Concomitant intracerebral infusion of tissue plasminogen activator and thrombin leads to brain injury.

Low doses of thrombin are neuroprotective while high doses are neurotoxic and lead to brain injury. However, evidence suggests that low doses of thrombin cause brain injury when infused concomitantly with tissue plasminogen activator (tPA), which is used clinically to facilitate evacuation of intracerebral hematomas. In this study, we examined the effects of intracerebral infusion of tPA and thrombin, individually and in combination. Rats were infused in the right basal ganglia with 50 microL saline solutions containing thrombin, tPA, or thrombin + tPA. In the first experiment, rats were used for blood-brain barrier (BBB) permeability measurements at 24 h after infusion. In the second experiment, animals were euthanized 3 days after infusion, and brain sections were stained with Fluoro-Jade to measure neuronal cell death. Behavioral tests were carried out before and after surgery. Infusion of thrombin + tPA markedly increased Evans blue tissue content in ipsilateral brain samples (p < 0.05). Fluoro-Jade-stained sections from thrombin + tPA group demonstrated significantly higher cell death counts (p < 0.01). Significant neurological deficit was revealed in thrombin + tPA group in forelimb-placing and corner-turn tests (p < 0.01). This study shows that tPA potentiates the neurotoxic effects of thrombin and leads to increased BBB permeability, neuronal cell death, and neurological deficit. Our results suggest that using tPA to lyse intracerebral hematomas has potential to produce neuronal cell death and disruption of BBB.

The role of thrombin in gliomas.

BACKGROUND: In a previous study we found that intracerebral infusion of argatroban, a specific thrombin inhibitor, reduces brain edema and neurologic deficits in a C6 glioma model. OBJECTIVES: To examine the role of thrombin in gliomas and whether systemic argatroban administration can reduce glioma mass and neurologic deficits and extend survival time in C6 and F98 gliomas. METHODS: The presence of thrombin in human glioblastoma samples and rat C6 glioma cells (in vitro and in vivo) was assessed using immunohistochemistry. The effect of thrombin on C6 cell proliferation in vitro was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay. The role of thrombin in vivo was assessed in rat C6 and F98 glioma cell models using argatroban, a thrombin inhibitor. The effects of argatroban on tumor mass, neurologic deficits and survival time were investigated. RESULTS: Thrombin immunoreactivity was found in cultured rat C6 glioma cells and human glioblastomas. Thrombin induced C6 cell proliferation in vitro. In C6 glioma, argatroban reduced glioma mass (P < 0.05) and neurologic deficits (P < 0.05) at day 9. In F98 glioma, argatroban prolonged survival time (P < 0.05). CONCLUSION: These results suggest that thrombin plays an important role in glioma growth. Thrombin may be a new therapeutic target for gliomas.

Systemic use of argatroban reduces tumor mass, attenuates neurological deficits and prolongs survival time in rat glioma models.

Our previous studies showed that intracerebral infusion of argatroban, a specific thrombin inhibitor, reduces brain edema and neurological deficits in a C6 glioma model. The present study investigated whether systemic argatroban administration can reduce glioma mass and neurological deficits and extend survival time in C6 and F98 gliomas. Rat C6 or F98 glioma cells were infused into the right caudate of adult male Fischer 344 rats. Osmotic minipump loaded with argatroban (0.3 mg/hour) or vehicle was implanted into abdomen immediately after glioma implantation. Tumor mass was determined at day 9. Over the period of the experiment, the animals underwent behavioral testing (forelimb placing and forelimb use asymmetry). In addition, survival time was tested in the F98 glioma model. In C6 glioma, argatroban reduced glioma mass (p < 0.05) and neurological deficits (p < 0.05) at day 9. In F98 glioma, agratroban prolonged the survival time (p < 0.05) and reduced the body weight loss (84 +/- 15 gram vs. 99 +/- 2 gram in the vehicle group, P < 0.05). In conclusion, systemic use of argatroban reduced tumor mass and neurological deficits, and prolonged survival time. These results suggest that thrombin plays a key role in glioma growth and thrombin inhibition with argatroban may be a novel treatment for gliomas.

Complete osseous regeneration of a large skull defect in a patient with cutis aplasia: a conservative approach.

