Microstructural abnormalities in the trigeminal nerves of patients with ...

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Objective: To investigate microstructural tissue changes of trigeminal nerve (TGN) in patients with uni- lateral trigeminal neuralgia (TN) by multiple diffusion ...
European Journal of Radiology 82 (2013) 783–786

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European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad

Microstructural abnormalities in the trigeminal nerves of patients with trigeminal neuralgia revealed by multiple diffusion metrics Yaou Liu a,e,1 , Jiping Li b,1 , Helmut Butzkueven c , Yunyun Duan a , Mo Zhang a , Ni Shu d , Yongjie Li b , Yuqing Zhang b,∗∗ , Kuncheng Li a,∗ a

Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing 100053, PR China Department of Functional Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, PR China c Department of Medicine, University of Melbourne, Parkville 3010, Australia d State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing 100875, PR China e Beijing Key laboratory of MRI and Brain Informatics, Beijing, PR China b

a r t i c l e

i n f o

Article history: Received 13 August 2012 Received in revised form 24 October 2012 Accepted 20 November 2012 Keywords: Trigeminal neuralgia Diffusion tensor imaging Demyelination

a b s t r a c t Objective: To investigate microstructural tissue changes of trigeminal nerve (TGN) in patients with unilateral trigeminal neuralgia (TN) by multiple diffusion metrics, and correlate the diffusion indexes with the clinical variables. Methods: 16 patients with TN and 6 healthy controls (HC) were recruited into our study. All participants were imaged with a 3.0 T system with three-dimension time-of-flight (TOF) magnetic resonance angiography and fluid attenuated inversion recovery (FLAIR) DTI-sequence. We placed regions of interest over the root entry zone of the TGN and measured fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). The mean values of FA, MD, AD and RD were compared between the affected and unaffected sides in the same patient, and to HC values. The correlation between the side-to-side diffusion metric difference and clinical variables (disease duration and visual analogy scale, VAS) was further explored. Results: Compared with the unaffected side and HC, the affected side showed significantly decreased FA and increased RD; however, no significant changes of AD were found. A trend toward significantly increased MD was identified on the affected side comparing with the unaffected side. We also found the significant correlation between the FA reduction and VAS of pain (r = −0.55, p = 0.03). Conclusion: DTI can quantitatively assess the microstructural abnormalities of the affected TGN in patients with TN. Our results suggest demyelination without significant axonal injury is the essential pathological basis of the affected TGN by multiple diffusion metrics. The correlation between FA reduction and VAS suggests FA as a potential objective MRI biomarker to correlate with clinical severity. © 2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Trigeminal neuralgia (TN) is characterized by recurrent episodes of sudden, severe, electric shock-like, stabbing pain localized to the sensory supply areas of trigeminal nerve (TGN). Currently, it is thought to be caused by neurovascular compression of the TGN at its root entry zone (REZ), and microvascular decompression (MVD) is considered the most effective treatment [1–3]. However, the exact pathogenesis of TN is unclear since neurovascular contact can

∗ Corresponding author. Tel.: +86 13911099059; fax: +86 10 83198376. ∗∗ Corresponding author. Tel.: +86 10 8319114; fax: +86 10 83198114. E-mail addresses: [email protected] (Y. Zhang), [email protected] (K. Li). 1 Dr Yaou Liu and Dr Jiping Li wish to be regarded as joint first authors. 0720-048X/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejrad.2012.11.027

also be present in the form of an anatomic variant in healthy subjects or on the unaffected side in patients with TN. Microstructural damages of the TGN, such as axonal loss and demyelination, are regarded as the possible underlying pathogenesis of TN [4,5]. Diffusion-tensor imaging (DTI) quantifies the amount of nonrandom water diffusion within tissues and provides unique in vivo information about the pathological processes that affect water diffusion as a result of microstructural damage [6,7]. Several recent studies [4,8–10] reported diffusion changes in TN. However in their studies the results were controversial, and only fractional anisotropy (FA) or mean diffusivity (MD) was analyzed. FA reflects the degree of directionality of cellular structures, while MD represents the diffusion in the noncolinear direction or free diffusion. They are believed to provide a general, nonspecific measure of tissue alteration. The directional diffusivity metrics axial diffusivity (AD) and radial diffusivity (RD) of white matter tracts have been

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hypothesized to more specifically differentiate axonal injury from demyelination in white matter tracts, respectively [11–13]. Thus, the aim of our study was to evaluate possible microstructural tissue changes of TGN in patients with unilateral TN by multiple diffusion metrics (FA, MD, AD and RD), and correlate the diffusion indexes with the clinical variables.

