A Novel Methodology for Applying Multivoxel MR Spectroscopy to Evaluate Convection-Enhanced Drug Delivery in Diffuse Intrinsic Pontine Gliomas.

BACKGROUND AND PURPOSE: Diffuse intrinsic pontine gliomas are inoperable high-grade gliomas with a median survival of less than 1 year. Convection-enhanced delivery is a promising local drug-delivery technique that can bypass the BBB in diffuse intrinsic pontine glioma treatment. Evaluating tumor response is critical in the assessment of convection-enhanced delivery of treatment. We proposed to determine the potential of 3D multivoxel (1)H-MR spectroscopy to evaluate convection-enhanced delivery treatment effect in these tumors. MATERIALS AND METHODS: We prospectively analyzed 3D multivoxel (1)H-MR spectroscopy data for 6 patients with nonprogressive diffuse intrinsic pontine gliomas who received convection-enhanced delivery treatment of a therapeutic antibody (Phase I clinical trial NCT01502917). To compare changes in the metabolite ratios with time, we tracked the metabolite ratios Cho/Cr and Cho/NAA at several ROIs: normal white matter, tumor within the convection-enhanced delivery infusion site, tumor outside of the infused area, and the tumor average. RESULTS: There was a comparative decrease in both Cho/Cr and Cho/NAA metabolite ratios at the tumor convection-enhanced delivery site versus tumor outside the infused area. We used MR spectroscopy voxels with dominant white matter as a reference. The difference between changes in metabolite ratios became more prominent with increasing time after convection-enhanced delivery treatment. CONCLUSIONS: The comparative change in metabolite ratios between the convection-enhanced delivery site and the tumor site outside the infused area suggests that multivoxel (1)H-MR spectroscopy, in combination with other imaging modalities, may provide a clinical tool to accurately evaluate local tumor response after convection-enhanced delivery treatment.

Assessment of disease severity in late infantile neuronal ceroid lipofuscinosis using multiparametric MR imaging.

BACKGROUND AND PURPOSE: LINCL is a uniformly fatal lysosomal storage disease resulting from mutations in the CLN2 gene that encodes for tripeptidyl peptidase 1, a lysosomal enzyme necessary for the degradation of products of cellular metabolism. With the goal of developing quantitative noninvasive imaging biomarkers sensitive to disease progression, we evaluated a 5-component MR imaging metric and tested its correlation with a clinically derived disease-severity score. MATERIALS AND METHODS: MR imaging parameters were measured across the brain, including quantitative measures of the ADC, FA, nuclear spin-spin relaxation times (T2), volume percentage of CSF (%CSF), and NAA/Cr ratios. Thirty MR imaging datasets were prospectively acquired from 23 subjects with LINCL (2.5-8.4 years of age; 8 male/15 female). Whole-brain histograms were created, and the mode and mean values of the histograms were used to characterize disease severity. RESULTS: Correlation of single MR imaging parameters against the clinical disease-severity scale yielded linear regressions with R2 ranging from 0.25 to 0.70. Combinations of the 5 biomarkers were evaluated by using PCA. The best combination included ADC, %CSF, and NAA/Cr (R2=0.76, P<.001). CONCLUSIONS: The multiparametric disease-severity score obtained from the combination of ADC, %CSF, and NAA/Cr whole-brain MR imaging techniques provided a robust measure of disease severity, which may be useful in clinical therapeutic trials of LINCL in which an objective assessment of therapeutic response is desired.

Purely endoscopic removal of intraventricular brain tumors: a consensus opinion and update.