Cutis aplasia (or aplasia cutis congenita) is a congenital absence of all skin layers, often extending through bone. This defect usually occurs in the scalp and can be extensive, exposing the dura mater, and deeper meninges. Treatment regimens for cutis aplasia have included early operative intervention, including skin and bone grafts, local scalp flaps, or free flaps to close the defect. In addition to the significant perioperative risks, these invasive procedures may inhibit the osteogenic potential of the dura to initiate and sustain bony closure of the defect. We report a case of an infant with Adams-Oliver syndrome and cutis aplasia involving a large portion of the skull that was treated conservatively with topical Silvadene dressings. No surgical treatment of bone or soft tissue reconstruction was necessary. This case report is the first to our knowledge to document complete bony restoration of the cranial vault through serial three-dimensional CT scans. The intensive therapeutic intervention in this case report allowed early discharge from the hospital, a gradual amelioration of the patient's alopecia as the hair-bearing scalp slowly covered the defect, and precluded the need for any subsequent bony reconstruction of the cranial vault. We hypothesize that conservative treatment of cutis aplasia maintains dural induction of osseous regeneration, and any treatment plan for bony defects of cutis aplasia should consider maintenance of dural integrity. Although further investigation is warranted, an initial trial of antimicrobial dressing care might optimally promote secondary closure of the cranial vault without the need for surgical intervention.

Magnetic resonance imaging of ethyl-nitrosourea-induced rat gliomas: a model for experimental therapeutics of low-grade gliomas.

Human low-grade gliomas represent a population of brain tumors that remain a therapeutic challenge. Preclinical evaluation of agents, to test their preventive or therapeutic efficacy in these tumors, requires the use of animal models. Spontaneous gliomas develop in models of chemically induced carcinogenesis, such as in the transplacental N-ethyl-N-nitrosourea (ENU) rat model. However, without the ability to detect initial tumor formation, multiplicity or to measure growth rates, it is difficult to test compounds for their interventional or preventional capabilities. In this study Fisher-334 rats, treated transplacentally with ENU, underwent magnetic resonance imaging (MRI) examination in order to evaluate this approach for detection of tumor formation and growth. ENU-induced intracranial cerebral tumors were first observable in T2-weighted images beginning at 4 months of age and grew with a mean doubling time of 0.487 +/- 0.112 months. These tumors were found histologically to be predominately mixed gliomas. Two therapeutic interventions were evaluated using MRI, vitamin A (all-trans retinol palmitate, RP), as a chemopreventative agent and the anti-angiogenic drug SU-5416. RP was found to significantly delay the time to first tumor observation by one month (P = 0.05). No differences in rates of tumor formation or growth rates were observed between control and RP-treated groups. MRI studies of rats treated with SU-5416 resulted in reduction in tumor growth rates compared to matched controls. These results show that MRI can be used to provide novel information relating to the therapeutic efficacy of agents against the ENU-induced tumor model.

Intramedullary spinal tumors of disordered embryogenesis.

Abnormal spinal embryogenesis is quite commonplace. While greater than 90 percent of these errors of embryogenesis leads to occult spinal dysraphism with minimal neurologic or orthopedic sequelae, there is a significant minority of these anomalies which leads to the formation of the so-called 'congenital tumors of disordered embryogenesis'. The purpose of this article is to discuss the embryology, presentation, diagnosis and management of the spinal dysraphic states with particular emphasis on those errors which lead to mass lesions in the spinal canal such as dermoids, epidermoids, lipoma/lipomyelomeningocoele and neurenteric cysts. We also include lesions such as dermal sinus tracts and thickened filum terminale in our discussion with particular emphasis on their relationship to the tethered cord syndrome. Proper surgical management of these various conditions necessitates a thorough understanding of their embryologic etiology and the anatomic/physiologic ramifications that such lesions have on the developing spinal cord.

Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Children's Cancer Group Study.

