臺灣博碩士論文加值系統

背景 過去幾年，放射手術治療藥物難治型三叉神經痛有許多的報告，但何時是最好的介入時機一樣沒有定論。在典型的的三叉神經痛常可見神經萎縮、血管壓迫，也常被指為影響放射手術治療三叉神經效果的重要因子。本研究的目的，在於決定三叉神經的狀態，是否影響加馬刀放射手術治療三叉神經的效果。我們同時使用腦部磁振上的巨觀及微觀變化(DTI), 來進行對神經狀態的評估

方法 本研究同時進行回溯性及前瞻性研究。2006-2014年，其有134位三叉神經痛的病人經由加馬刀治療，其中因研究的條件不同，分別有108位及67位病人進行假設1、及假設2的研究。2014-2017年，則有21位三叉神經痛的病人經由加馬刀治療，是經由前瞻性的病例收集，進行了DTI的研究。所有的病人，其加馬刀的照點，都是放在root entry zone (REZ)，使用80-90Gy的劑量。成效分析是使用Barrow Neurological Institute (BNI) 的疼痛及臉部麻木量表。MRI上會使收集近端神經的橫切面(CSA)、及是否有血管壓迫。DTI的研究中，則是收集了FA, MD, RD, AD, Cl, Cp, Cs等因子。我們將同時比較患側/健側、及症狀超過五年/小於五年的治療成效差異

結果 治療失敗的病人，有比較長的三叉神經痛病史，尤其以大於5年的疼痛病史，更為常見。單變量及多變量分析可以發現，超過5年的疼痛病史，其加馬刀後疼痛緩解較差(p=0.049 and p=0.045)。病人三叉神經痛的患側跟健側比起來，其近端神經的橫切面較小(4.95 mm2 vs 5.9 mm2, p < 0.001)，且此橫切面的大小可以預測疼痛緩解的程度(HR 0.81, p = 0.032)。神經比較萎縮(CSA <= 4.4 mm2)的病人，其5年內有較高的疼痛復發率(65% vs 86%, p = 0.044)

若以微觀角度，患側的三叉神經，若疼痛症狀小於5年，有較好的FA基礎值(0.314 vs. 0.244, p=0.02)。在進行加馬刀治療後，疼痛症狀小於5年的病人，其FA值會下降較快，且λ2 值增加 (FA: -0.068 vs. 0.031, p=0.04, λ2: 0.0003 vs. -0.0002, p=0.02)。此結果反應在臨床上，病人對加馬刀的止痛效果，反應也較好。

結論 三叉神經痛症狀小於5年，有較佳的加馬刀治療效果。三叉神經萎縮，不論從巨觀還是微觀，都有較差的加馬刀治療效果。因此，早期進行對藥物難治型三叉神經痛進行加馬刀手術，在神經還沒有出現變化前，會是較好的選擇。

Background The role of SRS in the management of trigeminal neuralgia (TN) had been investigated in previous studies, but the timing of intervention is still debated. Trigeminal nerve atrophy and neurovascular compression (NVC) are observed in affected nerves of classical TN, which are potentially affect the efficacy of SRS. The aim of this study was to determine whether these nerve characteristics contribute to Gamma Knife radiosurgery (GKRS) outcomes in medical refactory TN. We intend to measure the size of nerves via MR images, and detect microstructure changes by diffusion tensor imaging (DTI).
Methods This retrospective review covers 134 consecutive patients presenting with medically refractory, idiopathic TN between 2006 and 2014. All patients underwent GKRS targeting the root entry zone (REZ) with median maximum dose of 80-90 Gy. Outcomes pertaining to pain and facial numbness were scored using the Barrow Neurological Institute (BNI) pain and facial numbness scales, respectively. To analyze the presentation of trigeminal nerve, we analyzed the MR images including proximal nerve cross-sectional area (CSA), vessel type of neurovascular conflict (NVC), and site of NVC along the nerve. DTI was reconstructed in 21 cases pre- and post-SRS. DTI parameters recorded include fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD), linear anisotropy coefficient (Cl), planar anisotropy coefficient (Cp), and spherical anisotropy coefficient (Cs). Comparisons between ipsilateral (symptomatic) and contralateral (asymptomatic) trigeminal nerves, and symptom durations of <5 and ≧5 years were performed.
Results The treatment failure rates were highest among patients with a longer history of pain. Those with pain history of >5 years experienced longer latency prior to pain relief (p=0.027). Univariate and multivariate analyses demonstrated that pain history of ≤5 years was a significant predictor of pain relief (p=0.049 and p=0.045, respectively). The median CSA of the symptomatic nerves was significantly smaller than that of asymptomatic nerves (4.95 mm2 vs 5.9 mm2, p < 0.001). The nerve CSA was predictive of initial pain relief (hazard ratio 0.81 [95% CI 0.67—0.98], p = 0.032) and pain recurrence (hazard ratio 0.58 [95% CI 0.36—0.94], p = 0.028). Patients with nerve atrophy (defined as CSA of less than or equal to 4.4 mm2) had a lower 5-year probability of maintaining pain relief than those without nerve atrophy (65% vs 86%, p = 0.044).
For the pre-SRS DTI findings, ipsilateral trigeminal nerve with symptoms of <5 years was associated with higher baseline FA compared to trigeminal nerve with symptoms of ≧5 years (0.314 vs. 0.244, p=0.02).
For the post-SRS DTI findings, symptoms of <5 years was associated with decreased FA and increased λ2, while symptoms of ≧5 years was associated with increased FA and decreased λ2 after SRS (FA: -0.068 vs. 0.031, p=0.04, λ2: 0.0003 vs. -0.0002, p=0.02).
Conclusions Pain history of ≤5 years is a reliable predictor of pain relief and appears to be associated with shorter latency to pain relief following GKRS. Trigeminal nerve atrophy may predict pain recurrence in TN after GKRS, instead, the NVC are not associated with the GKRS outcomes. There were significant associations between duration of symptoms and changes in DTI. Early SRS for trigeminal neuralgia before the micro- or macro- nerves atrophic changes is recommend.

