Radiosurgery in the management of pediatric brain tumors.

OBJECTIVE: To describe the outcome of pediatric brain tumor patients following stereotactic radiosurgery (SRS), and factors associated with progression-free survival. METHODS: We reviewed the outcome of 90 children treated with SRS for recurrent (n = 62) or residual (n = 28) brain tumors over a 10-year period. Median follow-up from SRS was 24 months for all patients and 55.5 months for the 34 patients currently alive. RESULTS: The median progression-free survival (PFS) for all patients was 13 months. Median PFS according to tumor histology was medulloblastoma = 11 months, ependymoma = 8.5 months, glioblastoma and anaplastic astrocytoma = 12 months. Median PFS in patients treated to a single lesion was 15.4 months. No patient undergoing SRS to more than 1 lesion survived disease free beyond 2 years. After adjusting for histology and other clinical factors, SRS for tumor recurrence (RR = 2.49) and the presence of > 1 lesion (RR = 2.3) were associated with a significantly increased rate of progression (p < 0.05). Three-year actuarial local control (LC) was as follows: medulloblastoma = 57%, ependymoma = 29%, anaplastic astrocytoma/glioblastoma = 60%, other histologies = 56%. Nineteen patients with radionecrosis and progressive neurologic symptoms underwent reoperation after an interval of 0.6-62 months following SRS. Pathology revealed necrosis with no evidence of tumor in 9 of these cases. CONCLUSION: SRS can be given safely to selected children with brain tumors. SRS appears to reduce the proportion of first failures occurring locally and is associated with better outcome when given as a part of initial management. Some patients with unresectable relapsed disease can be salvaged with SRS. SRS to multiple lesions does not appear to be curative. Serious neurologic symptoms requiring reoperation is infrequently caused by radionecrosis alone.

Memory deficits among children with craniopharyngiomas.

OBJECTIVE: To describe neuropsychological functioning (with a specific focus on cognition and memory) after surgical treatment of craniopharyngiomas. METHODS: Sixteen patients who were between 6 and 15 years of age at the time of surgery comprised the sample. Each child had been treated for a craniopharyngioma with surgery only, on Dana-Farber Cancer Institute Protocol 92-077. RESULTS: The overall level of cognitive functioning was well within the average range, with both language and visuospatial functioning being generally intact; however, specific memory problems, in both the language and visuospatial domains, were evident. CONCLUSION: Although general cognitive functioning was intact after the surgical treatment of craniopharyngiomas, difficulties in the retrieval of learned information were observed. Neuropsychological assessments, with a focus on memory recall, should be a component of the medical management plan for each child.

Neurological dysfunction associated with postoperative cerebellar mutism.

BACKGROUND AND OBJECTIVES: The postoperative cerebellar mutism syndrome (CMS) is an unique acute postoperative complication characterized by transient decrease in speech output (often mutism), apathy, irritability as well as global cerebellar dysfunction. As much as 25% of patients undergoing a resection of a cerebellar or IV ventricular tumor may develop such a syndrome. In this retrospective study we characterize the clinical features of the CMS and explore potential etiologic mechanisms. METHODS: We conducted a retrospective analysis of medical records and imaging tests of 8 consecutive patients with the CMS identified through the database of the Children's Hospital and Dana-Farber Cancer Institute, Boston, and compared with a control group of 8 unaffected children undergoing a comparable tumor resection. RESULTS: In contrast to the control group, children in the affected group had marked decrease in speech output and comprehension, apathy and lack of initiative, inattention, persistent eye closure, flaccid hemiparesis and a severe global cerebellar dysfunction. Swallowing difficulties and bowel and bladder dysfunction were also observed. The median duration of the syndrome as judged by the persistence of the communication abnormalities was 4 weeks. The recovery was near complete with exception for a persistent global cerebellar dysfunction. A comparison of CT and MRI scans of children in both groups failed to identify distinguishing features. CONCLUSION: A surgical lesion of the midline cerebellum can cause a complex neurological dysfunction such as the CMS. Thus, we postulate that the cerebellum and its connections function as a 'modulatory system' in control of both motor and non-motor functions, including attention and language.

