Results of a long-term follow-up after neuroendoscopic biopsy procedure and third ventriculostomy in patients with intracranial germinomas

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1 J Neurosurg (3 Suppl Pediatrics) 107: , 2007 Results of a long-term follow-up after neuroendoscopic biopsy procedure and third ventriculostomy in patients with intracranial germinomas TADAHISA SHONO, M.D., PH.D., 1 YOSHIHIRO NATORI, M.D., PH.D., 2 TAKATO MORIOKA, M.D., PH.D., 1 RINA TORISU, M.D., 1 MASAHIRO MIZOGUCHI, M.D., PH.D., 1 SHINJI NAGATA, M.D., PH.D., 1 SATOSHI O. SUZUKI, M.D., PH.D., 3 TORU IWAKI, M.D., PH.D., 3 TAKANORI INAMURA, M.D., PH.D., 4 MASASHI FUKUI, M.D., PH.D., 5 KAZUNARI OKA, M.D., PH.D., 6 AND TOMIO SASAKI, M.D., PH.D. 1 Departments of 1 Neurosurgery and 3 Neuropathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka; 2 Department of Neurosurgery, Aso Iizuka Hospital, Iizuka; 4 Inamura Neurosurgical Clinic, Fukuoka; 6 Department of Neurosurgery, Yamamoto Memorial Hospital, Imari; and 5 Sasebo Kyosai Hospital, Sasebo, Japan Object. The authors report the results of long-term follow-ups in 12 patients with intracranial germinomas who underwent neuroendoscopic procedures before chemotherapy and radiotherapy, and discuss the usefulness and safety of these procedures. Methods. Between January 1996 and December 2005 at Kyushu University Hospital, 12 patients with intracranial germinomas underwent neuroendoscopic biopsy procedures involving a flexible fiberscope. Eight patients simultaneously underwent endoscopic third ventriculostomy (ETV) for existing obstructive hydrocephalus. All patients received chemotherapy and radiotherapy postoperatively, according to the regimen promulgated by the Japanese Pediatric Brain Tumor Study Group. The patients were followed for an average of 78.6 months (range months), and a retrospective study was conducted. Results. Germinomas were histologically verified in all patients. No postoperative deaths or permanent morbidity was related to the neuroendoscopic procedures. No other cerebrospinal fluid diversion, such as that achieved with a ventriculoperitoneal shunt, was needed for the management of hydrocephalus. A complete response to postoperative chemotherapy and radiotherapy was achieved in all cases. Only one patient had a recurrent lesion in the spinal cord 6 years after the initial treatment; however, this patient had undergone only the neuroendoscopic biopsy procedure without ETV. Conclusions. Neuroendoscopic procedures can permit a precise histological diagnosis of intracranial germinomas and are safe and effective in the management of hydrocephalus associated with these tumors. The risk of tumor dissemination due to the neuroendoscopic procedures appears to be minimal when the appropriate chemotherapy and radiotherapy are provided postoperatively. (DOI: /PED-07/09/193) KEY WORDS biopsy endoscopic third ventriculostomy germinoma neuroendoscope pediatric neurosurgery tumor dissemination T Abbreviations used in this paper: AFP = -fetoprotein; CARE = carboplatin and etoposide; CSF = cerebrospinal fluid; ETV = endoscopic third ventriculostomy; HCG = human chorionic gonadotropin; ICE = ifosfamide, cisplatin, and etoposide; JPBTSG = Japanese Pediatric Brain Tumor Study Group; KPS = Karnofsky Performance Scale; MR = magnetic resonance; STGC = syncytiotrophoblastic giant cell. J. Neurosurg: Pediatrics / Volume 107 / September, 2007 HE incidence of intracranial germinoma is relatively high in Japan, and accounts for an estimated 2% of all primary brain tumors and 10% of brain lesions in patients younger than 30 years. 3 These tumors tend to appear around the ventricular systems and often are associated with hydrocephalus. Recent data have revealed that patients with intracranial germinomas can be cured using radiotherapy or combined chemotherapy and radiotherapy. 1,4,7, 12,13,20 However, a precise histological diagnosis is necessary to differentiate this tumor from others. 1,4,12,13,20 Data from previous reports have shown the feasibility of neuroendoscopic biopsy and ETV for the management of intracranial germinomas, 2,15,17,19,22 but a possible risk of tumor dissemination has been associated with these procedures. 5 Because results from several reports have shown late recurrence and dissemination of these lesions, 4,10,18,23 a longterm follow-up is necessary to clarify the safety of these 193