Table of Contents
中文摘要 i
English Abstract iii
Table of Contents v
List of Figure viii
List of Table ix

Chapter 1. Introduction 1
1.1 The prevalence of trigeminal neuralgia 1
1.2 Treatment of choice for medically intractable trigeminal neuralgia 1
1.3 Stereotactic radiosurgery (SRS) for medically intractable trigeminal neuralgia 2
1.4 The role of neurovasular conflicts and nerve atrophy in patients with TN 2
1.5 The application of diffusion tensor imaging (DTI) to evaluate the microstructure of trigeminal nerve. 3
1.6 Hypotheses and aims of thesis 4
1.6.1 Hypothesis 1: the clinical evidence 4
1.6.2 Hypothesis 2: the evidence from MR images 5
1.6.3 Hypothesis 3: the evidence from diffusion tensor images 5
Chapter 2. Methods 6
2.1 Methods for Hypothesis 1 6
2.1.1 Ethical consideration 6
2.1.2 Study design and research team 6
2.1.3 GK registry and study participants 6
2.1.4 Materials and Methods 7
2.1.5 Outcome assessments 8
2.1.6 Statistical analysis 9
2.2 Methods for Hypothesis 2 9
2.2.1 Ethical consideration 9
2.2.2 Study design and research team 9
2.2.3 GK registry and study participants 10
2.2.4 Materials and Methods 10
2.2.5 Outcome assessments 13
2.2.6 Statistical analysis 13
2.3 Methods for Hypothesis 3 14
2.3.1 Ethical consideration 14
2.3.2 Study design and research team 14
2.3.3 GK registry and study participants 15
2.3.4 Materials and Methods 15
2.3.5 Outcome assessments 18
2.3.6 Statistical analysis 19
Chapter 3. Results 20
3.1 Results for hypothesis 1 20
3.1.1 Pain Relief and Facial Numbness 20
3.1.2 Historical Duration of Pain and Clinical Outcomes 20
3.2 Results for hypothesis 2 21
3.2.1 Outcomes of TN after GKS 22
3.2.2 Associations between Nerve Characteristics and GKS Outcomes 22
3.2.3 Associations Between NVC Characteristics and Nerve CSA 23
3.2.4 Facial Numbness after GKS 23
3.3 Results for hypothesis 3 24
3.3.1 Pain Relief and Facial Numbness 24
3.3.2 Historical Duration of Pain and Clinical Outcomes 24
3.3.3 The DTI parameters between the lesion side and unaffected side, root entry zone and distal portion, before and after GK. 25
Chapter 4. Discussion 27
4.1 the advantage of early SRS intervention 27
4.2 the nerve atrophy vs neurovascular conflicts 28
4.3 the DTI applications in medically intractable trigeminal neuralgia 31
4.4 the treatment strategy for the medically intractable trigeminal neuralgia 33
4.5 strengths and limitations. 33
Chapter 5. Summaries and Conclusions 36
5.1 Summary for hypothesis 1: 36
5.2 Summary for hypothesis 2: 36
5.3 Summary for hypothesis 3: 36
5.4 Conclusions of the thesis 37
Reference 38

List of Figure

Figure 1 Axial 3D SPGR-Gd image to show the CSA measurement. 48
Figure 2 The flow-chart showed the FSL pre-processing method. 49
Figure 3 Illutrative cases: patients who had symptoms> 5yrs and < 5 years 50
Figure 4 Initial pain relief in TN patients stratified by pain history (< 5 and >5 years) with corresponding p-value 51
Figure 5 Pain relief maintenance among TN patients stratified by pain history (< 5 and >5 years) with corresponding p-value 52
Figure 6 Actuarial probability of initial adequate pain relief (BNI I-IIIb) within 12 months after GKS for TN, based on whether CSA of nerve is more than 4.4 mm2 or not. 53
Figure 7 Actuarial probability of maintaining pain relief (BNI I-IIIb) within 5 years after GKS for TN, based on whether CSA of nerve is more than 4.4 mm2 or not. 54
Figure 8 FA value vs the duration of symptoms 55


List of Table
Table 1. Patient Demographics before GKRS treatment 56
Table 2. Clinical characteristics of 67 patients with TN who underwent GKS 58
Table 3. Characteristics of 21 patients underwent GKS for trigeminal neuralgia 59
Table 4. Outcomes among patients who underwent GKRS for trigeminal neuralgia 61
Table 5 Prognostic factors of outcomes after GK for trigeminal neuralgia* (logistic regression model) 63
Table 6 Outcomes for patients who underwent GKS for TN 65
Table 7 Cox regression analysis of GKS outcomes with nerve characteristics* 67
Table 8 Outcomes in patients who underwent GKRS for trigeminal neuralgia 69
Table 9A Compare DTI parameters between the lesion side and unaffected side before GK(n=21) 71
Table 9B Compare DTI parameters (lesion side) between the subgroups according to the duration of symptoms (< 5 years vs > 5years) (n=21) 72
Table 10 DTI changes of 18 patients who underwent GKS for trigeminal neuralgia 75

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