In vivo intracranial pressure dynamics in patients with hydrocephalus treated by shunt placement.

OBJECT: With the commercial availability of a variety of shunt systems, there is considerable controversy over the choice of the most appropriate shunt valve for each individual with hydrocephalus. Although the performance characteristics of all shunt systems are well documented in the laboratory setting, there is little description of the in vivo dynamics of intracranial pressure (ICP) after implantation of commonly used shunt systems in humans. The authors coupled telemonitoring devices to several different shunt systems to measure the performance characteristics of these valve systems with respect to intraventricular pressure (IVP) at increments of head elevation. METHODS: Twenty-five patients with different shunt systems and three control patients without shunts were studied for IVP at 0 degrees, 15 degrees, 30 degrees, 45 degrees, 60 degrees, 75 degrees, and 90 degrees of head elevation, and the resultant curves were analyzed for the best-fit regression coefficient. For purposes of analysis the authors grouped shunt valve systems by design characteristics into three groups: differential-pressure valves (r = -0.321 +/- 0.061; 11 patients), nonsiphoning systems (r = -0.158 +/- 0.027; 10 patients), and flow-regulated valves (r = -0.16 +/- 0.056; four patients); there were three control patients without shunts (r = -0.112 +/- 0.037). CONCLUSIONS: The authors found that differential-pressure valves always caused ICP to drop to 0 by 30 degrees of head elevation, whereas all other valve systems caused a more gradual drop in ICP, more consistent with pressures observed in the control patients without shunts. Not surprisingly, the differential-pressure valve group was found to have a significant difference in mean regression coefficient when compared with those in whom nonsiphoning shunts (p < 0.023) or no shunts were placed (p < 0.049). These data provide a basis for evaluating shunt valve performance and for predicting valve appropriateness in patients in whom characteristics such as pressure and flow dynamics are weighed in the choice of a specific valve for implantation.

Activation of neurotrophin-3 receptor TrkC induces apoptosis in medulloblastomas.

Elevated expression of the neurotrophin-3 (NT-3) receptor TrkC by childhood medulloblastomas is associated with favorable clinical outcome. Here, we provide evidence that TrkC is more than simply a passive marker of prognosis. We demonstrate that: (a) medulloblastomas undergo apoptosis in vitro when grown in the presence of NT-3; (b) overexpression of TrkC inhibits the growth of intracerebral xenografts of a medulloblastoma cell line in nude mice; and (c) trkC expression by individual tumor cells is highly correlated with apoptosis within primary medulloblastoma biopsy specimens. TrkC-mediated NT-3 signaling promotes apoptosis by activating multiple parallel signaling pathways and by inducing immediate-early gene expression of both c-jun and c-fos. Considered collectively, these results support the conclusion that the biological actions of TrkC activation affect medulloblastoma outcome by inhibiting tumor growth through the promotion of apoptosis.

Endoscopic approach to noncommunicating fluid spaces in the shunted patient.

INTRODUCTION: It is well known that shunted hydrocephalic patients can, over time, develop entrapped ventricles or cystic spaces not in communication with the remaining ventricles. This situation has traditionally been treated with placement of an additional catheter or shunt system in the noncommunicating fluid space. With the advent of minimally invasive endoscopic techniques, it has become possible to fenestrate trapped fluid spaces into the shunted ventricular system, thus preventing the need for additional catheters. METHODS: Fifteen shunted patients presented with noncommunicating fluid spaces over a 4-year period at our two institutions. We attempted fenestration procedures in 14 of those patients. The various procedures included: septum pellucidum fenestration, cyst fenestration, third ventriculocisternostomy and a combination of the above. RESULTS: Thirteen of 16 (81%) endoscopic fenestrations successfully prevented the need for a complicated shunting system. There were 3 technical failures (3/16, 19%) in which an additional catheter was added to the existing shunt system at the time of the endoscopic procedure. There were no adverse neurologic effects from the endoscopic procedures; however, in 4 of the 14 patients (29%) a shunt revision was performed between 2 and 30 days following the fenestration. CONCLUSIONS: These results show that the endoscopic approach to establishing communication between noncommunicating CSF spaces in the shunted patient is safe and efficacious in preventing the need for additional CSF catheters. Though we encountered failures, the majority of cases are technically feasible. In these patients early shunt malfunction may occur, most likely due to intraoperative bleeding and will require shunt revision.

