Jason Sheehan, Hung-Chuan Pan, Matei Stroila and Ladislau Steiner
Object. Microvascular decompression (MVD) and percutaneous ablation surgery have historically been the treatments of choice for medically refractory trigeminal neuralgia (TN). Gamma knife surgery (GKS) has been used as an alternative, minimally invasive treatment in TN. In the present study, the authors evaluated the long-term results of GKS in the treatment of TN.
Methods. From 1996 to 2003, 151 cases of TN were treated with GKS. In this group, radiosurgery was performed once in 136 patients, twice in 14 patients, and three times in one patient. The types of TN were as follows: 122 patients with typical TN, three with atypical TN, four with multiple sclerosis—associated TN, and seven with TN and a history of a cavernous sinus tumor. In each case, the chosen radiosurgical target was located 2 to 4 mm anterior to the entry of the trigeminal nerve into the pons. The maximal radiation doses ranged from 50 to 90 Gy. The median age of the patients was 68 years (range 22–90 years), and the median time from diagnosis to GKS was 72 months (range 1–276 months). The median follow up was 19 months (range 2–96 months). Clinical outcomes and postradiosurgical magnetic resonance (MR) imaging studies were analyzed. Univariate and multivariate analyses were performed to evaluate factors that correlated with a favorable, pain-free outcome.
The mean time to relief of pain was 24 days (range 1–180 days). Forty-seven, 45, and 34% of patients were pain free without medication at the 1-, 2-, and 3-year follow ups, respectively. Ninety, 77, and 70% of patients experienced some improvement in pain at the 1-, 2-, and 3-year follow ups, respectively. Thirty-three (27%) of 122 patients with initial improvement subsequently experienced pain recurrence a median of 12 months (range 2–34 months) post-GKS. Among those whose symptoms recurred, 14 patients underwent additional GKS, six MVD, four glycerol injection, and one patient a percutaneous radiofrequency rhizotomy. Twelve patients (9%) suffered the onset of new facial numbness post-GKS. Changes on MR images post-GKS were noted in nine patients (7%). On univariate analysis, right-sided neuralgia (p = 0.0002) and a previous neurectomy (p = 0.04) correlated with a pain-free outcome; on multivariate analysis, both right-sided neuralgia (p = 0.032) and patient age (p = 0.05) were statistically significant. New onset of facial numbness following GKS correlated with undergoing more than one GKS (p = 0.002).
Conclusions. At the last follow up, GKS effected pain relief in 44% of patients. Some degree of pain improvement at 3 years post-GKS was noted in 70% of patients with TN. Although less effective than MVD, GKS remains a reasonable treatment option for those unwilling or unable to undergo more invasive surgical approaches and offers a low risk of side effects.
Hung-Chuan Pan, Jason Sheehan, Matei Stroila, Melita Steiner and Ladislau Steiner
Object. The authors present data concerning the development of cysts following gamma knife surgery (GKS) in 1203 consecutive patients with arteriovenous malformations (AVMs) treated by the senior author (L.S.). The cyst was defined as a fluid-filled cavity at the site of a treated AVM. Cases involving regions corresponding to previous hematoma cavities were excluded. The incidence of cyst formation was assessed using magnetic resonance imaging studies performed in 196 cases with more than 10 years of follow up, in 332 cases with 5 to 10 years of follow up, and in 675 cases with less than 5 years of follow up. One hundred five cases were lost to follow-up study. The Cox regression method was used to analyze the factors related to cyst formation.
Methods. The incidence of cyst formation in the entire patient population was 1.6 and 3.6% in those undergoing follow-up examination for more than 5 years. Ten of 20 cysts developed between 10 to 23 years, nine between 5 to 10 years, and one in less than 5 years following the treatment. Cyst fluid aspiration, cystoperitoneal shunt placement, or craniotomy were used in three symptomatic cases. Analysis of age, sex, and treatment parameters yielded no significant relationship with cyst formation; however, radiation-induced tissue change following GKS (p = 0.027) and prior embolization (p = 0.011) were related to cyst formation.
Conclusions. Overall, the incidence of cyst formation in patients who underwent GKS for AVM was 1.6%. The development of the cyst was related to the duration of the follow-up period. When cysts are symptomatic, surgical intervention should be performed.
Hung-Chuan Pan, Jason Sheehan, Matei Stroila, Melita Steiner and Ladislau Steiner
Object. The authors conducted a study to evaluate the safety and efficacy of gamma knife surgery (GKS) for the treatment of brain metastases from lung cancer.
Methods. Between February 1993 and May 2003 191 patients underwent treatment for 424 brain metastases from non—small (171 cases) and small cell lung carcinoma (20 cases). Imaging and clinical status were monitored every 3 months following the treatment. Kaplan-Meier survival curves, Cox proportional hazards regression for risk factor analysis, and nonparametric methods for evaluating tumor response were used.
