neuropathic facial pain.

Similar Effect of Radiation on Peripheral and Central White Matter Microstructure

The effect of radiation on functional neurosurgical conditions such as TN and tremor is difficult to study based on the limited information available from traditional MRI and the fact that the dose is delivered not to a volume but to a point in a Cartesian coordinate space. While imaging findings such as T2 MR halos/enhancements after treatment have been reported,11,21 these changes are not specific to particular types of structural or microstructural neuronal alterations, nor do they represent clinical correlates of pain relief.20 DTI adds a significant benefit to traditional imaging protocols by capturing microstructural alterations, which can then be correlated to axonal integrity, degree of myelination, underlying inflammation, and overall white matter integrity.6,7,14,26,27

The long-term effect of radiation on nonneoplastic peripheral white matter, such as the trigeminal nerve, appears to parallel similar processes noted in GKRS of thalamic nuclei and central white matter, where radiation-induced macrostructural and microstructural changes are often seen with much longer temporal delay from the initial treatment time point.11,18,21,28,30,35 Prior studies looking into the effects of radiation on central white matter have documented maximal axial diffusivity, radial diffusivity, and FA changes between 9 and 18 months postradiation.18,35 Taken together with our current findings, this suggests that ionizing radiation results in delayed maximal microstructural changes detectable by DTI in both peripheral and central white matter.

Clinical Implications of Delayed FA Changes in GKRS-Treated Patients

Given that more than 30% of TN patients treated with GKRS reported the recurrence of their pain by 24 months posttreatment,10 biomarkers such as FA may serve as an adjunct indicator (in addition to clinical judgment) to help support clinicians in identifying patients who may require additional/alternative treatments for TN pain. The timeline of FA changes appears to parallel the timeline of DTI changes previously observed after GKRS radiation delivery to central white matter, thus it is possible that FA may serve as a DTI-based indicator of microstructural response to radiation for white matter pathways in general. This suggests that FA may have clinical applications well beyond simply the study of TN.

Study Limitations

As TN is a severe chronic facial neuropathic pain disorder, our patients were taking various neuropathic pain medications, such as carbamazepine (CBZ). To the best of our knowledge, there have not been reports of these drugs severely altering peripheral nerve microstructure. Nevertheless, we cannot rule out the possibility of pain medications having an involvement in the longitudinal diffusivity findings reported here.

Conclusions

We characterized the long-term microstructural consequences of GKRS on symptomatic trigeminal nerves in patients with classic TN. We discovered that delayed reductions in FA are specifically linked to successful pain relief; therefore, DTI may be important for long-term assessment of optimal treatment response to GKRS and should be aptly incorporated into the routine posttreatment imaging protocol for classic TN.

Acknowledgments

We would like to thank Erika Wharton-Shukster for maintaining the functional neurosurgery database. This study is supported by Canadian Institutes of Health Research Operating Grant (no. MOP130555) awarded to Dr. Hodaie and Canadian Institutes for Health Research Frederick Banting and Charles Best Doctoral Research Award (no. GSD157876) awarded to Mr. Hung.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Hodaie, Hung. Acquisition of data: Hung, Tohyama, Zhang. Analysis and interpretation of data: Hung. Drafting the article: Hung. Critically revising the article: all authors. Reviewed submitted version of manuscript: Hodaie, Hung. Approved the final version of the manuscript on behalf of all authors: Hodaie. Statistical analysis: Hung. Administrative/technical/material support: Zhang. Study supervision: Hodaie.

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    Hung PSP, Chen DQ, Davis KD, Zhong J, Hodaie M: Predicting pain relief: use of pre-surgical trigeminal nerve diffusion metrics in trigeminal neuralgia. Neuroimage Clin 15:710718, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Karunamuni RA, White NS, McDonald CR, Connor M, Pettersson N, Seibert TM, et al.: Multi-component diffusion characterization of radiation-induced white matter damage. Med Phys 44:17471754, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Kondziolka D, Lacomis D, Niranjan A, Mori Y, Maesawa S, Fellows W, et al.: Histological effects of trigeminal nerve radiosurgery in a primate model: implications for trigeminal neuralgia radiosurgery. Neurosurgery 46:971977, 2000

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Massager N, Abeloos L, Devriendt D, Op de Beeck M, Levivier M: Clinical evaluation of targeting accuracy of Gamma Knife radiosurgery in trigeminal neuralgia. Int J Radiat Oncol Biol Phys 69:15141520, 2007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Ohye C, Higuchi Y, Shibazaki T, Hashimoto T, Koyama T, Hirai T, et al.: Gamma knife thalamotomy for Parkinson disease and essential tremor: a prospective multicenter study. Neurosurgery 70:526536, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Peker S, Kurtkaya O, Uzün I, Pamir MN: Microanatomy of the central myelin-peripheral myelin transition zone of the trigeminal nerve. Neurosurgery 59:354359, 2006