BACKGROUND: The main purpose of this project is to define the major indications, preferences, techniques, limitations, and complications associated with intraventricular tumor removal using purely endoscopic techniques. METHODS: Published papers on neuroendoscopy were reviewed, and a questionnaire about purely endoscopic surgery for intraventricular brain tumors was designed. The questionnaire included details regarding neuroendoscopic techniques, surgeons' endoscopic experience, and clinical vignettes. 20 experienced neuroendoscopists from the 10 represented countries were surveyed. RESULTS: 15 physicians (75%) responded to the survey, having an estimated 264 cumulative years of endoscopic experience. There was general agreement regarding: the instrumentation used, endoscope features, irrigation, technique of colloid cyst and solid intraventricular tumor removal, complications, future technologies, and the treatment of sample clinical vignettes. There was appreciable variability in endoscope control preferences. CONCLUSIONS: Endoscopic intraventricular surgery is a feasible minimally invasive alternative to open transcranial surgery for specific ventricular tumors. With the currently available instrumentation, the technique can be applied to small avascular solid intraventriclular tumors and colloid cysts of the third ventricle. The majority of the complications are based on hemostasis potential. The development of compatible instrumentation with an enhanced ability for solid tumor removal and more adequate hemostasis appear to be the principle limitations in furthering the technique of endoscopic removal of intraventricular brain tumors.

Balloon-assisted superselective intra-arterial cerebral infusion of bevacizumab for malignant brainstem glioma. A technical note.

Malignant brainstem gliomas (BSG) are rare tumors in adults, associated with a grim prognosis and limited treatment options. Currently, radiotherapy represents the mainstay of treatment, although new studies suggest an increased role for certain chemotherapeutic agents. Intravenous (IV) administration of bevacizumab (Avastin, Genentech Pharmaceuticals) has been shown to be active in the treatment of some enhancing malignant brainstem gliomas. The IV route of administration, however, carries a risk of systemic side effects such as bowel perforation, wound disrepair and pulmonary embolism. In addition, the percentage of IV drug that reaches the tumor site is restricted by the blood brain barrier (BBB).Weill Cornell Brain Tumor Center, Department of Neurosurgery, Weill Cornell Medical College of Cornell University: New York, NY, USA. This technical report describes our protocol in performing superselective intra-arterial cerebral infusion (SIACI) of bevacizumab using endovascular balloon-assistance in the top of the basilar artery in a patient with a recurrent malignant brainstem glioma. It represents the first time such a technique has been performed for this disease. This method of drug delivery may have important implications in the treatment of both adult and pediatric brainstem gliomas.

Combined simultaneous endoscopic transsphenoidal and endoscopic transventricular resection of a giant pituitary macroadenoma.

Intrasellar and sellar-suprasellar adenomas are generally removed through a transsphenoidal approach. Giant adenomas with significant suprasellar extension often require a craniotomy or combined "above and below" approach. The use of endoscopes has increased the visualization capacity of the transsphenoidal route and made these surgeries less invasive. In this report, we describe a novel combination of the endoscopic transsphenoidal approach with the endoscopic transventricular approach to remove a giant pituitary macroadenoma extending into the third and lateral ventricles. The tumor was initially removed via an endoscopic transnasal transsphenoidal, transtuberculum, transplanum approach. A second endoscope was then advanced into the lateral ventricle through a pre-coronal burr hole to assist in mobilizing the tumor and assure a complete resection. Multilayer closure and a ventriculo-peritoneal shunt were performed to insure a watertight seal of the skull base. Giant pituitary adenomas have traditionally been removed with staged or combined transsphenoidal and transcranial approaches. We describe the successful implementation of a minimal access endoscopic combined extended transsphenoidal and transventricular approach that avoids craniotomy and brain retraction.

Neurological deterioration in late infantile neuronal ceroid lipofuscinosis.