PURPOSE: Medulloblastoma is the most common malignant brain tumor of childhood. After treatment with surgery and radiation therapy, approximately 60% of children with medulloblastoma are alive and free of progressive disease 5 years after diagnosis, but many have significant neurocognitive sequelae. This study was undertaken to determine the feasibility and efficacy of treating children with nondisseminated medulloblastoma with reduced-dose craniospinal radiotherapy plus adjuvant chemotherapy. PATIENTS AND METHODS: Over a 3-year period, 65 children between 3 and 10 years of age with nondisseminated medulloblastoma were treated with postoperative, reduced-dose craniospinal radiation therapy (23.4 Gy) and 55.8 Gy of local radiation therapy. Adjuvant vincristine chemotherapy was administered during radiotherapy, and lomustine, vincristine, and cisplatin chemotherapy was administered during and after radiation. RESULTS: Progression-free survival was 86% +/- 4% at 3 years and 79% +/- 7% at 5 years. Sites of relapse for the 14 patients who developed progressive disease included the local tumor site alone in two patients, local tumor site and disseminated disease in nine, and nonprimary sites in three. Brainstem involvement did not adversely affect outcome. Therapy was relatively well tolerated; however, the dose of cisplatin had to be modified in more than 50% of patients before the completion of treatment. One child died of pneumonitis and sepsis during treatment. CONCLUSION: These overall survival rates compare favorably to those obtained in studies using full-dose radiation therapy alone or radiation therapy plus chemotherapy. The results suggest that reduced-dose craniospinal radiation therapy and adjuvant chemotherapy during and after radiation is a feasible approach for children with nondisseminated medulloblastoma.

A comparison of continuous epidural infusion and intermittent intravenous bolus doses of morphine in children undergoing selective dorsal rhizotomy.

BACKGROUND AND OBJECTIVES: Selective dorsal rhizotomy (SDR) is associated with moderale to severe postoperative pain. Although the efficacy of epidural analgesia in this population has been demonstrated, it has not been compared with conventional intravenous (i.v.) analgesia. This prospective study compared the effects of epidural and i.v. morphine regarding postoperative analgesia, side effects, and outcomes in children following SDR. METHODS: Twenty-seven children were randomized to receive either epidural or i.v. analgesia. Children in the epidural group had a catheter placed by the neurosurgeon and received preservative-free morphine (Duramorph) 30 microg/kg, followed by an infusion of 3 microg/kg/h for 3 days. Children in the i.v. group received morphine 0.05-0.1 mg/kg intraoperatively, followed by 0.02 mg/kg doses postoperatively administered by nurses via a patient-controlled analgesia device. RESULTS: The epidural group experienced lower pain scores (P = .04) and fewer muscle spasms (P < or = .04), and tolerated activity better (P < or = .02) during the early postoperative period than the i.v. group. Side effects were similar between groups, with no respiratory depression in either group. Parents of children in both groups perceived an adequate level of comfort and were very satisfied with the analgesic technique. Additionally, parents believed that their child's postoperative pain was less than anticipated (P < or = .01). CONCLUSIONS: Both techniques provided effective postoperative analgesia with a similar incidence of side effects; however, our findings suggest that continuous infusions of epidural morphine improved overall comfort with lower pain scores, fewer muscle spasms, and improved tolerance of activity during the initial postoperative period.

Investigation of the influences of biomechanical force on the ultrastructure of human sagittal craniosynostosis.

This study presents comparisons of the ultrastructure of synostotic and open portions of synostotic sagittal sutures using histomorphometry, scanning electron microscopy, and microcomputed tomography. By using stereologic and histomorphometric analysis, this study proposes to demonstrate evidence of the influence of biomechanical force on the suture during the process of sagittal craniosynostosis. Finally, we propose to link the pathologic changes transforming normal suture fusion to craniosynostosis with concurrent changes in the polarity of suture fusion initiation. Seven infants (four boys and three girls) with sagittal craniosynostosis, ranging in age from 1.4 to 4.8 months (mean = 3.0 months), underwent sagittal synostectomies. The synostotic bone specimens were sectioned into three regions: an open suture, partial synostosis, and complete synostosis. Microcomputed tomographic and scanning electron microscopic scanning as well as histomorphometry was performed on all specimens to obtain detailed qualitative and quantitative information regarding the trabecular microarchitecture of the synostosed suture. Microcomputed tomographic analysis determined the bone volume fraction, trabecular thickness, trabecular separation, bone surface to bone volume ratio, and anisotropy for all specimens. Our results showed significant differences in all of these quantitative measurements when comparing the complete synostotic suture with the open portion of the synostotic sutures (p < 0.05). Microcomputed tomographic stereologic analysis showed evidence of the influence of biomechanical force on the synostotic and open portions of the synostotic sutures. Results of scanning electron microscopy show a definite qualitative difference in the trabecular pattern of the partial and complete synostotic suture when compared with the open portion of the synostotic sagittal suture. In this study, we performed both qualitative and quantitative comparisons of the ultrastructure of the complete synostotic and nonsynostotic sagittal sutures using stereologic and histomorphometric techniques. We also demonstrated evidence of the influence of biomechanical force on the synostotic sagittal suture. Finally, we established a link between the pathologic changes transforming normal suture fusion to craniosynostosis and concurrent changes in both the vector and direction of suture fusion initiation.