Intraventricular urokinase for the treatment of posthemorrhagic hydrocephalus.

This case series pilot study assessed the safety of intraventricular urokinase administration, alternating with cerebrospinal fluid (CSF) drainage. A secondary objective was to comment on whether this therapy achieves fibrinolysis, and whether this fibrinolysis is sufficient to prevent progression of hydrocephalus to requirement for ventriculoperitoneal shunt. Six preterm infants with progressive posthemorrhagic hydrocephalus requiring treatment with a ventricular drain received an infusion of intraventricular urokinase alternating with CSF drainage for 3 days. Of the 6 treated patients, the median gestation at birth was 26.5 weeks and the median age at treatment was 30 days. One patient had an elevation in CSF erythrocyte count most likely due to successful clot lysis. One patient had an elevated CSF leukocyte count consistent with transient meningeal irritation. No other side effects were noted. Fibrinolysis was achieved in the CSF, as documented by markedly elevated D-dimer levels. Clot size diminished ultrasonographically. However, all 6 patients eventually required a ventriculoperitoneal shunt. We conclude that intermittent infusion of intraventricular urokinase alternating with periods of CSF drainage is probably a safe way to achieve a fibrinolytic state. However, when administered at the relatively late point in the neonatal course when a ventricular drain is required, this fibrinolytic state is not sufficient to decrease the requirement for ventriculoperitoneal shunt.

Telemetric intraventricular pressure measurements after third ventriculocisternostomy in a patient with noncommunicating hydrocephalus.

OBJECTIVE: To examine and document intraventricular pressure (IVP) dynamics in an adult after endoscopic third ventriculocisternostomy performed as treatment for hydrocephalus associated with aqueductal stenosis. METHODS: A 30-year-old man who had undergone ventriculoperitoneal shunting at age 21 years for aqueductal stenosis caused by a tectal mass presented with symptoms and imaging studies consistent with shunt malfunction. He underwent urgent ventriculoscopic third ventricular ventriculocisternostomy, which resolved his symptomatology. The existing shunt was not revised. At the time of surgery, a catheter connected to an intracranial pressure TeleSensor device (Radionics, Burlington, MA) was inserted into the ventricular system. Postoperatively, the patient's recovery was assessed by IVP recordings. This system allowed us to record IVP in an awake patient with a functioning third ventriculocisternostomy. RESULTS: We observed an initial postoperative IVP of 17 cm H2O in the supine position, which decreased to 0 cm H2O at 90 degrees of head elevation. The IVP decreased during the first 48 hours postoperatively to 0 to 2 cm H2O when supine. By 1 week postoperatively, the patient's IVP had returned to a baseline of 15 to 17 cm H2O when supine, with a gradual decrease to 0 cm H2O at 30 degrees of head elevation. Three months postoperatively, the patient's IVP in the supine position was 8 cm H2O, with IVP decreasing to 0 cm H2O at 45 degrees of head elevation. Magnetic resonance (MR) imaging performed at that time revealed evidence of flow through the third ventriculocisternostomy. CONCLUSION: We conclude that after an initial period of adjustment, the IVP in this patient returned to an unremarkable baseline despite the novel fluid pathway into the prepontine cistern. This may represent maturation of the breach through the third ventricular floor or brain recovery from a period of high pressure. Also, the shape of the postural IVP curve closely resembled that observed in patients who are not hydrocephalic. These data represent the first documentation of the intraventricular pressure response to ventriculocisternostomy and suggest possible intracerebral responses to this alteration in cerebrospinal fluid flow.