BACKGROUND: Late infantile neuronal ceroid lipofuscinosis (LINCL) is associated with progressive degeneration of the brain and retina starting in early childhood. METHODS: Thirty-two individual neurologic, ophthalmologic, and CNS imaging (MRI and MRS) assessments of 18 children with LINCL were analyzed. Disease severity was followed by two rating scales, one previously established but modified to solely assess the brain and exclude the retinal disease (modified Hamburg LINCL scale), and a newly developed scale, with expanded evaluation of the CNS impairment (Weill Cornell LINCL scale). RESULTS: For the 18 children, the Weill Cornell scale yielded a closer correlation with both age and time since initial clinical manifestation of the disease than did the modified Hamburg scale. There were no significant differences as a function of age or time since initial manifestation of the disease in the rating scales among the most frequent CLN2 mutations (G3556C, 56% of all alleles or C3670T, 22% of all alleles). Measurements of cortical MRS N-acetyl-aspartate content, MRI ventricular, gray matter and white matter volume, and cortical apparent diffusion coefficient correlated to a variable degree with the age of the children and the time since initial clinical manifestation of the disease. All imaging measurements correlated better with the Weill Cornell CNS scale compared to the modified Hamburg LINCL scale. CONCLUSION: The data suggest that the Weill Cornell late infantile neuronal ceroid lipofuscinosis (LINCL) scale, together with several of the MRI measurements, may be useful in the assessment of severity and progression of LINCL and for the evaluation of novel therapeutic strategies.

Proton magnetic resonance spectroscopy of choroid plexus tumors in children.

A variety of lesions may present as intraventricular masses in children. We report quantitative proton magnetic resonance spectroscopy (MRS) of two intraventricular tumors of the choroid plexus: choroid plexus carcinoma (CPC) and choroid plexus papilloma (CPP). Both lesions were characterized by high levels of choline-containing compounds and a complete absence of creatine and the neuronal/axonal marker N-acetyl aspartate. The CPC showed higher levels of choline compared to the CPP, and it also had elevated lactate. These preliminary results, if confirmed in a larger cohort of patients, indicate that proton MRS may have a role in the presurgical diagnosis of choroid plexus tumors in children, which may also have important implications for therapy and prognosis.

MIB-1 staining index of pediatric meningiomas.

OBJECTIVE: For adult meningiomas, the staining index (SI) for the anti-Ki-67 monoclonal antibody MIB-1 is well correlated with histological atypia and tumor recurrence. MIB-1 SIs for meningiomas in the pediatric population have not been previously reported. Meningiomas tend to be more histologically aggressive and to recur more frequently in children, compared with adults. The objectives of this study were to determine whether MIB-1 SIs are correlated with pathological atypia and recurrence among pediatric meningiomas and to compare the MIB-1 SIs of pediatric meningiomas with those of adult meningiomas. METHODS: MIB-1 SIs were assessed on paraffin-embedded sections of 14 pediatric meningiomas (patient age, 2-17 yr), 5 of which contained atypical or malignant features. For comparison with benign pediatric meningiomas, MIB-1 SIs were also assessed on paraffin-embedded sections of 14 adult meningiomas (patient age, 38-90 yr), none of which displayed atypical or malignant features or recurred within a 5-month median follow-up period. RESULTS: MIB-1 SIs of pediatric meningiomas ranged from 1.2 to 31.6% (median, 9.1%). Significant differences were observed between the MIB-1 SIs for tumors with atypical or malignant features (median, 12.3%; range, 7.0-31.6%) and those for tumors without atypia (median, 7.0%; range, 1.2-12.6%; P = 0.045). There were six recurrences after gross total resection, during a 36.5-month median follow-up period. All five of the tumors with pathological atypia recurred; one tumor without atypia recurred. Significant differences were observed between MIB-1 SIs for nonrecurrent tumors (median, 6.6%; range, 1.2-12.2%) and those for recurrent tumors (median, 12.5%; range, 7.0-31.6%; P = 0.012). The median MIB-1 SI for adult control specimens was 8.8% (range, 1.2-19.3%), which did not differ significantly from that for pediatric meningiomas without atypia (P = 0.68). CONCLUSION: For this cohort of pediatric meningiomas, pathological atypia and the tendency to recur were correlated with elevated MIB-1 SIs. The median MIB-1 SI for pediatric meningiomas without histological atypia did not differ significantly from that for adult meningiomas without atypia, suggesting that the more aggressive clinical features of meningiomas in children may be attributable to factors other than the rate of cellular proliferation.

Early management of craniocerebral injury with avoidance of post-traumatic leptomeningeal cyst formation. Report of two cases.