Effect of dietary vitamin A or N-acetylcysteine on ethylnitrosourea-induced rat gliomas.

It is our hypothesis that low grade gliomas are the glial counterparts of other precancerous lesions such as colon polyps and, therefore, suitable targets for chemoprevention. Steps in the molecular progression of gliomas have been described, indicating that an accumulation of abnormalities is required for progression to a high grade and interruption of this progression might be possible. An animal model of chemical glial carcinogenesis was used to test this hypothesis. Pregnant rats were injected intravenously with ENU (ethylnitrosourea) on the 18th day of gestation to induce gliomas in the offspring, which were randomized to receive control diet, diet supplemented with vitamin A palmitate, or diet supplemented with N-acetylcysteine. Animals exposed to ENU and receiving a control diet developed brain tumors and had a shortened life expectancy compared with rats unexposed to ENU. The animals treated with NAC showed no statistically significant delay in the time to tumor and no change in the histologic grade of the tumors when compared with animals receiving control diet, but the time to death from any cause of NAC treated animals differed significantly from untreated animals. Animals receiving high dose VA had statistically significantly prolonged time to tumor, survived significantly longer than untreated animals, but had no reduction in the total number of tumors or change in the histologic grade of their tumors. The theoretical basis of these results is likely due to the putative mechanism of action of these agents. These data indicate that glioma chemoprevention is possible and deserves further exploration.

Intraventricular immunotoxin therapy for leptomeningeal neoplasia.

OBJECTIVE: The goals of this clinical trial of intraventricular 454A12-rRA therapy were to identify dose-limiting toxicities, to evaluate the pharmacokinetics of single-dose intraventricular 454A12-rRA, and to detect antitumor activity. METHODS: We performed a pilot study of intraventricular therapy with the immunotoxin 454A12-rRA in eight patients with leptomeningeal spread of systemic neoplasia. The immunotoxin 454A12-rRA is a conjugate of a monoclonal antibody against the human transferrin receptor and recombinant ricin A chain, the enzymatically active subunit of the protein toxin ricin. Patients were treated with single doses of 454A12-rRA ranging from 1.2 to 1200 micrograms. RESULTS: The early phase half-life of 454A12-rRA in ventricular cerebrospinal fluid (CSF) averaged 44 +/- 21 minutes, and the late phase half-life averaged 237 +/- 86 minutes. The clearance of the immunotoxin was faster than the clearance of coinjected technetium-99m-diethylenetriamine penta-acetic acid, averaging approximately 2.4-fold greater. No 454A12-rRA degradation was detected by Western blot analysis of ventricular CSF for a period of 24 hours, and bioactivity was retained in CSF paralleling the concentration of immunotoxin. No acute or chronic drug toxicity was identified in patients who received less than or equal to 38 micrograms of 454A12-rRA by intraventricular injection. Doses more than or equal to 120 micrograms caused a CSF inflammatory response that was associated with transient headache, vomiting, and altered mental status. This acute syndrome was responsive to steroids and CSF drainage. No systemic toxicity was detected. In four of the eight patients, a greater than 50% reduction of tumor cell counts in the lumbar CSF occurred within 5 to 7 days after the intraventricular dose of 454A12-rRA; however, no patient had their CSF cleared of tumor, and clinical or magnetic resonance imaging evidence of tumor progression was demonstrated in seven of the eight patients after treatment. CONCLUSION: Tumoricidal concentrations of the immunotoxin 454A12-rRA can be attained safely in the CSF of patients with leptomeningeal tumor spread.

Lymphocytic hypophysitis presenting with diabetes insipidus in a 14-year-old girl: case report and review of the literature.