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Riesenburger RI, Hwang SW, Schirmer CM, Zerris V, Wu JK, Mahn K, et al.: Outcomes following single-treatment Gamma Knife surgery for trigeminal neuralgia with a minimum 3-year follow-up. J Neurosurg 112:766771, 2010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Rogers CL, Shetter AG, Fiedler JA, Smith KA, Han PP, Speiser BL: Gamma Knife radiosurgery for trigeminal neuralgia: the initial experience of the Barrow Neurological Institute. Int J Radiat Oncol Biol Phys 47:10131019, 2000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TEJ, Johansen-Berg H, et al.: Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 23 (Suppl 1):S208S219, 2004

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Song SK, Sun SW, Ju WK, Lin SJ, Cross AH, Neufeld AH: Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia. Neuroimage 20:17141722, 2003

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Song SK, Sun SW, Ramsbottom MJ, Chang C, Russell J, Cross AH: Dysmyelination revealed through MRI as increased radial (but unchanged axial) diffusion of water. Neuroimage 17:14291436, 2002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Steen RG, Spence D, Wu S, Xiong X, Kun LE, Merchant TE: Effect of therapeutic ionizing radiation on the human brain. Ann Neurol 50:787795, 2001

  • 29

    Tohyama S, Shih-Ping Hung P, Zhong J, Hodaie M: Early postsurgical diffusivity metrics for prognostication of long-term pain relief after Gamma Knife radiosurgery for trigeminal neuralgia. J Neurosurg [epub ahead of print August 1, 2018. DOI: 10.3171/2018.3.JNS172936]

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Wang S, Wu EX, Qiu D, Leung LHT, Lau HF, Khong PL: Longitudinal diffusion tensor magnetic resonance imaging study of radiation-induced white matter damage in a rat model. Cancer Res 69:11901198, 2009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Wesselmann U, Lin SF, Rymer WZ: Selective decrease of small sensory neurons in lumbar dorsal root ganglia labeled with horseradish peroxidase after ND:YAG laser irradiation of the tibial nerve in the rat. Exp Neurol 111:251262, 1991

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Yagasaki Y, Hayashi M, Tamura N, Kawakami Y: Gamma knife irradiation of injured sciatic nerve induces histological and behavioral improvement in the rat neuropathic pain model. PLoS One 8:e61010, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Zhao ZF, Yang LZ, Jiang CL, Zheng YR, Zhang JW: Gamma Knife irradiation-induced histopathological changes in the trigeminal nerves of rhesus monkeys. J Neurosurg 113:3944, 2010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Zhong J, Chen DQ, Hung PSP, Hayes DJ, Liang KE, Davis KD, et al.: Multivariate pattern classification of brain white matter connectivity predicts classic trigeminal neuralgia. Pain 159:20762087, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Zhu T, Chapman CH, Tsien C, Kim M, Spratt DE, Lawrence TS, et al.: Effect of the maximum dose on white matter fiber bundles using longitudinal diffusion tensor imaging. Int J Radiat Oncol Biol Phys 96:696705, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Collapse
  • Expand

Illustration from Bernstock et al. (pp 655–663). Copyright Joshua D. Bernstock, NIH/NINDS. Published with permission.

  • FIG. 1.

    Temporal profiles of TN pain intensities after GKRS. Responders to GKRS had significantly reduced numerical rating of pain intensity (NRS) at all posttreatment time points compared to pretreatment levels (A–C, Wilcoxon signed-rank tests). Nonresponders to GKRS had significantly reduced NRS at 6- and 12-month time points (D and E). Pain intensity for nonresponders to GKRS at the 24-month posttreatment time point was statistically indistinguishable from pretreatment levels (F). Black whiskers indicate standard errors of the mean, gray dots indicate individual pain intensity ratings. Blue lines depict individual posttreatment decreases in NRS. ** p < 0.01, *** p < 0.001 (false discovery rate corrected). Figure is available in color online only.

  • FIG. 2.

    Posttreatment patterns of target microstructural diffusivities in responders. Microstructural diffusivities were contrasted between treatment target and contralateral controls within 6- (A–D), 12- (E–H), and 24-month posttreatment (I–L) time points. Successful TN pain relief was associated with significantly reduced treatment target FA at 12- (E) and 24-month (I) posttreatment time points compared to contralateral, untreated trigeminal nerve controls (Wilcoxon signed-rank tests). Black whiskers indicate 1.5 interquartile range, gray dots are individual diffusivity measurements. Blue lines depict individual decreases in diffusivity measurements in the treatment target compared to contralateral control. Red lines depict individual increases in diffusivity measurements in the treatment target compared to contralateral control. * p < 0.05 (false discovery rate corrected). 1e-3 = 1 × 10−3. Figure is available in color online only.

  • FIG. 3.

    Posttreatment patterns of target microstructural diffusivities in nonresponders. Microstructural diffusivities were contrasted between treatment target and contralateral controls within 6- (A–D), 12- (E–H), and 24-month posttreatment (I–L) time points. Bilateral diffusivities remained statistically indistinguishable between treated and contralateral control nerves across all posttreatment time points (Wilcoxon signed-rank tests). Black whiskers indicate 1.5 interquartile range, gray dots are individual diffusivity measurements. Blue lines depict individual decreases in diffusivity measurements in the treatment target compared to contralateral control. Red lines depict individual increases in diffusivity measurements in the treatment target compared to contralateral control. Figure is available in color online only.

