Quantitative short echo time 1H-MR spectroscopy of untreated pediatric brain tumors: preoperative diagnosis and characterization.

PURPOSE: Our aims were to evaluate the metabolic profiles of pediatric brain tumors with short echo time (TE) MR spectroscopy and absolute quantitation of metabolite concentrations (in mmol/kg of tissue) and to describe metabolic features that distinguish individual tumor types and that may help to improve preoperative diagnosis of specific tumors. METHODS: MR imaging examinations of 60 patients with untreated brain tumors (14 medulloblastomas, 5 anaplastic astrocytomas, 3 low-grade astrocytomas, 17 pilocytic astrocytomas, 4 anaplastic ependymomas, 5 ependymomas, 3 choroid plexus papillomas, 3 choroid plexus carcinomas, and 6 pineal germinomas) were reviewed. Single-voxel proton MR spectroscopy with a TE of 35 ms was performed and absolute metabolite concentrations were determined by using fully automated quantitation. RESULTS: Taurine (Tau) was significantly elevated in medulloblastomas (P < .00001) compared with all other tumors pooled (All Other). Tau was also observed consistently, at lower concentration, in pineal germinomas. Creatine (Cr) was significantly reduced in pilocytic astrocytomas, distinguishing them from All Other (P < .000001). The MR spectra of choroid plexus papillomas exhibited low Cr (P < .01) concentrations; however, myoinositol was elevated (P < .01) and total choline (tCho) (P < .0001) was reduced relative to All Other. Choroid plexus carcinomas had low Cr (P < .01 versus All Other) and the lowest Cr/tCho ratio (P < .0001 versus All Other) among all tumors studied. Guanidinoacetate was reduced in low-grade astrocytomas and anaplastic astrocytomas (P < .00001) versus All Other, whereas ependymoma and anaplastic ependymomas exhibited particularly low N-acetylaspartate (P < .00001 versus All Other). CONCLUSION: Quantitative proton MR spectroscopy reveals features of pediatric brain tumors that are likely to improve preoperative diagnoses.

Injuries from falls in the pediatric population: an analysis of 729 cases.

BACKGROUND/PURPOSE: Falls are classified as low or high level for triage purposes. Because triage criteria dictate less urgency for low-level falls, this classification scheme has important implications for pediatric emergency care. METHODS: Retrospective analysis was conducted of 729 (393 low-level and 336 high-level) pediatric patients treated for fall-related trauma (1992 through 1998). Falls were classified as low (<15 feet) or high-level (> or =15 feet). All falls were reported as accidental or unintentional. RESULTS: The overall mortality rate was 1.6% (2.4% for high-level falls compared with 1.0% for low-level falls). All 4 patients who died of a low-level fall had an abnormal head computed tomography (CT) scan and intracranial hypertension. Half of deaths from high-level falls were attributable to intracranial injuries, and half were caused by severe extracranial injuries. Common extracranial injuries were upper extremity fracture (6.2%), lower extremity fracture (5.6%), pulmonary contusion (1.8%), pneumothorax (1.1%), liver laceration (1.1%), bowel injury (1.0%), and splenic injury (2.1%). Orthopedic and thoracic injuries resulted more commonly from high-level falls, whereas abdominal injuries were as likely to occur after a low-level fall. CONCLUSIONS: Intracranial injury accounts for the majority of deaths from falls. Children suffering low-level falls were at similar risk for intracranial and abdominal injuries compared with those who fell from greater heights. Pediatric trauma triage criteria should account for these findings.

Maternal lung adenocarcinoma metastatic to the scalp of a fetus. Case report.

Maternal malignancy metastatic to the fetus is a rare event, with most neoplasms being either melanocytic or hematopoietic in origin. This report is the first known case of a maternal lung adenocarcinoma metastatic to a fetus. At 2 months of age, this male infant developed multiple scalp masses that were locally resected but rapidly recurred. The histology of the scalp lesions and that of a biopsy of the mother's tumor were both adenocarcinoma and were remarkably similar in appearance. In situ hybridization of tumor cells from this male infant found many large nuclei with XX signals indicating that the tumor was of maternal origin. This patient is alive, well and free of malignancy 5 years after a wide local resection of the scalp and skin grafting.