UNLABELLED: Lymphocytic hypophysitis is a rare disorder predominantly affecting females during the antepartum or postpartum period. It is characterized by destruction and lymphocytic infiltration of the pituitary gland, probably by an autoimmune process, leading to a pituitary mass lesion and/or various degrees of hypopituitarism. The lesion is usually confined to the adenohypophysis. Posterior pituitary gland or stalk involvement is rare, although patients presenting with diabetes insipidus have been reported. We describe a girl aged 13 years 9 months with lymphocytic hypophysitis who presented with diabetes insipidus and secondary amenorrhea. MRI of the brain revealed a 1 cm enhancing mass in the pituitary stalk. A biopsy of the mass by right pterional craniotomy showed lymphocytic infiltration without neoplastic cells or granuloma formation. To our knowledge, this is the youngest reported patient with a diagnosis of lymphocytic hypophysitis. In this case report, her clinical presentation is discussed along with a review of the literature. CONCLUSION: We present the first childhood case of lymphocytic hypophysitis which is an autoimmune inflammatory disorder of the pituitary gland. Although this is a rare condition in adults, it also needs to be considered in the pediatric population. Conservative management is preferred unless there are signs of increased intracranial pressure. Most importantly, close monitoring for multiple hormone deficiencies is indicated in this condition.

Desmoplastic medulloblastoma: MR findings.

In three cases of desmoplastic medulloblastoma, MR findings were varied. We report the unusual appearance of this tumor in two children and one adult.

Hepatoblastoma metastatic to brain: prolonged survival after multiple surgical resections of a solitary brain lesion.

PURPOSE: Pulmonary metastases of hepatoblastoma confined to the lung have been cured using therapy that included radical surgical resection. We report the case of a child with a hepatoblastoma metastatic to brain that was successfully treated with multiple surgical resections, irradiation, and chemotherapy. The case demonstrates that such an approach, employing aggressive surgery, can produce durable remission of an extrapulmonary metastasis with hepatoblastoma. PATIENTS AND METHODS: A 17-month-old girl presented with a hepatoblastoma that remained unresectable after chemotherapy and irradiation and underwent orthotopic liver transplantation 14 months after diagnosis. After twice undergoing surgical resections of pulmonary metastases 22 and 31 months from diagnosis, 1 month later (32 months from diagnosis), she developed a solitary metastatic right brain lesion that later recurred twice in the same location, 5 and 6 years from initial diagnosis. Each time she underwent surgical resection of the brain lesion and received local irradiation after the first two resections and chemotherapy after the third. At the last surgery, resection was continued until histologically negative tumor margins were obtained. RESULTS: The child is currently without evidence of disease or neurological deficit 10.5 years from initial diagnosis. CONCLUSION: The durable remission achieved after multiple resections of the recurrent solitary cerebral metastasis in this child demonstrates that an aggressive surgical approach to extrapulmonary metastases in such a setting can contribute to prolonged survival, just as has been shown with isolated metastatic pulmonary disease.

Leptomeningeal fibrosis and the delayed diagnosis of a central nervous system neoplasm (primitive neuroectodermal tumor).

We report a unique case of histologically confirmed meningeal fibrosis in a child who had progressive ischemic neurologic symptoms before the delayed diagnosis of an intracranial primitive neuroectodermal tumor (PNET) was made > 1 year after initial presentation. This pathology has previously been described after neurosurgical procedures, subarachnoid hemorrhage, cranial irradiation, and with no known etiology, but has never been reported in association with a central nervous system neoplasm. In a 6-year-old boy with headaches of several months' duration MRI demonstrated hydrocephalus, a right cerebellopontine angle cyst, and dural enhancement. Biopsies of the thickened meninges taken when the cyst was surgically fenestrated demonstrated only fibrosis with no evidence of infection, hemorrhage, or neoplasm. In the next 6 months, the child had two acute stroke-like episodes with alternating hemiparesis that gradually improved. There were ischemic changes in the diencephalon on MRI. Repeat dural biopsies were unchanged. One year after the initial operation, a left hemiparesis recurred and MRI demonstrated multiple intracranial masses in the cerebral cortex, cerebellum, suprasellar area, and cauda equina. After surgical resection, the cortical mass was found to be a PNET. All the lesions regressed after treatment with radiation and chemotherapy. We hypothesize that the meningeal fibrosis represented a "desmoplastic" reaction to an occult PNET, similar to the fibrous proliferation with cerebellar desmoplastic medulloblastoma except for the extent of the meningeal involvement and the long undetected parenchymal tumor. The mechanism of the ischemic brain injury was most likely vascular involvement by the fibrotic process, either directly or by predisposition to vasoconstriction.

Use of lumbar periosteal turnover flaps in myelomeningocele closure.

