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Chien-Yi Chiang, Meei-Ling Sheu, Fu-Chou Cheng, Chun-Jung Chen, Hong-Lin Su, Jason Sheehan and Hung-Chuan Pan

Object

Neuropathic pain is debilitating, and when chronic, it significantly affects the patient physically, psychologically, and socially. The neurobehavior of animals used as a model for chronic constriction injury seems analogous to the neurobehavior of humans with neuropathic pain. However, no data depicting the severity of histomorphological alterations of the nervous system associated with graded changes in neurobehavior are available. To determine the severity of histomorphological alteration related to neurobehavior, the authors created a model of chronic constrictive injury of varying intensity in rats and used the CatWalk XT system to evaluate neurobehavior.

Methods

A total of 60 Sprague-Dawley rats, weighing 250–300 g each, were randomly assigned to 1 of 5 groups that would receive sham surgery or 1, 2, 3, or 4 ligatures of 3-0 chromic gut loosely ligated around the left sciatic nerve. Neurobehavior was assessed by CatWalk XT, thermal hyperalgesia, and mechanic allodynia before injury and periodically after injury. The nerve tissue from skin to dorsal spinal cord was obtained for histomorphological analysis 1 week after injury, and brain evoked potentials were analyzed 4 weeks after injury.

Results.

Significant differences in expression of nerve growth factor existed in skin, and the differences were associated with the intensity of nerve injury. After injury, expression of cluster of differentiation 68 and tumor necrosis factor–α was increased, and expression of S100 protein in the middle of the injured nerve was decreased. Increased expression of synaptophysin in the dorsal root ganglion and dorsal spinal cord correlated with the intensity of injury. The amplitude of sensory evoked potential increased with greater severity of nerve damage. Mechanical allodynia and thermal hyperalgesia did not differ significantly among treatment groups at various time points. CatWalk XT gait analysis indicated significant differences for print areas, maximum contact maximum intensity, stand phase, swing phase, single stance, and regular index, with sham and/or intragroup comparisons.

Conclusions.

Histomorphological and electrophysiological alterations were associated with severity of nerve damage. Subtle neurobehavioral differences were detected by the CatWalk XT system but not by mechanical allodynia or thermal hyperalgesia. Thus, the CatWalk XT system should be a useful tool for monitoring changes in neuropathic pain, especially subtle alterations.

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Fu-Chou Cheng, Meei-Ling Sheu, Hong-Lin Su, Ying-Ju Chen, Chun-Jung Chen, Wen-Ta Chiu, Jason Sheehan and Hung-Chuan Pan

Object

Mobilization of hematopoietic progenitor cells (HPCs) from bone marrow involved in the process of peripheral nerve regeneration occurs mostly through deposits of CD34+ cells. Treadmill exercise, with either differing intensity or duration, has been shown to increase axon regeneration and sprouting, but the effect of mobilization of HPCs on peripheral nerve regeneration due to treadmill exercise has not yet been elucidated.

Methods

Peripheral nerve injury was induced in Sprague-Dawley rats by crushing the left sciatic nerve using a vessel clamp. The animals were categorized into 2 groups: those with and without treadmill exercise (20 m/min for 60 minutes per day for 7 days). Cytospin and flow cytometry were used to determine bone marrow progenitor cell density and distribution. Neurobehavioral analysis, electrophysiological study, and regeneration marker expression were investigated at 1 and 3 weeks after exercise. The accumulation of HPCs, immune cells, and angiogenesis factors in injured nerves was determined. A separate chimeric mice study was conducted to assess CD34+ cell distribution according to treadmill exercise group.

Results

Treadmill exercise significantly promoted nerve regeneration. Increased Schwann cell proliferation, increased neurofilament expression, and decreased Schwann cell apoptosis were observed 7 days after treadmill exercise. Elevated expression of S100 and Luxol fast blue, as well as decreased numbers of vacuoles, were identified in the crushed nerve 3 weeks after treadmill exercise. Significantly increased numbers of mononuclear cells, particularly CD34+ cells, were induced in bone marrow after treadmill exercise. The deposition of CD34+ cells was abolished by bone marrow irradiation. In addition, deposits of CD34+ cells in crushed nerves paralleled the elevated expressions of von Willebrand factor, isolectin B4, and vascular endothelial growth factor.

Conclusions

Bone marrow HPCs, especially CD34+ cells, were able to be mobilized by low-intensity treadmill exercise, and this effect paralleled the significant expression of angiogenesis factors. Treadmill exercise stimulation of HPC mobilization during peripheral nerve regeneration could be used as a therapy in human beings.