Vagus nerve stimulation for control of intractable seizures in childhood.

Vagus nerve stimulation (VNS) is gaining increasing popularity and credibility as a treatment option for children with intractable epilepsy. VNS offers several advantages over extant treatments. Its efficacy is maintained during prolonged stimulation, and seizure control actually improves with time. There is no associated cognitive impairment and no adverse drug interactions. Unlike cerebral surgery, VNS is a potentially reversible form of therapy. The computer-controlled characteristic of the device permits complete and involuntary treatment compliance. VNS is safe and well-tolerated. Its side effects are generally transient and mild, and no physiologic perturbations have been reported despite extensive monitoring. Serious adverse events are rare, and no deaths have been attributed to VNS therapy itself or to the technique of surgical insertion. In this article, we discuss the theoretical background behind VNS and review the clinical studies that substantiate its long-term safety, feasibility, tolerability and potential efficacy in children with refractory epilepsy.

Choroid plexus tumors in children: significance of stromal invasion.

OBJECTIVE: A group of choroid plexus tumors fit the cellular criteria for choroid plexus papilloma (CPP) except for invasion into the adjacent parenchyma, with associated loss of the normal villus architecture at the site of invasion. These tumors retain a benign cellular appearance. In the existing literature, it is unclear whether these tumors are classified as choroid plexus carcinomas or as CPPs. In our experience, although evidence of invasion is present, these tumors tend to exhibit benign behavior. We suggest that stromal invasion of this type remains consistent with a benign clinical course, although surgical results may demonstrate higher morbidity rates, given the invasive nature of the tumors. The failure to classify these tumors as CPPs may explain some of the variability in outcomes reported for various studies. METHODS: To study this question, clinical and histological data for children diagnosed with CPPs (either with or without stromal invasion) between 1985 and 1995 were examined. Only cases with pre- and postoperative magnetic resonance imaging data were included in the series. RESULTS: A total of 12 patients with CPPs were identified, with 4 tumors being notable for stromal invasion. After gross total tumor removal, none of the eight children with CPPs received adjuvant therapy at our institution; all are alive without evidence of tumor recurrence after surgical excision (mean, 108 mo). Of the four patients with stromal invasion, three underwent gross total resection. The one patient who underwent subtotal resection received chemotherapy at another facility. All four of these patients are alive, after a mean of 100 months of follow-up monitoring. CONCLUSION: It is recommended that CPPs with a benign cellular appearance but with evidence of local parenchymal invasion and loss of the normal villus architecture at the site of invasion be classified as CPPs. Patients with these tumors respond to surgical therapy alone, without the need for adjuvant treatment.

Long-term outcome of terminal myelocystocele patients.

INTRODUCTION: A terminal myelocystocele, a closed form of a neural tube defect (NTD), can present as a large, fully epithelialized, cystic lumbosacral mass containing fat, cerebrospinal fluid (CSF) and neural tissue. The spinal cord terminates at a neural placode wherein the central canal opens into a CSF-filled cavity that is distinct from fluid in the subarachnoid space surrounding the spinal cord. This form of NTD, in our experience, was only associated with major caudal cell mass abnormalities, as these patients often have maldevelopment of the lower spine, pelvis, genitalia, bowel, bladder, kidney and the abdominal wall. This study will describe the clinical manifestations, surgical management and long-term outcome of our terminal myelocystocele patients. METHODS: To characterize this rare entity, a 13-year retrospective review was undertaken at our institution. RESULTS: Nine patients with terminal myelocystoceles were identified. In all cases, there were multiple congenital defects including cloacal exstrophy, imperforate anus, omphalocele, pelvic deformity, equinovarus or renal abnormality. Only 1 out of 9 patients has required a shunt for hydrocephalus. The main goal of neurosurgical intervention was to reduce the size of the mass, which can slowly enlarge over time. The spinal cord was also untethered, although these patients have no chance of bowel or bladder control. With a mean follow-up of 63 months, all patients remained neurologically stable. Impairment of lower extremity function is usually severe. However, some patients were ambulatory with the aid of a walker or orthotic device. All patients required a prolonged hospital stay as well as multiple operations prior to initial discharge. CONCLUSION: Experienced, multispecialty care is needed to optimize the long-term outcome of these complex patients.