2 T. Shono et al. procedures, in particular, to evaluate the risk of tumor dissemination. We review a consecutive series of germinomas that were histologically verified using neuroendoscopic biopsy procedures; at present this series of lesions appears to be the largest from a single institute and to have the longest follow-up period. We report the clinical outcomes in these patients with special reference to tumor recurrence and dissemination and emphasize the utility and safety of neuroendoscopic procedures for intracranial germinomas. Patient Population Clinical Material and Methods Between January 1996 and December 2005, 34 patients with intracranial germ cell tumors were treated at Kyushu University Hospital. Among these patients, germinomas were histologically verified in 28. Twelve patients who underwent a neuroendoscopic biopsy procedure were selected for the present study (Table 1). There were 11 male and one female patient, with a mean age of years. There were 11 primary tumors and one recurrent tumor (Case 9) that had not been histologically verified or treated with chemotherapy. The levels of serum HCG were evaluated on admission in all cases. All patients underwent preoperative MR imaging studies and were shown to have various degrees of hydrocephalus and tumors exposed to the surface of the ventricle. Endoscopic Procedures Neuroendoscopic procedures were performed as described previously. 16,17 After a general endotracheal anesthetic was administered, the patient was placed supine in a neutral position. A linear skin incision was made 4 cm lateral to the midline and 1 cm in front of the coronal suture. The bur hole was created using a hand drill. The dura mater was incised, and the ventricle was cannulated using a 16-F peel-away sheath and stylet (Cook, Inc.). After withdrawal of the stylet, a 4-mm steerable fiberscope (VEF-1 or 2, Olympus Optical Co.) with a 2-mm-diameter working channel was inserted into the ventricle (Fig. 1A). Continuous irrigation with artificial CSF was used to maintain a fluid interface, to cool the CSF, and to prevent brain collapse. After inspection of the lateral and third ventricles, a tumor biopsy procedure was performed using 1.6-mm biopsy forceps (Fig. 1B). Because of the possibility of mixed histological features, a tumor biopsy specimen was obtained from at least three to six different sites. Hemorrhage from the tumor was controlled using local irrigation with artificial CSF or the contact laser endoprobe (PAL-1, M & M Co.). After irrigating away floating pieces of tumor tissue, ETV was performed unless tumor invasion of the premammillary area of the third ventricle floor was observed. A tiny stoma was made in the center of the tuber cinereum, among the infundibular recess and mammillary bodies, by using needle puncture (Fig. 1C). A percutaneous transarterial balloon catheter (Target Therapeutics) inserted into the stoma was inflated to enlarge the opening to 4 mm in diameter. The fiberscope sheath was then withdrawn, and a piece of Gelfoam was placed over the dura. A ceramic button was placed over the bur hole for cosmetic purposes. An external ventricular drain was placed through the bur hole to confirm complete hemostasis and to monitor intracranial pressure. Histopathological Examination Neuroendscopic biopsy samples were fixed in formalin before being processed into paraffin sections. Paraffin-embedded tumor samples were sectioned at 6 m and were processed for H & E staining and appropriate immuno- TABLE 1 Clinical characteristics in 12 patients with intracranial germinomas* Treatment Serum Chemotherapy Radiotherapy Current Case Age (yrs), Tumor HCG Level Histo Postop Type & No. of Type, Clinical FU KPS No. Sex Site (miu/ml) Dx ETV Complication Courses Dose (Gy) Outcome (mos) Score 1 18, M P, LV 0 G fever ICE 6 WB, 24 CR , M P, BG 2.7 G none CARE 8 EL, 30; L, 20 CR , M P 0 G none CARE 3 EL, 24 CR , M P, SS 2.1 G vomiting CARE 8 EL, 24 CR , F P, 4V, C G fever, transient CARE 3 EL, 24 CR lt hemiparesis 6 31, M P 0.6 G fever ICE 6 EL, 30; L, 20 CR , M P 0 G none CARE 3 EL, 24 CR , M P 0 G none CARE 6 EL, 30; L, 16 CR , M LV 0 G fever none WB, 30; EL, CR , M LV, 3V, 4V 225 G w/ fever CARE 3, EL, 50 rec at C STGCs ICE , M SS, BG, LV 0.3 G fever ICE 3 EL, 24 CR , M P, SS, LV 7.1 G none CARE 1, WB & spine, CR ICE 4 20; EL, 40 * BG = basal ganglia; CR = complete response; Dx = diagnosis; EL = extended local; FU = follow-up; G = germinoma; Histo = histological; L = local; LV = lateral ventricle; P = pineal; rec = recurrence; SS = suprasellar; WB = whole brain; 3V = third ventricle; 4V = fourth ventricle; = yes; = no. Recurrent tumor. 194 J. Neurosurg: Pediatrics / Volume 107 / September, 2007