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Hung-Chuan Pan, Jason Sheehan, Meei-Ling Sheu, Wen-Ta Chiu and Dar-Yu Yang

Object

Microsurgery is the primary treatment used for patients harboring a large vestibular schwannoma (VS). However, its outcome may lead to hearing impairment and facial nerve dysfunction particularly when resection is extended outside the tumor capsule. When surgery for a large VS consists of intracapsular resection and decompression, better preservation of facial and hearing function are obtained. In this study, the authors compared outcomes of intracapsular decompression followed by Gamma Knife surgery (GKS) with outcomes of standard microsurgery followed by radiosurgery.

Methods

Between August 2003 and October 2008, 35 patients harboring large VSs (> 3 cm in diameter) were enrolled in this study. Eighteen patients underwent intracapsular decompression followed by GKS (Group I), and 17 patients underwent radical extracapsular resection followed by GKS (Group II). In all cases GKS was performed with a margin dose of 12 Gy. All patients were followed up for at least 3 years. All patients also underwent periodic audiography, electroneuronography (ENoG), MR imaging, and testing with the SF-36 form. The Student t-test and repeated ANOVA were used for statistical analysis.

Results

The mean ages of the patients (± SEM) in Groups I and II were 50 ± 3.0 and 49 ± 2.3 years, respectively. The female/male ratios were 8:10 in Group I and 7:10 in Group II. All patients had excellent facial function as measured according to the House-Brackmann Facial Grading System (Grade I or II) preoperatively. After the operation, 16 patients (89%) in Group I retained excellent facial function, whereas only 6 patients (35%) in Group II had excellent facial function (p < 0.01). In Group I, 11 patients had serviceable hearing, and all 11 (100%) retained hearing function after the operation. In Group II, 11 patients had serviceable hearing, but none retained hearing function postoperatively (p < 0.001). In Group I, the mean tumor volume (± SEM) was 17.5 ± 1.1 cm3, and the postoperative volume was 9.35 ± 1.02 cm3. In Group II, the mean tumor volume was 16.4 ± 0.95 cm3, whereas the postoperative volume was 1.1 ± 0.14 cm3 (p < 0.001). After GKS, the tumor volume was reduced to 5.12 ± 1.1 cm3 and 0.9 ± 0.1 cm3 in Groups I and II, respectively. No patients experienced adverse effects after GKS. The mean return-to-work times were 2.4 ± 0.16 and 33.4 ± 4.3 weeks in Groups I and II, respectively (p < 0.001). According to the results obtained using the 36-Item Short Form Health Survey (SF-36), patients in Group I enjoyed more significant improvements in quality of life than patients in Group II (p < 0.001).

Conclusions

Intracapsular decompression followed by GKS afforded a better neurological outcome and quality of life than radical extracapsular resection followed by GKS. Further application of this approach in patients harboring large VSs seems warranted.

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Dar-Yu Yang, Meei-Ling Sheu, Hong-Lin Su, Fu-Chou Cheng, Ying-Ju Chen, Chun-Jung Chen, Wen-Ta Chiu, Jia-Jean Yiin, Jason Sheehan and Hung-Chuan Pan

Object

Human amniotic fluid–derived mesenchymal stem cells (AFMSCs) have been shown to promote peripheral nerve regeneration. The expression of stromal cell–derived factor-1α (SDF-1α) in the injured nerve exerts a trophic effect by recruiting progenitor cells that promote nerve regeneration. In this study, the authors investigated the feasibility of intravenous administration of AFMSCs according to SDF-1α expression time profiles to facilitate neural regeneration in a sciatic nerve crush injury model.

Methods

Peripheral nerve injury was induced in 63 Sprague-Dawley rats by crushing the left sciatic nerve using a vessel clamp. The animals were randomized into 1 of 3 groups: Group I, crush injury as the control; Group II, crush injury and intravenous administration of AFMSCs (5 × 106 cells for 3 days) immediately after injury (early administration); and Group III, crush injury and intravenous administration of AFMSCs (5 × 106 cells for 3 days) 7 days after injury (late administration). Evaluation of neurobehavior, electrophysiological study, and assessment of regeneration markers were conducted every week after injury. The expression of SDF-1α and neurotrophic factors and the distribution of AFMSCs in various time profiles were also assessed.