Treatment of progressive or recurrent pediatric malignant supratentorial brain tumors with herpes simplex virus thymidine kinase gene vector-producer cells followed by intravenous ganciclovir administration.

OBJECT: The outcome for children with recurrent malignant brain tumors is poor. The majority of patients die of progressive disease within months of relapse, and other therapeutic options are needed. The goal of this Phase I study was to evaluate the safety of in vivo suicide gene therapy in 12 children with recurrent, malignant, supratentorial brain tumors. METHODS: After optimal repeated tumor resection, multiple injections of murine vector-producing cells shedding murine replication-defective retroviral vectors coding the herpes simplex virus thymidine kinase type 1 (HSV-Tk1) gene were made into the rim of the resection cavity. Fourteen days after the vector-producing cells were injected, ganciclovir was administered for 14 days. The retroviral vector that was used only integrated and expressed HSV-Tk1 in proliferating cells, which are killed after a series of metabolic events lead to cell death. The median age of the patients was 11 years (range 2-15 years). Treated brain tumors included seven malignant gliomas, two ependyminomas, and three primitive neuroectodermal tumors. The patients were treated with one of three escalating dose concentrations of vector-producer cells. Four transient central nervous system adverse effects were considered possibly related to the vector-producing cells. In no child did permanent neurological worsening or ventricular irritation develop, and tests for replication-competent retroviruses yielded negative findings. CONCLUSIONS: This Phase I study demonstrates that in vivo gene therapy in which a replication-defective retroviral vector in murine vector-producing cells is delivered by brain injections can be performed with satisfactory safety in a select group of children with localized supratentorial brain tumors.

Integration of a variable action suction adapter into ultrasonic aspirators.

PURPOSE: Use of ultrasonic aspirators has become a mainstay in the neurosurgical armamentarium. The handpiece design and ultrasonic parameters have evolved to maximize its safe and efficacious use. Despite these modifications, continuous suction through the tip of the aspirator can result in neurovascular damage, especially when the aspirator is working in the cavernous sinus region or cerebellopontine angle. CONCEPT: We describe the integration of a variable suction adapter into the existing handpiece of an ultrasonic aspirator to minimize potential injury from the continuous forceful suction normally associated with the use of these devices. RATIONALE: The integration of such an adapter can reduce the potential for suction injury to cranial nerves or microvascular structures or smaller-caliber arteries and veins. DISCUSSION: This variable action suction adapter can decrease suction injuries to cranial nerves or the microvasculature.

Retroviral vector-mediated transfer and expression of human tissue plasminogen activator cDNA in bovine brain endothelial cells.

OBJECTIVES: Gene transfer of thrombolytic enzymes to vascular endothelial cells may influence the kinetics of intravascular thrombosis. This study defines the potential for gene transfer of tissue plasminogen activator (tPA) into bovine brain endothelial cells (BBEC). METHODS: The retroviral vectors derived from murine leukemia virus (MuLV) were used to transfer human tPA cDNA to BBEC. The tPA activity, tPA antigen and tPA inhibitor 1 (PAI-1) antigen were determined in the supernatant of transduced (BBEC/tPA) cell cultures by an immunoassay. RESULTS: The tPA antigen and enzymatic activity in cell culture supernatants of BBEC/tPA transduced cells were 75 ng/ml and 14 IU/ml after 4 days, that was 25 and 28-fold higher compared to the respective values in control cells. The PAI-1 antigen was not affected by tPA cDNA transfer. The Western blot assay of cell lysates confirmed that the majority of tPA in BBEC/tPA transduced cells was in the form of free tPA. While the maximal transduction efficiency of BBEC with an amphotropic MuLV vector was about 15%, a MuLV pseudotyped with vesicular stomatitis virus G glycoprotein envelope achieved high > 90% maximal transduction efficiency. CONCLUSIONS: The fibrinolytic activity of brain endothelial cells can be enhanced by transferring human tPA cDNA. These findings provide an initial step in implementation of future studies that investigate the use of this technology as an adjunctive treatment for cerebrovascular disease.

