Neurological grading, survival, MR imaging, and histological evaluation in the rat brainstem glioma model.

OBJECTIVE: Convection-enhanced delivery using carboplatin in brainstem glioma models was reported to prolong survival. Functional impairment is of additional importance to evaluate the value of local chemotherapy. We established a neurological scoring system for the rat brainstem glioma model. MATERIAL AND METHODS: In 46 male Fisher rats stereotactically 10(5) F-98 cells were implanted at 1.4-mm lateral to midline and at the lambdoid suture using guided screws. Following 4 days local delivery was performed using Alzet pumps (1 microl/h over 7 days) with either vehicle (5% dextrose) or carboplatin via one or two cannulas, respectively. All rats were subsequently tested neurologically using a specified neurological score. In 38 animals survival time was recorded. Representative MR imaging were acquired in eight rats, respectively, at day 12 after implantation. HE staining was used to evaluate tumor extension. RESULTS: Neurological scoring showed significantly higher impairment in the high dose carboplatin group during the treatment period. Survival was significantly prolonged compared to control animals in the high dose carboplatin-one cannula group as well as in both low dose carboplatin groups (18.6 +/- 3 versus 26.3 +/- 9, 22.8 +/- 2, 23.6 +/- 2 days; p < 0.05). Overall neurological grading correlated with survival time. MR imaging showed a focal contrast enhancing mass in the pontine brainstem, which was less exaggerated after local chemotherapy. Histological slices visualized decreased cellular density in treatment animals versus controls. CONCLUSION: Local chemotherapy in the brainstem glioma model showed significant efficacy for histological changes and survival. Our neurological grading enables quantification of drug and tumor-related morbidity as an important factor for functional performance during therapy.

Ototoxicity of carboplatin delivered locally in a monkey brainstem.

Ototoxicity is a common side effect of platinum-based chemotherapy. Intratumoral drug delivery theoretically could reduce the ototoxic effects of systemic drug infusions. However, local delivery to central nervous system (CNS) tumors might promote ototoxicity through drug release into cerebrospinal fluid (CSF). This report describes an examination of the cytoarchitecture of vestibular cells of cynomolgus monkeys that had chronic brainstem infusions with the maximum tolerated dose (MTD) of carboplatin. The brainstems of adult monkeys were infused for 30 days at 0.42 mu l/h with 0.025 to 0.25 mg/kg (MTD) of carboplatin. The vestibular sensory epithelia of eight drug-treated animals were isolated for microscopic examination of vestibular hair cells and support cells. Local infusions produced chronic elevated CSF levels of platinum, neurological symptoms, and radiographic evidence of pontine injury. Histology revealed significant cell damage at the infusion sites. Microscopic examinations of vestibular support cells and hair cells demonstrate a small reduction in cell counts in the drug-treated monkeys compared to a noninfused control animal. Parametric and nonparametric tests show no effect of dose in predicting the vestibular cell counts. In this single study of eight monkeys, a dose-dependent reduction of vestibular hair cells or support cells was not observed in animals infused with brainstem infusions of 0.025 to 0.25 mg/kg of carboplatin.

Toxicity and cerebrospinal fluid levels of carboplatin chronically infused into the brainstem of a primate.

PURPOSE: Carboplatin was infused into the brainstem of cynomolgus monkeys to investigate neurotoxicity and systemic exposures following chronic local delivery. METHODS: Infusions at 0.42 microl/h were intended to deliver 0.025 (n = 2), 0.075 (n = 3), 0.25 (n = 5), and 0.75 (n = 3) mg/kg by day 30. Laboratory tests, radiographic measurements, and clinical observations were used to monitor toxicity. Blood and cerebrospinal fluid (CSF) were sampled for platinum. RESULTS: Lethargy and ataxia were observed after week 4 in the monkeys given 0.075 mg/kg, and week 2 in the monkeys given 0.25 mg/kg when the infused doses were approximately 250 and 400 microg, respectively. Rapidly progressive neurotoxicity with the 0.75 mg/kg dose required termination of the infusions at days 4-10. Hematology and chemistry values were unremarkable in all groups. Blood levels of platinum remained undetectable in 0.025 and 0.075 mg/kg dose groups. Levels in the 0.25 mg/kg group were 3.1 +/- 0.6 microg/l at 2 weeks and 5.2 +/- 0.8 microg/l at 1 month. The CSF platinum levels varied. Animals in the 0.25 mg/kg group had higher CSF levels at 2 weeks (avg. 65 microg/l, range 36-89) compared to their 1 month value (avg. 60 microg/l, range 7-170), despite the constant infusion. CONCLUSION: Carboplatin can be chronically infused into monkey brainstems. Neurotoxicity is the predominant side effect and is dose-dependent. Pharmacokinetics of local and systemic delivery are different for carboplatin. Further studies are needed to monitor toxicity at higher flow rates and to investigate drug binding to abnormal central nervous system (CNS) tissues.