Leptomeningeal cyst, or growing skull fracture, is a rare complication of pediatric head trauma. This entity is typically diagnosed several weeks or months following head trauma when an enlarging scalp mass is recognized. Progressive neurologic deficits (seizures, paresis) can accompany this process, which typically do not improve following conventional surgical treatment. Given that radiographic findings are highly predictive of which children are likely to develop a leptomeningeal cyst, we have adopted a policy of early management in an effort to avoid difficult surgical dissections and progressive neurologic sequelae seen with delayed intervention. The cases of two infants with skull fractures are used to illustrate our approach toward early management of post-traumatic leptomeningeal cysts.

Endoscopic biopsy for tumors of the third ventricle.

Twelve patients underwent endoscopic biopsy of a tumor involving the third ventricle. Nine patients had no significant medical history while 3 had a history of cancer. Unique characteristics of each case dictated the optimal surgical technique. Endoscopic tumor biopsy was combined with additional procedures in 9 cases; shunt insertion (3), shunt insertion with endoscopic septostomy (5), and transcallosal craniotomy (1). Diagnosis was established in 11 patients (92%); 6 primary brain tumors, 3 metastatic central nervous system tumors, 1 metastatic systemic cancer, and 1 region of post-treatment gliosis. One case was aborted due to poor visualization. Therapy was directly influenced by endoscopic biopsy in 11/12 cases (92%) and craniotomy for tumor resection was avoided in 10/12 patients (83%). Of the 5 patients who underwent endoscopic septostomy, 4 required no subsequent procedures for hydrocephalus. There were no complications, and hospital stay averaged 1.78 days for patients who underwent successful endoscopic biopsy. Tumors of the third ventricle are amenable to endoscopic biopsy with excellent diagnostic yield and low morbidity. The procedure must be tailored depending upon the tumor location within the third ventricle, the degree of ventriculomegaly, and the need to perform a septostomy. Singularly or combined with other endoscopic procedures, patients can be spared multiple and more invasive surgical procedures.

Rolandic encephalopathy and epilepsia partialis continua following bone marrow transplant.

Epilepsia partialis continua (EPC) is a condition defined by prolonged focal myoclonus. Often resistant to therapy, EPC in children is frequently present in Rasmussen encephalitis, a form of chronic encephalitis of uncertain etiology. We discuss a child who developed bilateral EPC 5 months after a bone marrow transplant. Neuroimaging studies showed signal abnormalities on both sensory-motor areas. An extensive search failed to reveal the etiology of the disorder, but treatment with a broad-spectrum anti-viral agent was associated with resolution of the process. An unidentified infectious agent may be responsible for an encephalitis of the motor strip in immunosuppressed patients.

An integrated functional magnetic resonance imaging procedure for preoperative mapping of cortical areas associated with tactile, motor, language, and visual functions.

OBJECTIVE: To evaluate an integrated battery of preoperative functional magnetic resonance imaging (fMRI) tasks developed to identify cortical areas associated with tactile, motor, language, and visual functions. METHODS: Sensitivity of each task was determined by the probability that a targeted region was activated for both healthy volunteers (n = 63) and surgical patients with lesions in these critical areas (n = 125). Accuracy of each task was determined by the correspondence between the fMRI maps and intraoperative electrophysiological measurements, including somatosensory evoked potentials (n = 16), direct cortical stimulation (n = 9), and language mapping (n = 5), and by preoperative Wada tests (n = 13) and visual field examinations (n = 6). RESULTS: For healthy volunteers, the overall sensitivity was 100% for identification of the central sulcus, visual cortex, and putative Wernicke's area, and 93% for the putative Broca's area (dominant hemisphere). For patients with tumors affecting these regions of interest, task sensitivity was 97% for identification of the central sulcus, 100% for the visual cortex, 91% for the putative Wernicke's area, and 77% for the putative Broca's area. These sensitivities were enhanced by the use of multiple tasks to target related functions. Concordance of the fMRI maps and intraoperative electrophysiological measurements was observed whenever both techniques yielded maps and Wada and visual field examinations were consistent with fMRI results. CONCLUSION: This integrated fMRI task battery offers standardized and noninvasive preoperative maps of multiple critical functions to facilitate assessment of surgical risk, planning of surgical routes, and direction of conventional, intraoperative electrophysiological procedures. Thus, a greater range of structural and functional relationships is brought to bear in the service of optimal outcomes for neurosurgery.