3 Neuroendoscopic procedures in intracranial germinomas Tumor specimens were successfully obtained during neuroendoscopic biopsy procedures in all 12 cases. At no time were we required to convert a neuroendoscopic procedure to an open craniotomy. All tumor specimens were histopathologically confirmed to consist of germinoma cells, although one specimen contained STGCs (Case 10). Endoscopic third ventriculostomy was performed in eight cases; in the other four cases, it was not performed because the floor of the third ventricle was occupied by the tumors. In all cases, no other CSF diversion procedure, such as ventriculoperitoneal shunt insertion, was needed for the management of hydrocephalus. Postoperative Complications No postoperative deaths or permanent morbidity was related to the endoscopic procedures. Six patients (50%) had transient fever, which was relieved within a few days. No infectious complications were observed. In one patient, transient left hemiparesis (Medical Research Council Grade 4/5) was marked, probably because of a transient obstruction of the thalamostriate vein, but this deficit resolved completely within 2 days (Case 5). FIG. 1. Images depicting stages of a tumor biopsy and third ventriculostomy using a flexible neuroendoscope in a patient with a pineal germinoma. A: Neuroendoscopic view of the foramen of Monro. B: Neuroendoscopic view of a large tumor in the pineal region. C: Neuroendoscopic view of the third ventriculostomy. Arrows indicate the focus of each inset. staining for diagnosis, as described previously. 13 Histological diagnoses were made by two neuropathologists (T. Iwaki and S.O.S.) according to the latest World Health Organization classification of brain tumors. 8 Postoperative Treatment Postoperative chemotherapy was administered in all patients except one, according to the protocols proposed by the JPBTSG. 12 One patient with recurrent germinoma (Case 9) received only radiotherapy, because he had experienced serious myelosuppression following previous chemotherapy. Eleven patients received combination chemotherapy consisting of CARE or ICE. The CARE regimen consisted of carboplatin (450 mg/m 2 ) administered on Day 1 and etoposide (150 mg/m 2 ) for 3 consecutive days (Days 1 3). For the ICE regimen, ifosfamide (900 mg/m 2 ), cisplatin (20 mg/ m 2 ), and etoposide (60 mg/m 2 ) were given for 5 consecutive days (Days 1 5). For large or multiple/disseminated tumors, the ICE regimen was preferentially used. These regimens were repeated every 4 weeks for three courses as initial chemotherapy. After chemotherapy, all patients received radiotherapy consisting of 20 to 50 Gy directed to the whole brain or to an area covering the lateral and third ventricles, with or without a local boost. For large or multiple/disseminated tumors, a maximum of five courses of maintenance chemotherapy (CARE or ICE) were added. Results Tumor Biopsy Procedures and ETV J. Neurosurg: Pediatrics / Volume 107 / September, 2007 Response to Treatment and Follow-Up The response to postoperative chemoradiotherapy was evaluated on MR images in all 12 cases; a complete response was achieved in all patients. Follow-up studies, including clinical examinations and MR imaging, were performed in all patients. The follow-up periods ranged from 15 to 134 months (mean 78.6 months). All patients survived; however, one patient had a tumor recurrence in the cervical spinal cord (Case 10). At the latest follow-ups, the KPS score was 90 or higher in nine patients, 80 in one patient, and 70 in two patients. Illustrative Case History and Examination. This 30-year-old man was admitted to our hospital on May 17, 2000, with vertigo and vomiting. Computed tomography scans and MR images revealed multiple mass lesions in the lateral, third, and fourth ventricles. These lesions were heterogeneously enhanced on T1-weighted MR images following intravenous injection of Gd-diethylenetriamine pentaacetic acid (Fig. 2A C). Although the level of serum AFP was normal, the level of serum HCG was elevated (250 miu/ml). To confirm the histological diagnosis, a neuroendoscopic biopsy procedure was performed on May 24, During surgery, multiple tumor disseminations were observed on the wall of the ventricle, and specimens were obtained from the lesions in the third ventricle. Endoscopic third ventriculostomy was not performed because the floor of the third ventricle was occupied by tumor. Histological examination of the surgical specimens revealed that the lesion consisted of a solid proliferation of large polygonal tumor cells with prominent nucleoli and clear cytoplasm. Lymphocytic cuffing was seen around the blood vessels. A small number of multinucleated giant cells were also observed, and these giant cells were immunopositive for HCG- ; therefore, the tumor was diagnosed as a germinoma with STGCs. Treatment. As initial therapy, three courses of CARE, followed by radiotherapy consisting of 50 Gy directed to the area covering the lateral, third, and fourth ventricles, were 195