Hemispherectomy for intractable unihemispheric epilepsy etiology vs outcome.

BACKGROUND: Surgical removal of one hemisphere has been performed for several decades to treat intractable unihemispheric epilepsy. A prior case series focused on the outcomes after 58 surgeries at Johns Hopkins Hospital in 1997. This series, and an additional 53 cases, were reviewed to bring the outcomes up to date. METHODS: Charts of the 111 patients undergoing hemidecortications at the Pediatric Epilepsy Center from 1975 to 2001 were reviewed and families were contacted. Three children died in the immediate perioperative period and three were lost to follow-up immediately after surgery. Follow-up ranged from 3 months to 22 years. RESULTS: Two children died several years later due to intractable seizures. Overall, 65% are seizure-free, 21% have occasional, non-handicapping seizures, and 14% have troublesome seizures. Eighty percent are on one anticonvulsant or none and 89% are able to walk without assistance. Etiology strongly predicted seizure outcome. Patients with migrational disorders are less likely to be seizure-free than all other etiologies (predominantly Rasmussen and congenital vascular injuries) combined (51% vs 71%, p = 0.05). CONCLUSIONS: Hemidecortication continues to be a beneficial procedure in reducing seizure frequency in cases of unilateral cortical epilepsy. Fewer children with migrational disorders are seizure-free.

The postoperative course and management of 106 hemidecortications.

RATIONALE: The excellent long-term outcome for most children undergoing hemispherectomy is well documented. However, the condition of these children in the immediate postoperative period is poorly described. The purpose of this study was to evaluate the short-term issues surrounding hemispherectomy and their management in a series of patients from our institution. METHODS: 106 hemispherectomies were performed at our institution from 1975 to 2001 (102 hemidecortications). Medical records were retrospectively examined for information regarding immediate postoperative problems and care. RESULTS: Three children died in the immediate perioperative period, while 3 others had significant postoperative morbidity. 82% of these children had postoperative fevers (temperature >38.5 degrees C). Of these children, 62% had lumbar punctures. Ten cases had positive CSF growth, of which 6 cases were felt to have actual meningitis. Patients with CSF growth had a significantly longer prior duration of steroid therapy and higher maximum temperature peaks. CSF pleocytosis and an ill clinical appearance neared significance for prediction of CSF growth. Shunting was performed in 19% of all children and was associated with CSF growth. CONCLUSIONS: Postoperative fevers are common after hemidecortication, but meningitis is not. Children with CSF growth tended to appear more ill and have higher temperature spikes and CSF pleocytosis. Shunting was related to CSF growth.

Experimental rodent models of brainstem tumors.

Despite recent advances in surgical technology, resection is not an option for many brainstem tumors. Experimental models have played essential roles in examining new approaches to therapy. The objective of the present study was to generate models by determining coordinates for safe inoculation into the brainstem of mice and rats, and to establish whether the implantation of heterotopic cells would create reproducible survival curves. Morbidity and survival studies were used to map stereotactic coordinates allowing successful inoculation of tumor cells. Survival studies were used to investigate the time course of tumor growth. Tumor location was examined by light microscopy and magnetic resonance imaging. Mice survived injections of 2 microL of saline at interaural, lateral, and depth coordinates of -2.5, 1.0, and 3.5 mm and -1.5, 1.0, and 3.5 mm. Rats survived injections at interaural, lateral, and depth coordinates of -2.0, 2.0, and 7.0 mm and -3.0, 0, and 7.0 mm. Median survival of mice challenged with 5 x 10(5) EMT6 and 10(4) B16 tumor cells was 11 and 10 days, respectively. Median survival for rats challenged with 10(4) 9L and F98 cells was 14 and 13 days, respectively. The present study demonstrates a feasible approach to preparing models of brainstem tumors. Limitations of these models are discussed.

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.

Second surgery for recurrent pilocytic astrocytoma in children.