Results

Stromal cell–derived factor-1α increased the migration and wound healing of AFMSCs in vitro, and the migration ability was dose dependent. Crush injury induced the expression of SDF-1α at a peak of 10–14 days either in nerve or muscle, and this increased expression paralleled the expression of its receptor, chemokine receptor type-4 (CXCR-4). Most AFMSCs were distributed to the lung during early or late administration. Significant deposition of AFMSCs in nerve and muscle only occurred in the late administration group. Significantly enhanced neurobehavior, electrophysiological function, nerve myelination, and expression of neurotrophic factors and acetylcholine receptor were demonstrated in the late administration group.

Conclusions

Amniotic fluid–derived mesenchymal stem cells can be recruited by expression of SDF-1α in muscle and nerve after nerve crush injury. The increased deposition of AFMSCs paralleled the expression profiles of SDF-1α and its receptor CXCR-4 in either muscle or nerve. Administration of AFMSCs led to improvements in neurobehavior and expression of regeneration markers. Intravenous administration of AFMSCs may be a promising alternative treatment strategy in peripheral nerve disorder.

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Meei-Ling Sheu, Fu-Chou Cheng, Hong-Lin Su, Ying-Ju Chen, Chun-Jung Chen, Chih-Ming Chiang, Wen-Ta Chiu, Jason Sheehan and Hung-Chuan Pan

Object

Increased integration of CD34+ cells in injured nerve significantly promotes nerve regeneration, but this effect can be counteracted by limited migration and short survival of CD34+ cells. SDF-1α and its receptor mediate the recruitment of CD34+ cells involved in the repair mechanism of several neurological diseases. In this study, the authors investigate the potentiation of CD34+ cell recruitment triggered by SDF-1α and the involvement of CD34+ cells in peripheral nerve regeneration.

Methods

Peripheral nerve injury was induced in 147 Sprague-Dawley rats by crushing the left sciatic nerve with a vessel clamp. The animals were allocated to 3 groups: Group 1, crush injury (controls); Group 2, crush injury and local application of SDF-1α recombinant proteins; and Group 3, crush injury and local application of SDF-1α antibody. Electrophysiological studies and assessment of regeneration markers were conducted at 4 weeks after injury; neurobehavioral studies were conducted at 1, 2, 3, and 4 weeks after injury. The expression of SDF-1α, accumulation of CD34+ cells, immune cells, and angiogenesis factors in injured nerves were evaluated at 1, 3, 7, 10, 14, 21, and 28 days after injury.

Results

Application of SDF-1α increased the migration of CD34+ cells in vitro, and this effect was dose dependent. Crush injury induced the expression of SDF-1α, with a peak of 10–14 days postinjury, and this increased expression of SDF-1α paralleled the deposition of CD34+ cells, expression of VEGF, and expression of neurofilament. These effects were further enhanced by the administration of SDF-1α recombinant protein and abolished by administration of SDF-1α antibody. Furthermore, these effects were consistent with improvement in measures of neurological function such as sciatic function index, electrophysiological parameters, muscle weight, and myelination of regenerative nerve.

Conclusions

Expression of SDF-1α facilitates recruitment of CD34+ cells in peripheral nerve injury. The increased deposition of CD34+ cells paralleled significant expression of angiogenesis factors and was consistent with improvement of neurological function. Utilization of SDF-1α for enhancing the recruitment of CD34+ cells involved in peripheral nerve regeneration may be considered as an alternative treatment strategy in peripheral nerve disorders.

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Hung-Chuan Pan, Jason Sheehan, Chuan-Fu Huang, Meei-Ling Sheu, Dar-Yu Yang and Wen-Ta Chiu

Object

Gamma Knife surgery (GKS) is an important part of the neurosurgical armamentarium for treatment of patients with trigeminal neuralgia (TN) and is regarded as the first-line treatment in patients with TN who have serious medical comorbidities. In this study, the authors investigated the efficacy of GKS on TN in patients with serious medical comorbidities.

Methods

Between May 2004 and September 2007, 52 severely ill patients who also had TN with Barrow Neurological Institute (BNI) facial pain scores of IV or V were entered into this study. The patients' medical records and imaging findings were reviewed by an anesthesiologist and neurosurgeons to determine whether GKS was a reasonable approach to palliate the patient's pain. All patients underwent GKS, in which a maximum dose of 80 Gy was targeted to the trigeminal nerve with or without plugging to keep the dose received by the brainstem at less than 16 Gy. After treatment, every patient had clinical follow-up every 1–3 months and filled out questionnaires designed to assess BNI facial pain and numbness scores, visual analog scale scores, and 36-Item Short Form Health Survey (SF-36) scores every 3 months until the end of the study. Statistical analysis was performed to find favorable prognostic factors related to pain relief and changes in quality of life.