4 T. Shono et al. FIG. 2. Case 10. Axial (A and B) and sagittal (C) T1-weighted Gd-enhanced MR images showing multiple tumors in the lateral, third, and fourth ventricles before a neuroendoscopic biopsy procedure in May The tumor was diagnosed as germinoma with STGCs. Postoperative chemoradiotherapy led to a complete treatment response, and the patient was followed up for 6 years. Axial (D and E) and sagittal (F) follow-up MR images obtained in September 2006, demonstrating a Gd-enhanced mass lesion in the cervical spinal cord at the C-6 level, although no intracranial tumor was observed. administered. A complete response was achieved after this initial chemoradiotherapy, and the level of serum HCG was decreased to within normal range. Three courses of ICE were administered as maintenance chemotherapy. Posttreatment Course. The patient was followed-up for 6 years. On September 13, 2006, follow-up MR images demonstrated a Gd-enhanced mass lesion in the cervical spinal cord at the C-6 level (Fig. 2F). The levels of HCG in the serum and CSF were elevated to 6.9 and 114 miu/ml, respectively; therefore, a recurrent HCG-producing germinoma was clinically diagnosed. Salvage chemotherapy (three courses of CARE) and radiotherapy consisting of 30 Gy directed to the whole spinal cord were administered. These treatments induced a complete response, and the patient is presently being followed-up again. Discussion Some germ cell tumors can be clinically diagnosed from findings in neuroimaging studies and examination of serum tumor markers, such as HCG in choriocarcinomas and AFP in yolk sac tumors, without a tumor biopsy procedure. 9,12,13 Although the detection of some tumor markers in the CSF (such as placental alkaline phosphatase, 21 HCG, 6 and soluble c-kit 14 ) is helpful in diagnosing germinomas, elevations of these markers in germinomas are not as prominent as those of HCG in choriocarcinomas or AFP in yolk sac tumors. Moreover, collection of CSF by spinal tap includes some risk of brain herniation because of the increased intracranial pressure, and neuroradiological findings in some neuroepithelial tumors, such as gliomas and pineocytomas, sometimes resemble those of germinomas. Thus, histological confirmation is necessary for the precise diagnosis of intracranial germinomas. To sample tumor tissue, an open, a stereotactic, or a neuroendoscopic biopsy procedure is conducted. Recently, the usefulness of a neuroendoscopic biopsy procedure incorporating rigid or flexible devices has been highlighted because of its minimal invasiveness; 2,15, 17,19,22 however, a possible risk of tumor dissemination has been associated with these procedures. 5 In the present series, seven patients had elevated levels of serum HCG. In these cases, although germ cell tumors were highly suspected preoperatively, we still thought histological confirmation was necessary to determine the appropriate adjuvant therapy (dose and field of irradiation and intensity of chemotherapy) given that these lesions may consist of different components (that is, mixed germ cell tumors). In addition, we have noted a suprasellar pilomyxoid astrocytoma with a slight increase of HCG in CSF (unpublished data). According to the literature, the incidence of spinal dissemination in patients with intracranial germinomas ranges from 6 to 36%. 7,11,13 Jennings and colleagues 7 reviewed 253 germinoma cases and found that 11% of the patients had 196 J. Neurosurg: Pediatrics / Volume 107 / September, 2007

5 Neuroendoscopic procedures in intracranial germinomas J. Neurosurg: Pediatrics / Volume 107 / September, 2007 presented with spinal metastasis. Maity and associates 11 reported on 39 patients with biopsy-proven intracranial geminomas, which were treated with radiotherapy alone, and the incidence of dissemination was 36%. Matsutani and colleagues 13 described 50 patients with histologically verified germinomas, which were treated with radiotherapy alone or combined with chemotherapy; three recurrent or disseminated tumors appeared outside the irradiated fields. In the present series, spinal dissemination occurred in only one (8%) of 12 patients after neuroendoscopic biopsy procedures. The incidence of spinal dissemination in the present series