There was no difference in median survival following combined whole-brain radiation therapy (WBRT) and gamma knife surgery (14 months) and GKS alone (15 months). There was also no difference between the median survival rates for either tumor type. In the multivariate analysis, age less than 65 years, Karnofsky Performance Scale score greater than 70, normal neurological status, multiple GKS treatments, and pre-GKS craniotomy were related to longer survival.
Tumor control rates varied according to the volume of the metastases and were as follows: 84.4% (< 0.5 cm3), 94% (0.5–2 cm3), 89.1% (2–4 cm3), 93.4% (4–8 cm3), 85.7% (8–14 cm3), and 87.5% (> 14 cm3). Four lesions required post-GKS craniotomy due to swelling or rapid tumor progression. The rate of tumor shrinkage was higher when a volume was 2 cm3, lower in cystic lesions, lower in tumors with previous WBRT, and lower for margin doses less than 14 Gy.
Conclusions. The risk—benefit ratio of GKS in this series was satisfactory. There was no difference in response rates of the two tumor types, and WBRT did not improve the duration of survival.
Hung-Chuan Pan, Ming-Hsih Sun, Clayton Chi-Chang Chen, Chun-Jung Chen, Chen-Hui Lee and Jason Sheehan
Gamma Knife surgery (GKS) has been shown to be effective for treating many patients with brain metastasis. Some brain metastases demonstrate significant peritumoral edema; radiation may induce cerebral edema or worsening preexisting edema. This study was conducted to evaluate the imaging and neurobehavioral outcomes in patients with preexisting peritumoral edema who then undergo GKS.
Between August 2003 and January 2008, 63 cases of brain metastasis with significant peritumoral edema (> 20 cm3) were prospectively studied. The study inclusion criteria were as follows: 1) a single metastatic lesion with significant edema (perilesional edema signal volume on FLAIR > 20 cm3); and 2) inclusion of only 1 lesion > 20 cm3 in the study (in cases of multiple lesions noted on FLAIR images). All patients received MR imaging with pulse sequences including T1-weighted imaging and FLAIR with or without contrast and T2-weighted imaging at an interval of 3 months. A neurological assessment and Brain Cancer Module (BCM-20) questionnaire were obtained every 2–3 months. Kaplan–Meier, Cox regression, and logistic regression were used for analysis of survival and associated factors.
At the time of GKS, the median Karnofsky Performance Scale (KPS) score was 70 (range 50–90), and the mean BCM-20 score was 45.5 ± 6.1. The mean tumor volume (± standard deviation) was 5.2 ± 4.6 cm3 with corresponding T2-weighted imaging and FLAIR volumes of 59.25 ± 37.3 and 62.1 ± 38.8 cm3, respectively (R2 = 0.977, p < 0.001). The mean edema index (volume of peritumoral edema/tumor volume) was 17.5 ± 14.5. The mean peripheral and maximum GKS doses were 17.4 ± 2.3 and 35 ± 4.7 Gy, respectively. The median survival was 11 months. The longer survival was related to KPS scores ≥ 70 (p = 0.008), age < 65 years (p = 0.022), and a reduction of > 6 in BCM-20 score (p = 0.007), but survival was not related to preexisting edema or tumor volume. A reduction in BCM-20 score of > 6 was related to decreased volume in T1-weighted and FLAIR imaging (p < 0.001). Thirty-eight (79.2%) of 48 patients demonstrated decreased tumor volume and accompanied by decreased T2-weighted imaging and FLAIR volume. Eight (16.7%) of the 48 patients exhibited increased or stable tumor volume. A margin dose > 18 Gy was more likely to afford tumor reduction and resolution of peritumoral edema (p = 0.005 and p = 0.006, respectively). However, prior external-beam radiation therapy correlated with worsened preexisting peritumoral edema (p = 0.013) and longer maintenance of corticosteroids (p < 0.001).
Patients demonstrating a reduction in the BCM-20 score > 6, age < 65 years, and KPS score ≥ 70 exhibited longer survival. Significant preexisting edema did not influence the tumor response or clinical outcome. The resolution of edema was related to better quality of life but not to longer survival.
Hung-Chuan Pan, Jason Sheehan, Meei-Ling Sheu, Wen-Ta Chiu and Dar-Yu Yang
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.
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.
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).
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.
Chien-Yi Chiang, Meei-Ling Sheu, Fu-Chou Cheng, Chun-Jung Chen, Hong-Lin Su, Jason Sheehan and Hung-Chuan Pan
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.
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.
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.
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.
Hung-Chuan Pan, Jason Sheehan, Chuan-Fu Huang, Meei-Ling Sheu, Dar-Yu Yang and Wen-Ta Chiu
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.
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.
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%).
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.
Fu-Chou Cheng, Meei-Ling Sheu, Hong-Lin Su, Ying-Ju Chen, Chun-Jung Chen, Wen-Ta Chiu, Jason Sheehan and Hung-Chuan Pan
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.
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.
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.
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.