Pilocytic astrocytoma (PA) is the most common childhood brain tumor. In cases where the tumor progresses or recurs following primary surgical resection, the appropriate treatment is unclear. Options include chemotherapy, radiation therapy, surgical resection or a combination thereof. To analyze the utility of further surgery, we performed a retrospective, single-institution review of pediatric patients with recurrent PAs from 1990 to 1999 who were treated with a second surgical resection. Patients were excluded if they received adjuvant chemotherapy or radiation therapy. Twenty cases were identified. Tumor locations included: cerebral hemisphere (3), cerebellum (7), optic pathway/hypothalamus (5), thalamus (1) and brainstem (4). The indication for 4 surgeries included an enlarging tumor-associated cyst. At second surgery, 10 of 20 patients had a gross total resection (GTR), 2 a near total resection (NTR), and the remaining 8 patients had a subtotal resection (STR). No patients have died. Two of 10 tumors after GTR, 0 of 2 tumors after NTR, and 7 of 8 tumors after STR had second recurrence/progression at a mean of 15 months (range 4-33 months) following second surgery. The remaining 11 patients are recurrence/progression-free at a mean of 40.7 months (range 19-119 months). Surgery for tumors or midline structures rarely resulted in a GTR (1 of 10 cases). Surgery for tumors located in the cerebral hemispheres or cerebellum resulted in GTR or NTR in all cases and can result in long periods of progression-free survival without further adjuvant treatment.

A clinicopathologic reappraisal of brain stem tumor classification. Identification of pilocystic astrocytoma and fibrillary astrocytoma as distinct entities.

BACKGROUND: Brain stem tumors in children have been classified pathologically as low grade or high grade gliomas and descriptively as diffuse gliomas, intrinsic gliomas, midbrain tumors, tectal gliomas, pencil gliomas, dorsal exophytic brain stem tumors, pontine gliomas, focal medullary tumors, cervicomedullary tumors, focal gliomas, or cystic gliomas. METHODS: To search for a simplified and prognostic clinicopathologic scheme for brain stem tumors, the authors reviewed a consecutive cohort of patients younger than age 21 years with tumors diagnosed from 1980 through 1997. Pathology specimens and neuroimaging were classified by masked review. Statistical and survival analysis along with Cox proportional hazards regression was performed. RESULTS: Seventy-six patients were identified, with initial diagnostic magnetic resonance imaging available for 51 and pathology specimens for 48 patients. Twenty cases were classified histologically as pilocytic astrocytoma (PA), 14 as fibrillary astrocytoma (FA), and 14 as other tumors or indeterminate pathology. For all tumors, characteristics significantly associated with a worse survival rate were: symptom duration less than 6 months before diagnosis (P = 0.004); abducens palsy at presentation (P < 0.0001); pontine location (P = 0.0002); and engulfment of the basilar artery (P = 0.006). Pilocytic astrocytoma was associated with location outside the ventral pons (P = 0.001) and dorsal exophytic growth (P = 0.013); Fibrillary astrocytoma was associated with symptoms less than 6 months (P = 0. 006), abducens palsy (P < 0.001), and engulfment of the basilar artery (P = 0.002). Pilocytic astrocytoma showed 5-year overall survival (OS) of 95% (standard error [SE], 5%) compared with FA 1-year OS of 23% (SE, 11%;P < 0.0001). CONCLUSIONS: Brain stem tumors can be succinctly and better biologically classified as diffusely infiltrative brain stem gliomas-generally FA located in the ventral pons that present with abducens palsy, often engulf the basilar artery, and carry a grim prognosis-and focal brain stem gliomas-frequently PA arising outside the ventral pons, often with dorsal exophytic growth, a long clinical prodrome, and outstanding prognosis for survival. Our findings emphasize the individuality of PA as a distinct clinicopathologic entity with an exceptional prognosis.

Asymptomatic Chiari Type I malformations identified on magnetic resonance imaging.