The use of clinical practice guidelines (CPGs) to evaluate practice and control costs in ventriculoperitoneal shunt management.

BACKGROUND: As a step toward maximizing the quality and cost-effectiveness of neurosurgical care, we designed clinical practice guidelines (CPGs) for the management of VP shunt malfunctions and infections at a tertiary care pediatric teaching institution. The detailed CPGs determine the use of radiographic studies, laboratory tests, and invasive procedures in the management of this problem. One purpose of the CPGs is to provide clear clinical guidelines for the medical trainee, thereby reducing variability in care and unnecessary utilization of resources. METHODS: The CPGs were developed in stages over a 2-year period. The practice patterns in our institution for the management of shunt malfunctions and infections were articulated. They were compared with those published in the neurosurgical literature, and areas of clinical decision-making variability were identified. Preliminary guidelines were formulated, and data regarding patient care were prospectively collected. Based on this data, final CPGs were formulated and implemented. Total and itemized hospital charges for patients managed according to the CPGs were compared with those for patients in the 3 years before CPG implementation. RESULTS: CPG-managed patients had generally lower total and itemized charges as compared with control patients. Decreased charges per hospital day and charges for shunt films in the CPG group were statistically significant. CONCLUSIONS: The process by which the CPGs were developed and implemented, as well as the CPGs themselves, are described. We also present the clinical, demographic, and financial data that were prospectively collected for all patients managed within the CPGs over an initial 1-year period and compare it with data obtained for control groups of shunt malfunction patients admitted during the 3 years before implementation of the CPGs. We find a trend toward reduction of charges after implementation of the CPG.

Presentation and management of Chiari I malformation in children.

To determine the efficacy of operative treatment for children with Chiari I malformation, the medical records and magnetic resonance imaging (MRI) studies of 68 consecutive patients cared for at The Children's Hospital, Boston, Mass., USA, from December, 1988 to November, 1996 were retrospectively reviewed. All patients underwent suboccipital craniectomy, C1 laminectomy, and dural grafting. Bipolar coagulation to shrink and reduce the volume of the cerebellar tonsils was carried out in 40 patients. In 32 of 40 patients with associated syringomyelia, the procedure included placement of a IVth ventricle to cervical subarachnoid space shunt. Twenty-three patients with syringomyelia also had plugging of the obex. There was no operative mortality. Morbidity included a 22% incidence of nausea/vomiting and a 10% incidence of headache, both limited to the immediate postoperative period. Within the first postoperative month, all patients or their parents reported clear improvement in their presenting symptoms and 93% were found to have clear improvement in their presenting signs. In follow-up periods of 6-70 months, all patients had continued unequivocal symptom improvement and all patients were found on examination to have clear improvement in neurological signs. In patients with syringomyelia, MRI studies carried out at least 6 months postoperatively revealed near total or total syrinx resolution in 80% of the cases. This study demonstrates that a standard bony and dural decompression of the foramen magnum region with modifications designed to maximize the restoration of CSF circulation across the foramen magnum is a safe, effective operative treatment for Chiari I malformation in children.

Treatment of hydrocephalus with third ventriculocisternostomy: outcome and CSF flow patterns.

Third ventriculocisternostomy was performed in 23 patients for management of hydrocephalus. The procedure was offered as the first treatment in 18 cases and in lieu of a shunt revision in 4 cases. Median follow-up was 17 months (range 7-44 months). In 16 patients the operation was successful in treating their symptoms (73%). Cine MRI was helpful in evaluating patients with persistent ventriculomegaly. Resolution of symptoms in association with decreased ventricular size correlated best with outcome following this procedure. Third ventriculocisternostomy is technically safe and minimally invasive and should be offered as the first procedure in the management of noncommunicating hydrocephalus.

Neurotrophins in cerebellar granule cell development and medulloblastoma.