  • FIG. 4.

    A biomarker of successful pain relief after GKRS. Microstructural diffusivity analyses revealed that delayed reductions in FA may uniquely indicate treatment success as it coincides with successful pain relief (defined as 75% or greater reduction in pain intensity after radiosurgery) at 12- and 24-month posttreatment time points. Furthermore, given that FA is a measure of myelination, this suggests that a unique association exists between altered myelination and successful pain relief. Figure is available in color online only.

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    Hung PSP, Chen DQ, Davis KD, Zhong J, Hodaie M: Predicting pain relief: use of pre-surgical trigeminal nerve diffusion metrics in trigeminal neuralgia. Neuroimage Clin 15:710718, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Karunamuni RA, White NS, McDonald CR, Connor M, Pettersson N, Seibert TM, et al.: Multi-component diffusion characterization of radiation-induced white matter damage. Med Phys 44:17471754, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Kondziolka D, Lacomis D, Niranjan A, Mori Y, Maesawa S, Fellows W, et al.: Histological effects of trigeminal nerve radiosurgery in a primate model: implications for trigeminal neuralgia radiosurgery. Neurosurgery 46:971977, 2000

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Massager N, Abeloos L, Devriendt D, Op de Beeck M, Levivier M: Clinical evaluation of targeting accuracy of Gamma Knife radiosurgery in trigeminal neuralgia. Int J Radiat Oncol Biol Phys 69:15141520, 2007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Ohye C, Higuchi Y, Shibazaki T, Hashimoto T, Koyama T, Hirai T, et al.: Gamma knife thalamotomy for Parkinson disease and essential tremor: a prospective multicenter study. Neurosurgery 70:526536, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Peker S, Kurtkaya O, Uzün I, Pamir MN: Microanatomy of the central myelin-peripheral myelin transition zone of the trigeminal nerve. Neurosurgery 59:354359, 2006

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Riesenburger RI, Hwang SW, Schirmer CM, Zerris V, Wu JK, Mahn K, et al.: Outcomes following single-treatment Gamma Knife surgery for trigeminal neuralgia with a minimum 3-year follow-up. J Neurosurg 112:766771, 2010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Rogers CL, Shetter AG, Fiedler JA, Smith KA, Han PP, Speiser BL: Gamma Knife radiosurgery for trigeminal neuralgia: the initial experience of the Barrow Neurological Institute. Int J Radiat Oncol Biol Phys 47:10131019, 2000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TEJ, Johansen-Berg H, et al.: Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 23 (Suppl 1):S208S219, 2004

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Song SK, Sun SW, Ju WK, Lin SJ, Cross AH, Neufeld AH: Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia. Neuroimage 20:17141722, 2003

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Song SK, Sun SW, Ramsbottom MJ, Chang C, Russell J, Cross AH: Dysmyelination revealed through MRI as increased radial (but unchanged axial) diffusion of water. Neuroimage 17:14291436, 2002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Steen RG, Spence D, Wu S, Xiong X, Kun LE, Merchant TE: Effect of therapeutic ionizing radiation on the human brain. Ann Neurol 50:787795, 2001

  • 29

    Tohyama S, Shih-Ping Hung P, Zhong J, Hodaie M: Early postsurgical diffusivity metrics for prognostication of long-term pain relief after Gamma Knife radiosurgery for trigeminal neuralgia. J Neurosurg [epub ahead of print August 1, 2018. DOI: 10.3171/2018.3.JNS172936]

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Wang S, Wu EX, Qiu D, Leung LHT, Lau HF, Khong PL: Longitudinal diffusion tensor magnetic resonance imaging study of radiation-induced white matter damage in a rat model. Cancer Res 69:11901198, 2009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Wesselmann U, Lin SF, Rymer WZ: Selective decrease of small sensory neurons in lumbar dorsal root ganglia labeled with horseradish peroxidase after ND:YAG laser irradiation of the tibial nerve in the rat. Exp Neurol 111:251262, 1991

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Yagasaki Y, Hayashi M, Tamura N, Kawakami Y: Gamma knife irradiation of injured sciatic nerve induces histological and behavioral improvement in the rat neuropathic pain model. PLoS One 8:e61010, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Zhao ZF, Yang LZ, Jiang CL, Zheng YR, Zhang JW: Gamma Knife irradiation-induced histopathological changes in the trigeminal nerves of rhesus monkeys. J Neurosurg 113:3944, 2010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Zhong J, Chen DQ, Hung PSP, Hayes DJ, Liang KE, Davis KD, et al.: Multivariate pattern classification of brain white matter connectivity predicts classic trigeminal neuralgia. Pain 159:20762087, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Zhu T, Chapman CH, Tsien C, Kim M, Spratt DE, Lawrence TS, et al.: Effect of the maximum dose on white matter fiber bundles using longitudinal diffusion tensor imaging. Int J Radiat Oncol Biol Phys 96:696705, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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