2. Materials and methods 2.1. Participants We recruited 16 patients (7 males, 9 females, mean age ± SD: 50.0 ± 7.8 years) with a history of two to twelve years of TN. All patients were diagnosed with primary TN according to the International Classification of Headache Disorders criteria (second edition) [14] for classic primary TN and treated with MVD at Department of Functional Neurosurgery, Xuanwu Hospital, Capital Medical University. Visual analogue scale (VAS) of pain was assessed at the same day as the MR scan taken. Table 1 presents the main demographic and clinical characteristics of the study participants. To ensure the validity of the study, 6 healthy controls (HC) (3 females and 3 males), with ages ranging from 30 to 52 years, were also included in the study. HC had no history of significant facial pain. Written informed consent was obtained from each participant and this study was approved by the institutional review board of Xuanwu Hospital, Capital Medical University. 2.2. Data acquisition All participants were imaged with a 3.0 T system (Trio Tim, Siemens, Erlangen, Germany). A standard head coil was used with foam padding to restrict head motion. The following protocol was applied. First, a three-dimension time-of-flight (TOF) magnetic resonance angiography was acquired to display the anatomic relationship between the vessels and trigeminal nerve and for the localization of the slice position of the DTI sequence. Second, a fluid attenuated inversion recovery (FLAIR) DTI-sequence was used to avoid obscuration from CSF signal; repetition time/echo time/inversion time 8700/106/2500, field of view 240 mm × 240 mm, matrix 128 × 128, b = 0 and 1000 s/mm2 with diffusion gradients applied in twelve non-collinear directions, twenty 3-mm-slices without gap, acquisition time: 11:46 min. The localizing procedure allowed prescribing a 3 mm axial slice to cover both TGNs including the root entry zone at the pons and the proximal part of the cisternal course to avoid partial volume effects. 2.3. Data processing The data of DTI were transferred to the workstation (Leonardo syngo 2003A, Siemens) and analyzed by two experienced neuroradiologists. A motion correction algorithm was applied to correct for patient motion and image distortions due to eddy current artifacts. The diffusion tensor was calculated for each voxel, and was diagonalized to yield eigenvectors and values from which the FA, MD, AD and RD values were calculated for each voxel. Regions of interest (ROI) for quantitative assessment of FA, MD, AD and RD were positioned on the root entry zone of the TGN to avoid potential partial volume effects (Fig. 1). The difference between both sides is given as percentage in relation to the unaffected side. These DTI parameters were calculated independently by two observers, who were blinded to the side of the face with symptoms. The inter-observer coefficients of variation for the average MD, FA, AD and RD were less than 5%. For statistical analysis we utilized the mean values of the two observers.

Fig. 1. Color FA image with example of box-shaped regions of interest used for quantitative analysis of FA in the TGN root entry zone.

2.4. Statistical analysis The mean values of MD, FA, AD and RD were compared among the affected and unaffected sides in the same patient, and HC by using a one-way analysis of variance (ANOVA) followed by Bonferroni’s multiple comparison test. Therefore, p < 0.005 was considered to indicate a significant difference. Pearson correlation analysis was used to assess correlation between the side-to-side diffusion metric difference and clinical variables (disease duration and VAS). All statistical calculations were performed with SPSS12 software (SPSS, Inc., Chicago, IL). 3. Results The left side was affected in 8 patients, and in the other 8 patients, the right side was involved. Neurovascular contact at the root entry or exit zone of the TGN on the affected side was observed in 12 patients (12/16, 75.0%). In more than half of the patients (9/16, 56.3%), contact with the superior cerebellar artery (SCA) was identified; other patients had nerve contact with other arteries including the posterior cerebellar artery (PICA), veterbral artery (VA), and anterior inferior cerebellar artery (AICA) (Table 1). In all the patients and HC, the TGNs could be delineated on both sides. FA was significantly decreased on the affected side ((mean ± std): 0.32 ± 0.08; −28.2%) than on the contralateral unaffected side ((mean ± std): 0.45 ± 0.07) (p = 4.4 × 10−6 ), while RD was observed to be significantly increased on the affected side ((mean ± std): (1.72 ± 0.34) × 10−3 mm2 /s; 36.3%) compared to the contralateral unaffected side ((mean ± std): (1.34 ± 0.33) × 10−3 mm2 /s) (p = 0.002). We observed a trend toward increased MD on the affected side ((mean ± std): (2.11 ± 0.40) × 10−3 mm2 /s; 21.4%) compared to the contralateral unaffected side ((mean ± std): (1.83 ± 0.39) × 10−3 mm2 /s) (p = 0.05). There were no significant differences in AD between the affected side ((mean ± std): (2.90 ± 0.57) × 10−3 mm2 /s; 7.6%) and the unaffected side ((mean ± std): (2.82 ± 0.54) × 10−3 mm2 /s) (p = 0.72) (Table 2). Compared with the mean diffusion metrics of both sides of the healthy controls, the affected side showed significantly decreased FA, increased MD and RD (p < 0.005), without significant difference in AD (p = 0.34). No significant differences in all the diffusion indexes were found between the unaffected side and the mean value of both sides of HC (p > 0.01) (Table 2). We examined the relationships between the VAS, disease duration and DTI metrics differences. The only significant correlation which we found was between the FA reduction and VAS (r = −0.55, p = 0.03). The other correlations were all less than ±0.28 (p > 0.09).