Medulloblastomas may be derived from granule cells of the developing cerebellum. Children with tumors expressing high levels of the neurotrophin-3 receptor, TrkC, have a more favorable outcome. During development, TrkC is expressed in the most mature granule cells. Favorable medulloblastomas may be derived from more highly differentiated granule cells.

Magnetic resonance imaging changes after stereotactic radiation therapy for childhood low grade astrocytoma.

BACKGROUND: Stereotactic radiotherapy (SRT) is fractionated radiotherapy delivered under stereotactic guidance to produce highly focal and precise therapy. We studied the incidence of imaging changes that can mimic tumor progression after completion of SRT for childhood low grade astrocytoma. METHODS: Between June 1992 and September 1994, we prospectively treated 28 children with low grade astrocytomas with SRT. The patients ranged in age from 2 to 22 years (median: 10 yrs) and none had received prior radiation therapy or radiosurgery. Routine fractionation was employed (180-200 centigray[cGy]) to a total dose of 5220-6000 cGy over 5 to 6 weeks. All of the patients underwent initial and follow-up magnetic resonance imaging (MRI) according to protocol. RESULTS: Median clinical follow-up for the 28 patients was 24 months (range, 5-32 mos) with a median radiographic follow-up of 15 months (range, 3-26 mos). Fifteen patients had reduction in tumor size, one patient had stable disease. Twelve patients (43%) developed increased size of the lesion, increased signal intensity or enhancement, cysts or cavitations, and an increase in edema or mass effect on follow-up MRI. Most of these changes occurred between 9 and 12 months after the start of SRT and resolved or decreased by 15 to 21 months. All but one patient had normal or stable neurologic examinations. CONCLUSIONS: Treatment-related MRI changes are common after conventionally fractionated schedules using stereotactic radiation techniques for patients with low grade astrocytomas. These changes can be distinguished from tumor progression by their transient nature as well as the general absence of clinical symptoms.

Growth factor receptors and medulloblastoma.

Growth factors and their receptors play important roles in the regulation of cell division, development and differentiation. Neurotrophins are growth factors which have not been shown, until recently, to be associated with human neoplasia. Medulloblastoma is a central nervous system tumor which is thought to arise from the external granule cell layer of the cerebellum. Platelet Derived Growth Factor (PDGF) or Epidermal Growth Factor (EGF) and/or their receptors have not been found to have a significant role in the development of this tumor. Neurotrophins, however, which regulate cerebellar development in a time-dependent manner, appear to be important in medulloblastoma and the presence of high levels of TrkC expression, a neurotrophin receptor, is associated with a better outcome. The potential role of these growth factors and their receptors in manipulating the behavior of this tumor is discussed.

Hemorrhagic vasculopathy after treatment of central nervous system neoplasia in childhood: diagnosis and follow-up.

PURPOSE: To review the clinical data, imaging findings, and intermediate outcomes of a series of children with hemorrhagic vasculopathy after treatment for intracranial neoplasia. METHODS: We retrospectively analyzed the medical records and imaging examinations of 20 pediatric patients (ages 1 to 15 years) with intracranial neoplasia in whom delayed intracranial hemorrhage developed after cranial irradiation or radiation combined with systemic or intrathecal chemotherapy. Patients with intracranial hemorrhage from other identifiable causes were excluded. Histopathologic analysis was available in four patients. RESULTS: Twenty patients with delayed intracranial hemorrhage received cranial irradiation alone (n = 9) or combined radiation and chemotherapy (n = 11) for primary brain tumors (n = 13), leukemia (n = 6), or lymphoma (n = 1). Imaging findings were consistent with hemorrhages of varying ages. The hemorrhages were not associated with tumor recurrence nor second tumors. Except for location of the hemorrhage, no significant relationship was established between outcome and original diagnosis, radiation dose (range, 1800 to 6000 centigray), chemotherapeutic agent or dosage, age at treatment, or interval between therapy and hemorrhage (mean, 8.1 years). Only brain stem hemorrhage was associated with a poor outcome. CONCLUSION: In children with central nervous system neoplasia who have undergone cranial irradiation, or radiation combined with chemotherapy, delayed intracranial hemorrhage may develop.