A prospective analysis of the use of octylcyanoacrylate tissue adhesive for wound closure in pediatric neurosurgery.

OBJECTIVE: Cyanoacrylate monomers have been developed for use as skin adhesives. Previous studies have demonstrated that using this skin adhesive for the closure of traumatic lacerations results in excellent cosmesis, decreased procedure-related pain and timesavings. SURGICAL TECHNIQUE: Octylcyanoacrylate skin adhesive is applied after the placement of deep fascial sutures with close approximation of the skin edges. The adhesive is applied in liquid form and polymerizes rapidly to solid form. Multiple layers are applied forming a hard impenetrable barrier. RESULTS: This technique was prospectively evaluated in the closure of 102 elective neurosurgical operations with 142 incisions: ventriculoperitoneal shunt insertion/revision (53%) and craniotomy for tumors (10%) were the commonest procedures. There were a total of 83 scalp, 36 abdominal, 8 neck, 6 chest and 6 lumbar incisions. The mean incision length was 5.1 cm (range 0.25-50 cm). Fifty-nine percent of the wounds had previous areas of operative incisions. Complications included 1 poor cosmetic result and 4 cerebrospinal fluid (CSF) leaks. Of the 4 patients with CSF leaks, 2 required operative wound revision, and 1 required ventriculoperitoneal shunting for hydrocephalus. CONCLUSION: Cyanoacrylate skin adhesive is a viable means of obtaining cosmetic wound closure. Its use requires attention to proper skin approximation and hemostasis. In our experience, propensity for CSF leakage especially in reoperative procedures is a relative contraindication.

Intraoperative angiography in the management of pediatric vascular disorders.

We reviewed our experience with intraoperative angiography in the management of 7 cerebral aneurysms and 15 arteriovenous malformations (AVMs) in children over the past 5 years. The patients ranged from 4 months to 18 years of age with a mean age of 9 years. In 4 of the 22 cases, angiography provided information that led to changes during surgery. In 3 cases, the intraoperative angiogram revealed residual AVMs that were then completely resected. In 1 patient with an anterior circulation aneurysm, intraoperative studies revealed findings which resulted in clip repositioning. Intraoperative angiography added a mean of 43 (+/-19) min to the operative time, with a mode of 40 minutes. There was 1 complication, a groin hematoma that readily resolved. Intraoperative angiography prolongs to operative course; however, it is a useful adjunct to the management of vascular disorders in children. We now routinely use and recommend intraoperative angiography to assist with the surgical management of vascular malformations in children.

Omental transfer to the brain: an experimental study in hydrocephalic rabbits.

Hydrocephalus is a common and potentially lethal condition in children that results from an imbalance between absorption and production of cerebral spinal fluid (CSF). Silastic shunts are inserted to drain excess CSF, but they are prone to a number of problems, and at times may be unreliable and ineffective. This study examines the physiological basis of a pedicled omental transfer to the brain as a functional conduit for CSF in an experimentally induced hydrocephalic rabbit model. The ability of the omentum to transport CSF from the subarachnoid space was tested using radioactive tracer substances: radio-iodinated serum albumin (125I-RISA), chromium 51-ethylenediaminetetraacetate (51Cr-EDTA), and technetium 99m (99mTc) glucoheptonate. Immediate ability of exteriorized omentum to transport artificial CSF, as well as transposed omental transport of subarachnoid CSF at 1 month, were examined. Nuclear scan measurements were correlated with clinical observation and a double-blind histological analysis with trichrome and hematoxylin-eosin stain. Exteriorized omentum rapidly absorbed 99mTc glucoheptonate-labeled artificial CSF, with a rapid appearance in the systemic circulatory and urinary systems. Transposed omentum to the brain in animals with artificially created hydrocephalus showed evidence of CSF-labeled 125I-RISA and 51Cr-EDTA absorption in those animals demonstrating histologically viable omentum.