is not higher than those in other reported series. Haw and Steinbok 5 reported on a case of ventriculoscope tract recurrence after endoscopic biopsy of a pineal pure germinoma. The patient in this particular case had received local radiotherapy of 45 Gy without chemotherapy, and the ventriculoscope tract appeared to be outside the irradiated field. Among the cases in the present study, 11 patients received both chemotherapy and radiotherapy, and one patient who did not receive chemotherapy was treated with whole-brain radiotherapy. To avoid tumor recurrence or dissemination, combined chemotherapy and radiotherapy or radiotherapy alone, applied to the endoscope tract as well, appears to be necessary after neuroendoscopic biopsy of a germinoma. The role of chemotherapy in the treatment of intracranial germinomas remains controversial. A long-term survival rate of more than 90% has been achieved with craniospinal irradiation alone. 11 However, sole treatment with radiation requires a dose of 40 to 55 Gy applied to entire ventricles or larger fields, which can cause endocrine disorders and cognitive impairment. 1 Given that platinum-based chemotherapy has proven to be effective in the treatment of intracranial germinomas as well as gonadal germ cell tumors, several groups have tried to use chemotherapy in conjunction with radiotherapy to reduce the radiation dose and field. In Japan, Matsutani and the JPBTSG 12 have conducted a multiinstitutional Phase II study of combined chemotherapy with reduced-dose radiotherapy in patients with intracranial germinomas. We have followed their protocol, and the clinical results appear to be excellent, with a high tumor control rate thus far; only one relapse has occurred (Case 10). In the present series, three patients had a relatively lower performance status (KPS Score 70 80) during the followup. One patient (Case 5) had a disseminated lesion in the spinal cord at the C-1 level and presented with a gait disturbance caused by deterioration in deep sensation; despite complete remission of the tumor, this symptom remains. Another patient (Case 9) had impaired cognitive function, although the symptom was already apparent on admission. Nonetheless, the postoperative radiotherapy may have been associated with this symptom because the patient received whole-brain radiotherapy. In Case 12, the patient presented with impairment of visual acuity preoperatively, and the symptom has not resolved during the follow-up period. Matsutani and associates 13 reported that the recurrence rates of germinomas with STGCs are higher than those of pure germinomas. Among the seven patients in their study who had germinomas with STGCs, one patient treated with radiation alone and two patients treated with chemoradiotherapy experienced tumor recurrences. In the recurrent case in the present study (Case 10), the level of serum HCG was elevated, and the tumor was pathologically diagnosed as a germinoma with STGCs. Moreover, this patient had multiple disseminated lesions in the ventricular system on presentation and did not undergo ETV. This evidence suggests that the spinal dissemination in this patient might have been due to the natural course of the disease and not the result of the neuroendoscopic procedures. Yamini and associates 24 reviewed data in 54 patients who had undergone neuroendoscopic biopsy of pineal tumors, including gliomas, pineocytomas, and other tumor types, and reported that the accuracy of the histological diagnosis was 89%. In the present study, tumor specimens were successfully obtained in all cases and were diagnosed as germinomas. The accuracy of the histological diagnoses is supported by the fact that all tumors responded immediately to postoperative chemoradiotherapy. In comparison with gliomas, which are often covered by the ependymal wall, tumor samples of germinomas are relatively easy to obtain via neuroendoscopic biopsy procedures, because these lesions are usually extruded from the surface of the ventricle. In addition, with the aid of two neuropathologists, we recently performed intraoperative histological diagnosis using frozen sections. We repeated biopsy sampling until the pathologists became confident with the diagnosis, which is extremely important for a precise histological diagnosis of the tumor and a decision regarding subsequent treatment. Early postoperative complications of the neuroendoscopic procedures included transient fever in six cases (50%) and vomiting in one case (8%). Chernov and associates 2 reported that 15 patients (65%) who had undergone neuroendoscopic biopsy