Ommaya reservoirs for the treatment of leptomeningeal metastases.

OBJECTIVE: Ommaya reservoirs are frequently used to deliver intraventricular chemotherapy in cancer patients with leptomeningeal metastases. We review techniques of catheter placement and complication avoidance. METHODS: Between January 1995 and June 1998, Ommaya reservoirs were placed in 107 patients for the treatment or prophylaxis of leptomeningeal metastases at the Memorial Sloan-Kettering Cancer Center. Patients with slit ventricles (total, 25) underwent preoperative pneumoencephalography for ventricular dilation. Intraoperative fluoroscopic guidance was used in 77 patients to confirm the catheter tip position at the foramen of Monro. Other intraoperative aids included endoscopy in 21 patients, ultrasound in 7, and stereotaxy in 6. No aids were used in 3 patients, more than one aid was used in 9, and the technique could not be determined retrospectively in 3. RESULTS: The median survival of patients treated for leptomeningeal metastases was 9 months (Kaplan-Meier method). Eight patients developed hydrocephalus requiring conversion of the Ommaya reservoir to a ventriculoperitoneal shunt and precluding delivery of chemotherapeutic agents. An additional 11 patients referred for Ommaya reservoir placement demonstrated elevated intracranial pressure requiring an initial ventriculoperitoneal shunt. Complications of Ommaya reservoir placement occurred in 10 patients (9.3%) and included two infections, five catheter malpositions, and three intracranial hemorrhages. Two deaths occurred secondary to intracranial hemorrhage: one after postoperative anticoagulation for a mechanical heart valve, and one attributed to treatment-related thrombocytopenia. Nine patients (8.4%) had treatment-related imaging abnormalities; seven were asymptomatic and two developed symptomatic leukoencephalopathy. CONCLUSION: Complications associated with Ommaya reservoirs can be minimized by intraoperative confirmation of the catheter position with fluoroscopic guidance and/or endoscopy. We recommend postoperative computed tomographic scans before initiation of intraventricular chemotherapy. Patients with elevated intracranial pressure may require shunting procedures in lieu of Ommaya reservoir placement.

Hemifacial spasm caused by a pilocytic astrocytoma of the fourth ventricle.

An 11-year-old male in whom hemifacial spasm was the presenting sign of a pilocytic astrocytoma within the fourth ventricle is reported. The child's hemifacial spasm decreased substantially after resection of the tumor. Hemifacial spasm is largely a disease of adults and only rarely is attributed to brain tumors. In contrast, this marks the fifth case of hemifacial spasm reported in a child, three of which have been attributed to tumors of the fourth ventricle.

Volumetric reduction of a choroid plexus carcinoma using preoperative chemotherapy.

We report for the first time a measured volumetric reduction of a choroid plexus carcinoma utilizing preoperative chemotherapy. Histologically proven choroid plexus carcinoma was diagnosed in a fifteen month old female. She was treated with three courses of chemotherapy including etoposide (VP16), cyclophosphamide, vincristine, and cisplatin. Computer-assisted three dimensional reconstruction of the tumor volume was performed prior to and after three courses of chemotherapy. An overall reduction of 29.5% of tumor volume was accomplished preoperatively. Staged surgical procedures resulted in a complete resection of her lesion and she has remained disease-free for 31 months. A volumetric measurement as a response to preoperative chemotherapy may prove valuable in determining future optimal treatment regimens for choroid plexus carcinoma of childhood.

Endoscopic-guided proximal catheter placement in treatment of posterior fossa cysts.