OBJECT: Chiari Type I malformation (CMI) is a congenital disorder recognized by caudal displacement of the cerebellar tonsils through the foramen magnum and into the cervical canal. Frequently, associated findings include abnormalities of nearby bony and neural elements as well as syringomyelia. Cerebellar tonsillar ectopia is generally considered pathological when greater than 5 mm below the foramen magnum. However, asymptomatic tonsillar ectopia is an increasingly recognized phenomenon, the significance of which is poorly understood. METHODS: The authors retrospectively reviewed the records of all brain magnetic resonance (MR) images obtained at our hospital over a 43-month period in an attempt to ascertain the relative prevalence and MR imaging characteristics of asymptomatic CMIs. Of 22,591 patients who underwent MR imaging of the head and cervical spine, 175 were found to have CMIs with tonsillar herniation extending more than 5 mm below the foramen magnum. Of these, 25 (14%) were found to be clinically asymptomatic. The average extent of ectopia in this population was 11.4 +/- 4.86 mm, and was significantly associated with a smaller cisterna magna. Syringomyelia and osseous anomalies were found in only one asymptomatic patient. CONCLUSIONS: The authors suggest that the isolated finding of tonsillar herniation is of limited prognostic utility and must be considered in the context of all available clinical and radiographic data. Strategies for treating patients with asymptomatic CMIs are discussed.

A heterotopic cerebellum presenting as a suprasellar mass with associated nasopharyngeal teratoma.

We present a case of nasopharyngeal teratoma that was discovered in association with a suprasellar heterotopic cerebellum in a newborn. Well-differentiated, heterotopic, cerebellar masses have been reported in the orbits, spine, and frontal encephalocele but not, to our knowledge, in the suprasellar region. In this report, we describe the imaging findings and discuss the possible origins of the two masses discovered in this case.

Tectal gliomas: natural history of an indolent lesion in pediatric patients.

The mesencephalic tectal glioma is a distinctive form of brain stem glioma with an unusually benign clinical course. Periaqueductal location, lack of contrast enhancement, and long periods of stability are classic features. The clinical management of these lesions, especially at the time of radiographic enlargement varies widely in the published literature. It is unclear whether these progressive lesions need to be treated. Accordingly, clinical and radiologic features of 7 patients were reviewed, with attention to the clinical course of the disease after radiologic enlargement. The age at diagnosis ranged from 3.3 to 16.6 years. Six of 7 had MRI tumor enlargement beginning 0.3-5.7 years after initial diagnosis. One of these 6 patients had radiographic progression coupled with a new clinical symptom which was treated with stereotactic radiation therapy. The remaining 5 patients with MRI progression and normal neurological exams were not treated and remain free of new neurologic deficits 1.8-6.9 years after the first radiographic tumor enlargement. The results suggest that pediatric tectal gliomas are a very low-grade lesion. Conservative management in the absence of new clinical symptoms could be argued, reserving radiotherapy or chemotherapy for clinical progression.

An assistive device for the treatment of positional plagiocephaly.

An assistive device (AD) was used to treat 122 infants with moderate-to-severe positional plagiocephaly. Clinical evaluations indicate that the AD provided the most benefit when applied to 2- to 8-month-old children. Our results suggest that the AD may join molding helmets and physical therapy as a treatment for moderate-to-severe positional plagiocephaly in infants under the age of 1 year.

Current opinions for the treatment of syringomyelia and chiari malformations: survey of the Pediatric Section of the American Association of Neurological Surgeons.

INTRODUCTION: A variety of surgical interventions have been recommended for patients with syringomyelia and Chiari malformation. To obtain a better understanding of currently used management strategies and surgical interventions, this study evaluates current opinions in the treatment of these entities. METHODS: Members of the Pediatric Section of the American Association of Neurological Surgeons (AANS) were surveyed in July of 1998. A questionnaire was designed to assess (1) management of asymptomatic and symptomatic cases; (2) signs and symptoms that warrant surgical intervention, and (3) surgical strategies. Seventy-seven of 234 surveys (33%) were returned. Responses were entered in a Microsoft Excel spreadsheet for data analysis. RESULTS: Each year, respondents evaluated on average 10 patients with confirmed syringomyelia and operated on 7. There was substantial agreement to operate on patients with syringomyelia who had progressive scoliosis or progressive motor/sensory loss. For isolated syringomyelia without a Chiari malformation, the majority of respondents recommended shunting of the syrinx. Opinion was mixed concerning physical restrictions for asymptomatic patients with syringomyelia and Chiari malformations. For Chiari malformations, the majority of respondents recommended a minimum cervicomedullary decompression with dural patch grafting. No consensus was obtained on whether dural patch grafting should be done alone or in combination with intradural dissection or manipulation of the tonsils. CONCLUSION: Although many respondents agreed on the management and surgical treatment of symptomatic patients with syringomyelia and/or Chiari malformations, there was disagreement with regard to the optimal surgical procedure. Respondents rejected prophylactic surgery for their asymptomatic patients, choosing to follow them conservatively with serial imaging and neurological examinations.