Stereoscopic head-mounted display incorporated into microsurgical procedures: technical note.

OBJECTIVE: We have previously evaluated video technologies that have allowed for the use of electronic imaging during microneurosurgical and endoscopic procedures. This stereoscopic camera set and monitor/recording system allows for the use of stereoscopic images during surgery by the primary surgical assistant and ancillary personnel. It also allows for stereoscopic recording and playback using a wide video home system format. We describe a novel prototype of a head-mounted display (HMD) that allows the surgical team to simultaneously visualize the surgical field stereoscopically and includes picture-in-picture, voice control, and stereoscopic recording capabilities. INSTRUMENTATION: A stereoscopic HMD with 640 x 480 (video graphics array) pixel resolution and the ability to display 24-bit images has been designed. This device weighs 900 g. It is interfaceable with common video display formats. RESULTS: This stereoscopic HMD is being evaluated in a prospective multicenter trial of open microsurgical and endoscopic minimally invasive procedures. In our experience to date, there have been no equipment failures or complications attributable to the use of the display system. The equipment was well accepted by users who reported significant benefits in visualization. CONCLUSION: The use of a stereoscopic HMD may result in improved efficiency and safety in both endoscopic and open microsurgical procedures. We have verified that the HMD is comfortable during the course of a surgical procedure, is reliable, and allows for accessibility to the operative field with an excellent field of view and three-dimensional perception. Positioning and dexterity within the operative field are also enhanced. Additional uses relate to surgical training, multimodal information display, and operative rehearsals.

Intravenous RMP-7 increases delivery of ganciclovir into rat brain tumors and enhances the effects of herpes simplex virus thymidine kinase gene therapy.

Herpes simplex virus thymidine kinase (HSV-tk) gene therapy for brain tumors depends on ganciclovir (GCV) and its transport across the blood-brain tumor barrier (BBTB). We examined whether RMP-7, the bradykinin analog and potent BBTB permeabilizer, could enhance the efficacy of GCV treatment of brain tumors by increasing the BBTB delivery of GCV. In vitro, a significant bystander cytocidal effect of GCV was shown in mixed HSV-tk-transduced (HSV-tk+) and control vector-transduced (HSV-tk-) C6 glioma cultures. A dose-dependent cytotoxic effect of GCV on untransformed C6 cells was also shown. In vivo, rats with 100% HSV-tk+ or 100% HSV-tk- intracerebral C6 gliomas were treated for 7 days with intravenous infusions of GCV alone or with GCV and RMP-7 (2.5 microg/kg/day). The growth of HSV-tk+ and HSV-tk- gliomas decreased with increasing doses of GCV. A high dosage (100 mg of GCV/kg/day) eradicated all HSV-tk- and HSV-tk+ tumors. An intermediate dosage (5 mg of GCV/kg/day) reduced the growth of HSV-tk- gliomas by 42% if given alone, and by 88% in combination with RMP-7. A low dosage (0.5 mg of GCV/kg/day) in combination with RMP-7 enhanced the regression of HSV-tk+ gliomas by 87% compared with GCV alone. Low-dose GCV was ineffective in HSV-tk- tumors. RMP-7 increased [3H] GCV tumoral uptake by 2.6- and 1.7-fold in the tumor center and periphery, respectively. We conclude that RMP-7 could be an important adjunctive treatment for suicide gene therapy of brain tumors, while an RMP-7/GCV combination may also have a significant antitumor effect in untransfected gliomas.

Spinal and cranial neural tube defects.