PURPOSE: Treatment of posterior fossa cysts by cystoperitoneal shunting may be complicated by a malpositioned proximal catheter located within the brainstem or cerebellum causing acute shunt malfunction or neurological deficits. We propose that proximal catheter placement from a posterior fossa approach aided by a malleable endoscope may prevent malposition and its complications. METHODS: We present 4 procedures we performed on 3 patients with posterior fossa cysts using a posterior fossa approach. In each case, the proximal catheter was molded along with a malleable endoscope to place the catheter parallel to the long axis of the fourth ventricle. Direct visualization during catheter placement insured an intracavitary position. RESULTS: Ultimately, the procedure was successful in all 3 patients as judged by intracavitary catheter position and decrease in cyst size on postoperative imaging. In 1 patient, revision using the same technique was required based upon suboptimal catheter position within one of numerous cystic compartments within the posterior fossa. There were no complications related to direct or indirect brainstem injury. CONCLUSIONS: Many posterior fossa cysts can be treated effectively and safely via a posterior fossa approach with the aid of a malleable endoscope. Direct visualization facilitates intracavitary catheter placement and orientation of the catheter in the long axis of the cyst, thereby decreasing the risk of injury to surrounding structures.

Globular glioma of the tectum.

Brainstem gliomas are a heterogeneous group of tumors whose prognosis and treatment depend not only on the histologic features but also on the location within the brainstem. Magnetic resonance imaging allows the recognition of a distinct type of brainstem glioma of the tectal region of the midbrain, leading to aqueductal compression and hydrocephalus. The radiologic appearance of these tumors is usually rather uniform, with a characteristic nonenhancing thickening of the tectal plate. Because of its protracted course, no further treatment is necessary beyond cerebrospinal fluid diversion and close clinicoradiologic follow-up. The authors report two children with tectal plate gliomas of unusual but strikingly similar appearance. They present a clinical picture suggestive of intracranial hypertension without localizing signs. Magnetic resonance images reveal hydrocephalus related to the presence of perfectly circular lesions, hypointense on T1 and hyperintense on T2, which could be mistaken for parasitic cysts or represent dilated rostral portions of the sylvian aqueduct. After the cerebrospinal fluid diversion procedures, no further treatment was given, with one of the patients being monitored for 10 years and the other for 8 months, without tumor progression. These patients demonstrate that tectal gliomas, despite sharing a good prognosis, may have various patterns of growth, leading to unusual radiologic appearances that may pose diagnostic difficulties.

Brain mapping in sedated infants and young children with passive-functional magnetic resonance imaging.

Functional magnetic resonance imaging (fMRI) in pediatric patients presents a unique set of problems due to the need for patient compliance, the frequent need for sedation and an early developmental status. A new method for using fMRI in sedated infants and young children is presented using passive stimuli focused on visual, sensorimotor and language functions. All of these stimuli are presented such that no patient interaction is required. Eight sedated children undergoing diagnostic MRI scans of the brain participated in these passive fMRI procedures. Cortical regions were identified using standard techniques applied to the blood-oxygen-level-dependent signal which is the basis for fMRI. The results support the feasibility of brain mapping in sedated children with passive fMRI techniques.

The role of chemotherapy in newly diagnosed ependymoma of childhood.

The use of chemotherapy in treating children with newly diagnosed ependymoma is currently being investigated, both clinically and experimentally. Assessment of the true efficacy of this modality is hampered by a lack of prospective randomized trials comparing conventional treatment schemes of aggressive surgical excision followed by radiation therapy with or without addition of chemotherapy. Although with current regimens, the role of chemotherapy in newly diagnosed disease appears limited, measurable disease responses have been recognized. Preliminary studies support the potential use of chemotherapy in infants in an effort to delay radiation therapy or even avoid radiation therapy, although with conventional chemotherapy, a delay exceeding 12 months is inadvisable. Additionally, preliminary data suggest that in children with incompletely resected tumors, chemotherapy may be of benefit as an adjunct to second-look surgery. Experimental work investigating chemotherapeutic sensitivity, molecular genetics, or mechanisms to overcome drug resistance may offer some benefit in utilizing chemotherapy for ependymoma of childhood.