Three-dimensional morphological analysis of isolated metopic synostosis.

Morphological differences were quantified in three-dimensions among individuals with untreated isolated metopic synostosis and between those individuals and similar aged-matched normal dry skulls to test two hypotheses: first, that the dysmorphology is a self-correcting condition; and second, that a lack of vertical growth of the skull produces this dysmorphology. Three-dimensional (3D) coordinates were recorded for 22 craniofacial landmarks from CT scans of 15 metopic patients, ranging from 5- to 32-months-old, and of four normal dry skulls, ranging in age from 6- to 36-months-old. The patient population was diagnosed with isolated metopic synostosis at The Johns Hopkins Medical Institutions in Baltimore, Maryland or Children's Hospital in St. Louis, Missouri. Comparisons between the metopic age groups indicate that the trigonocephalic phenotype worsens through time. Between 5 and 14 months, the neurocranium displays an increase in vertical growth. This was followed by a lack of vertical growth between 14 and 32 months. The face displays a lack of vertical growth from 5 to 14 months and an increase in vertical growth after 14 months. Comparisons between the metopic age groups and the normal skulls indicate that the trigonocephalic head is taller superoinferiorly and longer anteroposteriorly. Relative to the normal phenotype, the inferior temporal region in the metopic phenotype is narrow. These findings enabled the rejection of both hypotheses and localized form differences between normal and metopic phenotypes. Based on these results, we suggest that the trigonocephalic phenotype worsens with age and the amount of vertical growth that produces the trigonocephalic phenotype varies throughout growth with respect to location within the skull and age.

Fiberoptic delivery of laser energy to remove occlusions from ventricular shunts: technical report.

OBJECTIVES: Shunts frequently require surgical replacement because occlusions block the ventricular tubing. We have examined the hypothesis that a surgical laser coupled to an optical fiber can deliver sufficient energy to disrupt the occlusion in situ and thus afford a less invasive method of repair. METHODS: Choroid plexus tissue found in shunts explanted from patients, model tissues such as polyacrylamide gel, and animal tissues inserted into shunts were examined. Occlusions were fragmented by pulsed laser energy of 2.09-microm wavelength and 300-microsecond duration delivered via a flexible optical fiber several meters in length. The methods and conditions were similar to those likely to be used for preclinical in vivo studies. RESULTS: Short-lived vapor bubbles generated at the fiber tip disrupted occlusions within the shunt and expelled tissue blocking the inflow holes. Energy requirements to disrupt and remove occlusions in vitro were determined. Laser pulse energies and exposure thresholds that cause intentional damage to shunts also were determined. CONCLUSION: Laser energies needed to disrupt occlusions were below the energy needed to damage the shunt components. Our results show that a strategy using surgical lasers and optical fibers is feasible and suggest that the procedure could be used to repair blocked shunts without requiring surgical replacement.

Increased hematocrit and decreased transfusion requirements in children given erythropoietin before undergoing craniofacial surgery.

OBJECT: This study was undertaken to determine the efficacy of preoperative erythropoietin administration in infants scheduled for craniofacial surgery and, in so doing, to minimize problems associated with blood transfusions. METHODS: Families were offered the option of having their children receive erythropoietin injections before undergoing craniofacial surgery. The children whose families accepted this option received daily iron and 300 U/kg erythropoietin three times per week for 3 weeks preoperatively. Weekly complete blood counts with reticulocyte counts were measured and transfusion requirements were noted. Blood transfusions were administered depending on the clinical condition of the child. A case-matched control population was also evaluated to compare initial hematocrit levels and transfusion requirements. Thirty patients in the erythropoietin treatment group and 30 control patients were evaluated. The dose of erythropoietin administered was shown to increase hematocrit levels from 35.4 +/- 0.9% to 43.3 +/- 0.9% during the course of therapy. The resulting hematocrit levels in patients treated with erythropoietin at the time of surgery were higher compared with baseline hematocrit levels obtained in control patients at the time of surgery (34.2 +/- 0.5%). Transfusion requirements also differed: all control patients received transfusions, whereas 64% (19 of 30) of erythropoietin-treated patients received transfusions. CONCLUSIONS: The authors conclude that treatment with erythropoietin in otherwise healthy young children will increase hematocrit levels and modify transfusion requirements. Erythropoietin therapy for elective surgery in children of this age must be individualized according to the clinical situation, family and physician beliefs, and cost effectiveness, as evaluated at the individual center.