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Table 1 Demographics and MRI results of 16 patients with TN. Patient no.

Sex

Age (year)

Disease duration (year)

Affected side/branches

VAS

Offending vessels revealed by MRI

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

F M F M F F F M F M M M F F F M

47 49 44 57 56 45 49 47 35 48 54 66 42 46 62 53

10 4 10 3 11 3 4 4 2 12 7 3 9 7 5 5

L/V2–3 L/V1–2 L/V3 L/V2–3 L/V2–3 R/V2 R/V2 R/V3 R/V2–3 R/V1–2 R/V2–3 R/V2–3 R/V2 L/V1–2 L/V2–3 L/V2–3

10 10 8 6 9 8 8 9 8 10 7 8 8 9 8 7

SCA SCA SCA VA SCA PICA SCA SCA SCA SCA SCA SCA and AICA No NVC No NVC No NVC No NVC

Table 2 The mean values of FA, MD, AD and RD compared among the affected and unaffected sides in the same patient, and healthy controls. Affected side (mean ± std)

FA MD (×10−3 mm2 /s) AD (×10−3 mm2 /s) RD (×10−3 mm2 /s) *

0.32 2.11 2.90 1.72

± ± ± ±

0.08 0.40 0.57 0.34

Unaffected side (mean ± std)

0.45 1.83 2.82 1.34

± ± ± ±

0.07 0.39 0.54 0.33

Healthy controls (mean ± std) 0.51 1.68 2.75 1.11

± ± ± ±

0.09 0.25 0.25 0.28

Affected side vs unaffected side (difference %)

Affected side vs healthy controls (difference %)

Unaffected side vs healthy controls (difference %)

−28.2* 21.4 7.6 36.3*

−36.9* 26.0* 5.4 54.4*

−11.7 9.0 2.7 19.9

p < 0.005 was considered to indicate a significant difference.

4. Discussion As far as we know, this study is the first one to demonstrate microstructural abnormalities in the TGNs of patients with TN by multiple diffusion metrics. Compared with the unaffected side and HC, the affected side showed significantly decreased FA and increased RD. However no significant changes of AD were found in the affected side. A trend toward significantly increased MD was identified on the affected side comparing with unaffected side. These differential changes in multiple diffusion metrics support the hypothesis that TN is generated by root entry zone demyelination rather than axonal loss. TN is a facial pain syndrome characterized by sudden and intense pain in one of the branches of the TGN. Neurovascular compression at the root entry or exit zone is widely regarded as the underlying pathomechanism. MRI is needed to exclude other causes of TN (e.g., posterior fossa tumors or multiple sclerosis lesions) and assess the neurovascular relationship before treatment [15,16]. However, routine MRI does not characterize a nerve as affected, as many healthy individuals also have evidence of apparent neurovascular loops close to the TGN [17]. Our results suggest that the MRI DTI metrics FA and MD, which represent the two diffusion tensor imaging indexes that are most widely used to investigate white matter changes, are altered at the root entry zones of affected nerves. Many studies of CNS neurological diseases have observed regional reductions in diffusion anisotropy [18–21], and some researchers have proposed that the primary determinant of anisotropy is the packing density of axons within a voxel. Axonal packing density encompasses a variety of micro-structural level variables (e.g. degree of myelination, axonal diameters, and extracellular space) [19,22]. FA reduction of affected TGN in TN has been reported in several previous studies [1,4,9], with the exception of a study from Fujiwara et al. [8]. Decreased FA of the affected side was found in our study consistent with previous studies. MD alteration in the affected TGN is less consistently reported across different studies. Two studies