of pineal region tumors had presented with transient fever. The nature of this transient fever is unknown, but it is speculated to be due to an adverse effect of the artificial CSF, irritation of the hypothalamus caused by small hemorrhages, a mechanical effect of the third ventricle floor perforation, or the possible presence of air in the ventricles and subarachnoid space. One of the patients (Case 5) in the current series presented with mild left hemiparesis, which resolved completely within 2 days. We speculated that the disorder resulted from a transient obstruction of the thalamostriate vein, because postoperative computed tomography scanning revealed a small hemorrhage at the right foramen of Monro within the neuroendoscopic tract and a small lowdensity area in the ipsilateral thalamus and the internal capsule. The most serious reported complication of neuroendoscopic procedures is intraoperative bleeding, especially that caused by injury of the basilar artery or its perforating arteries during ETV. 2 We performed ETV in eight cases in the present series and have not experienced these fatal complications. In these cases, we observed obstructive hydrocephalus due to stenosis of the sylvian aqueduct, and tumor invasion of the premammillary area was not evident during neuroendoscopic inspection. Computed tomography scans revealed that the hydrocephalus was relieved immediately after the operation, and we were able to remove the ventricular drain within a few days. Conversely, we did not perform ETV in four cases, because tumor invasions of the premammillary area of the third ventricle were evident. All of these patients had various degrees of hydrocephalus; however, none of them needed ventriculoperitoneal shunt insertion. We continued the ventricular drainage for 1 or 2 weeks and started chemotherapy immediately after a histological diagnosis had been made. After the first course of chemotherapy, computed tomography scans revealed that 197

6 T. Shono et al. the tumors had started to shrink, and hydrocephalus was relieved in all cases. As a consequence, we could remove the external ventricular drain within 2 weeks, without infectious complications. Therefore, the indication for ETV might be limited when the intraoperative diagnosis is pure germinoma and tumor invasion of the premammillary area is observed. Conclusions Neuroendoscopic procedures can permit a precise histological diagnosis of intracranial germinomas, especially intraoperatively. The risk of tumor dissemination due to neuroendoscopic procedures appears to be minimal when the appropriate chemotherapy and radiotherapy regimens are provided postoperatively. Although ETV is effective in the management of hydrocephalus associated with these lesions, it might have limited indications when tumor invasions of the premammillary area are observed. References 1. 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J Neurosurg 91: , Oka K, Yamamoto M, Nagasaka S, Tomonaga M: Endoneurosurgical treatment for hydrocephalus caused by intraventricular tumors. Childs Nerv Syst 10: , Ono N, Isobe I, Uki J, Kurihara H, Shimizu T, Kohno K: Recurrence of primary intracranial germinomas after complete response with radiotherapy: recurrence patterns and therapy. Neurosurgery 35: , Pople IK, Athanasiou TC, Sandeman DR, Coakham HB: The role of endoscopic biopsy and third ventriculostomy in the management of pineal region tumors. Br J Neurosurg 15: , Sawamura Y, Shirato H, Ikeda J, Tada M, Ishii N, Kato T, et al: Induction chemotherapy followed by reduced-volume radiation therapy for newly diagnosed central nervous system germinoma. J Neurosurg 88:66 72, Shinoda J, Yamada H, Sakai N, Ando T, Hirata T, Miwa T: Placental alkaline phosphatase as a tumor marker for primary intracranial germinoma. J Neurosurg 68: , Wellons JC III, Reddy AT, Tubbs RS, Abdullatif H, Oakes WJ, Blount JP, et al: Neuroendoscopic findings in patients with intracranial germinomas correlating with diabetes insipidus. J Neurosurg 100 (5 Suppl Pediatrics): , Wenger M, Lovblad KO, Markwalder R, Taub E: Late recurrence of pineal germinoma. Surg Neurol 57:34 40, Yamini B, Refai D, Rubin CM, Frim DM: Initial endoscopic management of pineal region tumors and associated hydrocephalus: clinical series and literature review. J Neurosurg 100 (5 Suppl Pediatrics): , 2004 Manuscript submitted March 7, Accepted June 1, Address reprint requests to: Tadahisa Shono, M.D., Ph.D., Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka , Japan. tshono@ns.med.kyushu-u.ac.jp. 198 J. Neurosurg: Pediatrics / Volume 107 / September, 2007