OBJECTIVE: We report our experience with a previously undescribed method of myelomeningocele closure, which is the use of bilateral lumbar periosteal flaps as an additional tissue layer in complex cases. These flaps reinforce the dural repair, act to protect the spinal cord, and may help to contain any potential cerebrospinal fluid leak from the primary repair of the cord, thereby preventing pseudomeningocele formation. METHODS: The repair involves the development of bilateral thoracolumbar fascial flaps in conjunction with periosteal flaps, which are elevated from adjacent lumbar pedicles and transverse processes, thus forming a composite tissue flap. These periosteally based flaps may be closed in a "pants over vest" fashion to completely cover the spinal defect, reinforcing the neurosurgical repair. The flap anatomy and dissection are detailed. RESULTS: Two representative cases in which the lumbar periosteal turnover flap procedure was used are reported. One patient was operated on during the early neonatal period for primary myelomeningocele repair; the other was operated on at age 5 years after a tethered cord release. Durable, stable soft tissue coverage of the spinal cord was obtained in both patients, with a postoperative follow-up period of at least 12 months. There was no recurrence of the pseudomeningocele noted preoperatively in the second patient. CONCLUSION: The lumbar periosteal turnover flap may be used to reinforce tenuous spinal cord and dural repairs in the myelomeningocele patient. This method provides a secure and watertight closure over the primary repair of the cord, may help to contain potential cerebrospinal fluid leaks, and adds an additional autologous tissue layer to standard skin or muscle flap repairs.

In vivo MR determination of water diffusion coefficients and diffusion anisotropy: correlation with structural alteration in gliomas of the cerebral hemispheres.

PURPOSE: To determine whether a relationship exists between water diffusion coefficients or diffusion anisotropy and MR-defined regions of normal or abnormal brain parenchyma in patients with cerebral gliomas. METHODS: In 40 patients with cerebral gliomas, diffusion was characterized in a single column of interest using a motion-insensitive spin-echo sequence that was applied sequentially at two gradient strength settings in three orthogonal directions. Apparent diffusion coefficients (ADCs) were derived for the three orthogonal axes at 128 points along the column. An average ADC and an index of diffusion anisotropy (IDA = diffusion coefficientmax-min/diffusionmean) was than calculated for any of nine MR-determined regions of interest within the tumor or adjacent parenchyma. RESULTS: In cerebral edema, mean ADC (all ADCs as 10(-7) cm2/s) was 138 +/- 24 (versus 83 +/- 6 for normal white matter) with mean IDA of 0.26 +/- 0.14 (versus 0.45 +/- 0.17 for normal white matter). Solid enhancing central tumor mean ADC was 131 +/- 25 with mean IDA of 0.15 +/- 0.10. Solid enhancing tumor margin mean ADC was 131 +/- 25, with IDA of 0.25 +/- 0.20. Cyst or necrosis mean ADC was 235 +/- 35 with IDA of 0.07 +/- 0.04. CONCLUSION: In cerebral gliomas ADC and IDA determinations provide information not available from routine MR imaging. ADC and IDA determinations allow distinction between normal white matter, areas of necrosis or cyst formation, regions of edema, and solid enhancing tumor. ADCs can be quickly and reliably characterized within a motion-insensitive column of interest with standard MR hardware.

Pediatric midbrain tumors: a benign subgroup of brainstem gliomas.

The presentation, radiographic findings and course of 17 children with MRI-documented intrinsic midbrain lesions are reviewed. The anatomic centers of all the lesions were tectal, peritectal, or tegmental. Lesions centered at the pineal gland were excluded. Signs of increased intracranial pressure from hydrocephalus requiring shunt placement were present in 14 patients. Histopathological diagnosis was confirmed in three tumors; these were low grade astrocytomas and all received focal irradiation, as did one unbiopsied tumor. The remaining 13 patients with no histopathological diagnosis received no therapy other than shunt placement in 11. All but one of the lesions have remained clinically and radiographically stable, with a 4-year progression-free and total survival of 94 and 100%, respectively. We conclude that mass lesions originating in the upper midbrain are a subset of intrinsic brainstem tumors with a relatively benign course, usually presenting with hydrocephalus after infancy. They may remain stable for considerable periods and may require no further therapy after treatment of hydrocephalus. Surgical biopsy and/or resection can usually be reserved for progressive or atypical lesions which may also require further adjuvant therapy.