Results

The median age of the patients was 71 years, and the male/female ratio was 30:22. The median follow-up period was 54 months (at least 2 years). All patients had a positive initial response to GKS, with BNI facial pain scores at least 1 point less than respective pre-GKS scores. Three patients (5.7%) obtained BNI facial pain Score I. Twenty-three patients (44.2%) experienced pain recurrence at a median follow-up of 33 months. One patient suffered from angina and required time in an intensive care unit; another patient had bleeding from a pin wound that required suturing. Alterations in BNI scores were highly correlated to visual analog scale scores (R2 = 0.978). In both univariate and multivariate analyses, a decreased BNI facial pain score at different time points was significantly (p < 0.05) related to younger patient age, no previous treatment, evidence of vessel compression on MR imaging, time of first GKS ≤ 24 months, physical function (SF-36), role limitation due to a physical problem (SF-36), role limitation due to an emotional problem (SF-36), mental health (SF-36), social functioning (SF-36), bodily pain (SF-36), and general health (SF-36), but was not related to vitality (SF-36). Five patients (9.6%) experienced facial numbness at a mean of 13.2 ± 3.1 months after GKS (4 patients with BNI facial numbness Score II and 1 with BNI facial numbness Score III). Post-GKS MR imaging changes, including focal contrast enhancement or T2-weighted signal alterations, were identified in 3 patients (5.7%).

Conclusions

Gamma Knife surgery produced significant pain relief in severely ill patients who had TN without causing appreciable morbidity. The effect of reduced pain significantly paralleled an improvement in SF-36 quality-of-life indices.

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Hung-Chuan Pan, Ming-Hsi Sun, Jason Sheehan, Meei-Ling Sheu, Clayton Chi-Chang Chen, Hsu-Tung Lee, Wen-Ta Chiu and Dar-Yu Yang

Object

In the modern era, stereotactic radiosurgery is an important part of the multidisciplinary and multimodality approach used to treat dural carotid-cavernous fistulas (DCCFs). Based on the ease of performance of techniques to fuse cerebral angiography studies with MR images or CT scans during the radiosurgical procedure, the Gamma Knife and XKnife are 2 of the most popular radiosurgical instruments for patients with DCCF. In this study, the authors compared the efficacy, neurological results, and complications associated with these 2 radiosurgical devices when used for DCCF.

Methods

Records for 41 patients with DCCF (15 treated using the XKnife and 26 with Gamma Knife surgery [GKS]) were retrieved from a radiosurgical database encompassing the period of September 2000 to August 2008. Among these patients, at least 2 consecutive MR imaging or MR angiography studies obtained after radiosurgery were available for determining radiological outcome of the fistula. All patients received regular follow-up to evaluate the neurological and ophthalmological function at an interval of 1–3 months. The symptomatology, obliteration rate, radiation dose, instrument accuracy, and adverse effects were determined for each group and compared between 2 groups. The data were analyzed using the Student t-test.

Results

The mean age of the patients was 63 ± 2.6 years, and the mean follow-up period was 63.1 ± 4.4 months (mean ± SD). Thirty-seven patients (90%) achieved an obliteration of the DCCF (93% in the XKnife cohort and 88% for the GKS cohort). In 34 of 40 patients (85%) with chemosis and proptosis of the eyes, these symptoms were resolved after treatment (4 had residual fistula and 2 had arterializations of sclera). All 5 patients with high intraocular pressure demonstrated clinical improvement. Ten (71%) of 14 patients with cranial nerve palsy demonstrated improvement following radiosurgery. Significant discrepancies of treatment modalities existed between the XKnife and GKS groups, such as radiation volume, conformity index, number of isocenters, instrument accuracy, peripheral isodose line, and maximum dosage. The XKnife delivered significantly higher radiation dosage to the lens, optic nerve, optic chiasm, bilateral temporal lobe, and brainstem. Few adverse events occurred, but included 1 patient with optic neuritis (GKS group), 1 intracranial hemorrhage (XKnife group), 1 brainstem edema (XKnife), and 3 temporal lobe radiation edemas (XKnife).

Conclusions

Radiosurgery affords a substantial chance of radiological and clinical improvement in patients with DCCFs. The Gamma Knife and XKnife demonstrated similar efficacy in the obliteration of DCCFs. However, a slightly higher incidence of complications occurred in the XKnife group.