Developmental lesions of the central nervous system with failure of normal midline fusion are often referred to as being dysraphic and vary from inapparent and insignificant to a massive deformity incompatible with survival. Several different schemata are used to classify this wide variety and often complex set of malformations; however, the nomenclature is confusing and even contradictory. As most of these congenital lesions of clinical significance involve an aberration in the formation of the neural tube, it is suggested that the term neural tube defects (NTD) be used to characterize this entire group of anomalies. From a practical clinical standpoint, NTD can be subdivided into three main groupings: open spinal NTD, closed spinal NTD, and cranial NTD. This article briefly covers the epidemiology, embryology, classification, clinical presentation, and management of this group of congenital lesions.

Surgical treatment of craniosynostosis: outcome analysis of 250 consecutive patients.

OBJECTIVE: Surgery for craniosynostosis has evolved rapidly over the past two decades, with increased emphasis on early, extensive operations. Older published series may not accurately reflect more recent experience. Our study was designed to analyze outcome in a large series of consecutive patients treated recently at a single center. METHODS: We reviewed 250 consecutive patients who underwent surgical treatment of craniosynostosis between January 1, 1987 and December 31, 1992. They were divided into nine groups by suture involvement: sagittal, unilateral coronal, bilateral coronal, unilateral lambdoid, bilateral lambdoid, metopic, multiple suture, the Klee-blattschädel deformity (cloverleaf skull), and acquired craniosynostosis. Outcome was analyzed in terms of residual deformities and irregularities, complications, mortality, as well as the need for additional surgery. RESULTS: There were 157 males (62. 8%) and 93 females (37.2%), with most of the male preponderance accounted for by the large sagittal synostosis group, which consisted of 82 males and 25 females. Median age at first operation was 147 days. A named syndrome was present in 23 patients (9.2%) and was more common than expected with bilateral and unilateral coronal synostosis, the Kleeblattschädel deformity, and multiple suture synostosis. There were two deaths (0.8%), both with Klee-blattschädel patients, and 17 other complications (6.8%). Morbidity and mortality were significantly associated with secondary vs primary operations and syndromic vs nonsyndromic patients. Outcome analysis revealed the best surgical results with metopic synostosis and significantly less good results with the Kleeblattschädel deformity, multiple suture synostosis, and bilateral coronal synostosis. CONCLUSIONS: Using modern surgical techniques, craniosynostosis can be corrected with good outcomes and relatively low morbidity and mortality, particularly for otherwise healthy, nonsyndromic infants.

Recurrence patterns and anaplastic change in a long-term study of pilocytic astrocytomas.

Thirty-six cases of pilocytic astrocytomas treated at the Childrens Hospital of Los Angeles from 1984 through 1995 were reviewed. The mean age at initial presentation was 8 years (range 15 months to 14 years). These patients were followed for an average of 5.5 years. No patient was given chemotherapy or radiation therapy after the initial surgery for pilocytic astrocytoma. Twenty-three patients (64%) had a gross total resection with no residual tumor on immediate postoperative imaging studies. Three of these children had tumor recurrences 2-5 years after their initial surgery, requiring re-excision of their tumors. All 3 patients are subsequently tumor-free, with follow-up ranging from 4 to 10 years. In 4 patients with residual tumor involving the brainstem, there has been neither imaging evidence of tumor enlargement nor progression of clinical findings at 2.5, 4, 6 and 6 years, respectively. Nine of the 13 patients with residual tumor underwent re-excision, either for progression of symptoms or documented tumor growth on imaging studies. The second operation was undertaken an average of 1 year (range 1 month to 6 years) after the first. In 4 of these children (11% of our whole series), the recurrent tumor was classified as anaplastic astrocytoma. Three of these 4 children received radiation and/or chemotherapy, with only 1 patient showing disease progression in the follow-up period. Repeat blinded histopathological examination of these tumors confirmed both diagnoses. However, it was noted that 3 of the 4 pilocytic astrocytomas which subsequently showed anaplastic change initially displayed increased perivascular cellularity, while only 2 of the remaining 32 tumors exhibited this feature. These results encourage continued vigilance in the follow-up of pilocytic astrocytomas, and describe a histological feature which might indicate a more aggressive disease course.