Results of radiosurgery in the management of recurrent and residual medulloblastoma.

Between June 1989 and January 1994, 14 patients with recurrent (n = 11) or posttreatment residual (n = 3) medulloblastoma were enrolled in a program to evaluate the efficacy and toxicity of stereotactic radiosurgery (SR). Initial treatment consisted of subtotal surgical resection in 12 patients and complete surgical resection in 2. Thirteen patients received systemic chemotherapy, and all had craniospinal irradiation prior to SR. SR was used as a technique for boosting sites of posttreatment residual disease in 3 patients (3 tumors) and as salvage therapy in 11 patients (14 tumors) with radiographically well-defined, discrete recurrent tumors. Patients underwent SR 1-97 (median 20) months after completing craniospinal irradiation. The median minimum peripheral tumor dose was 12 Gy. The median tumor volume at the time of SR was 6.9 cm3. With a median follow-up period from diagnosis of 27 (range 8-39) months, all patients treated with SR as a boost to sites of residual disease are alive without evidence of disease. In contrast, 6 of 11 patients who underwent SR for treatment of recurrent disease have died of progressive medulloblastoma. The median survival from the time of SR for patients treated for recurrent disease was 10 (range 5-59+) months. The predominant site of failure after SR was distant within the central nervous system, with 6 patients (43%) failing outside the posterior fossa. No patient failed locally within the radiosurgical target volume. Two patients (14%) developed marginal recurrences.(ABSTRACT TRUNCATED AT 250 WORDS)

Expression of the neurotrophin receptor TrkC is linked to a favorable outcome in medulloblastoma.

Medulloblastoma, the most common malignant brain tumor of childhood, has a variable prognosis. Although half of the children and young adults with the disease survive longer than 10 years after diagnosis, the others relapse and die despite identical therapy. We have examined the expression of neurotrophins and their receptors in medulloblastoma samples snap frozen in the operating room to preserve RNA integrity. All tumors (n = 12) were found to express mRNA encoding neurotrophin 3 and its receptor TrkC. The level of trkC expression was highly variable, with a more than 50-fold difference between the highest and lowest values. By Kaplan-Meier analysis, patients with tumors expressing high levels of trkC mRNA had significantly longer intervals without disease progression than those with low levels (log-rank, P = 0.03) and a more favorable overall survival (log-rank, P = 0.05). Thus, trkC expression is a prognostic indicator for patients with medulloblastoma.

Thallium-201 versus technetium-99m-MIBI SPECT in evaluation of childhood brain tumors: a within-subject comparison.

We previously found that 201TI SPECT is a highly specific agent for detection of metabolic activity of childhood brain tumors. To compare the relative diagnostic accuracy of 201TI and a technetium-based tumor-avid agent, we have obtained SPECT in 19 children using 201TI (37-111 MBq) followed immediately by 99mTc-methoxyisobutylisonitrile (MIBI) (370-740 MBq) intravenously. Moderate to intense focal uptake of both tracers characterized true positive cases (n = 6). Lesion boundaries were better defined by MIBI. Uptake of MIBI by choroid plexus occurred despite pretreatment with potassium perchlorate (6 mg/kg) and complicated interpretation of deep/paraventricular lesions. Preliminary assessment indicated sensitivity approximately 67% (TI and MIBI); specificity approximately 91% (TI); approximately 100% (MIBI). Two tumors (medulloblastoma, dysgerminoma) were TI/MIBI nonavid. Semi-quantitative assessment of tracer uptake was made using a ratio of radioactivity in tumor-containing areas compared to uninvolved brain. Ratio values were (mean +/- s.d.) 7.88 +/- 7.70 (TI) and 27.1 +/- 36.41 (MIBI). The spectrum of tumor avidity is similar for TI and MIBI. Clearer identification of boundaries by MIBI may be an advantage in applications, e.g., radiotherapy port planning.