[8,9] found that MD was similar between the unaffected and TNaffected nerve, while Leal [10] reported the MD of affected TGN was significantly higher compared with the contralateral TGN and control values. In our study, the affected side had a trend toward significantly increased MD. The discordant results of MD may be due to the different diffusion sequences, protocols or ROI placements. And it suggested MD, a mean diffusivity being averaged in all spatial directions as a result of the loss of myelin and axonal membranes, is likely to be less sensitive than FA (which measures alterations in anisotropy) in detecting the microstructure changes of vascular trigeminal nerve compression. As far as we know, no prior study has reported the results of RD and AD, which are believed to partially differentiate axonal injury from demyelination in white matter tracts [19,22]. Our results showed an increase in RD, without accompanying significant changes of AD, which suggests that the primary TN pathology is not axonal loss or damage. This finding is consistent with the theory that focal demyelination of the sensory axons at the site of the neurovascular compression [5], and that ephaptic “short circuits” are responsible for neuralgia, as hypothesized by Gardner [23]. Interestingly, a negative correlation between FA reduction and VAS was identified in our study. It suggests that FA, which reflects the overall directional organization of TGN, could be further explored as a potential objective MRI biomarker to confirm TN and monitor clinical severity. Our study had several limitations. Firstly, the potential partial volume effects caused by the small size of the root that is bathed in cerebrospinal fluid may influence the quantitative diffusion metrics ; however, two observers double checked the ROI placement and we used FLAIR-DTI to suppress the fluid signal to avoid the partial volume effects. Secondly, the thickness and volume of TGN were not assessed in our study; further study is warranted to analyze the correlation between diffusion and volume changes in TGN. Thirdly, a long time follow-up of the patients is necessary to assess the prognostic values of the multiple diffusion metrics in TN.

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5. Conclusion Abnormal TGN DTI reflects the microstructural abnormalities of the affected nerve in patients with TN. Compared with HC and the unaffected side, the affected side showed significantly reduced FA, increased RD and unchanged AD, confirming demyelination without significant axonal injury is the essential pathological basis of the affected TGN. The correlation between FA reduction and pain VAS suggests FA as a potential objective MRI biomarker to confirm TN diagnosis and monitor clinical severity.

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Author contributions All the authors had collectively poured in a lot of efforts into this study. Mo Zhang, Yunyun Duan and Yaou Liu had done data acquisition, whereas Yaou Liu, Yunyun Duan and Jiping Li had formed the study design. Yaou Liu, Jiping Li and Yongjie Li have devised the study concepts and Yaou Liu had defined the intellectual content. Yaou Liu and Yunyun Duan and Jiping Li had done data analysis whereas Yaou Liu and Jiping Li had done statistical analysis. Yaou Liu and Jiping Li had done clinical studies and literature research, but Yaou Liu combined with Yunyun Duan to do experimental studies. Yaou Liu himself had done manuscript preparation and combined with Ni Shu and Helmut Butzkueven to do editing of the manuscript. Kuncheng Li and Yuqing Zhang reviewed the manuscript thoroughly with help from Helmut Butzkueven, but these two were the guarantors of integrity of the entire study.

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Disclosure Dr Yaou Liu, Dr Jiping Li, Dr Helmut Butzkueven, Dr Yunyun Duan, Dr Mo Zhang, Dr Ni Shu, Professor Yongjie Li, Professor Yuqing Zhang and Professor Kuncheng Li report no disclosures.

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Dr Yaou Liu was supported by McDonald Fellowship from Multiple Sclerosis International Federation (MSIF). This work was supported by the State Key Program of National Natural Science of China (No. 30930029) and the National Science Foundation of China (Nos. 81000633 and 81101038). References [1] Love S, Coakham HB. Trigeminal neuralgia: pathology and pathogenesis. Brain 2001;124(Pt 12):2347–60. [2] Cruccu G, Gronseth G, Alksne J, et al. AAN-EFNS guidelines on trigeminal neuralgia management. European Journal of Neurology 2008;15(10):1013–28. [3] Gronseth G, Cruccu G, Alksne J, et al. Practice parameter: the diagnostic evaluation and treatment of trigeminal neuralgia (an evidence-based review):

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