Corey Raffel

MDR1 Gene Expression in Brain of Patients with Medically Intractable Epilepsy

Summary: Why some patients with seizures are successfully treated with antiepileptic drugs (AEDs) and others prove medically intractable is not known. Inadequate intraparenchymal drug concentration is a possible mechanism of resistance to AEDs. The multiple drug resistance gene (MDRI) encodes P‐glycoprotein, an energy‐dependent efflux pump that exports planar hydrophobic molecules from the cell. If P‐glycoprotein is expressed in brain of some patients with intractable epilepsy and AEDs are exported by P‐glycoprotein, lower intraparenchymal drug concentrations could contribute to lack of drug response in such patients. Eleven of 19 brain specimens removed from patients during operation for intractable epilepsy had MDR1 mRNA levels > 10 times greater than those in normal brain, as determined by quantitative reverse transcriptase‐polymerase chain reaction (RT‐PCR) method. Immunohistochemistry for P‐glycoprotein from 14 of the patients showed increased staining in capillary endothelium in samples from epileptic patients as compared with staining in normal brain samples. In epileptic brain specimens with high MDR1 mRNA levels, expression of P‐glycoprotein in astrocytes also was identified. Last, steady‐state intracellular phenytoin (PHT) concentrations in MDR1 expressing neuroectodermal cells was one fourth that in MDR1‐negative cells. MDR1 expression is increased in brain of some patients with medically intractable epilepsy, suggesting that the patients’ lack of response to medication may be caused by inadequate accumulation of AED in brain.

To shunt or to fenestrate: which is the best surgical treatment for arachnoid cysts in pediatric patients?

The treatment options for intracranial arachnoid cysts are either craniotomy and fenestration of the cyst into the cerebrospinal fluid spaces or shunting of the cyst contents extracranially. Fenestration may eliminate the need to shunt, but it is a major operative procedure and is not always successful. To determine which treatment provides the greatest benefit with the fewest complications, the records of 31 patients with 34 arachnoid cysts treated at the Childrens Hospital of Los Angeles between 1976 and 1986 were reviewed. The mean age of the patients was 4.4 years, with a range of 0 to 15.5 years. The most common location was the middle fossa (14 cases), followed by the posterior fossa (7 cases), the suprasellar region (5 cases), and hemispheric (5 cases) and other locations (3 cases). Signs and symptoms were related to abnormally rapid head growth in infants and to increased intracranial pressure and seizures in older children. The initial treatment of 29 cysts was fenestration. Twenty-two (76%) procedures were successful, with no additional treatment needed for the cyst. The other 7 cysts required the subsequent placement of a cystoperitoneal shunt. In 5 cases, the cysts were treated initially with cystoperitoneal shunts. Of the total 12 cystoperitoneal shunts, 5 have required revisions on one or more occasions. No significant difference in morbidity was noted between the two treatment options. Because we consider shunt independence to be a major goal of therapy, we suggest that patients with arachnoid cysts be divided into two categories, those presenting with associated hydrocephalus and those without hydrocephalus.(ABSTRACT TRUNCATED AT 250 WORDS)

Benign Cerebellar Astrocytomas of Childhood

Benign cerebellar astrocytomas of childhood are potentially surgically curable lesions. Histologically, these neoplasms can be divided into pilocytic and diffuse astrocytomas. Whether there is a difference in the recurrence rate between these two tumor types after a surgical resection is not clear. In addition, the role of immediate postoperative imaging in predicting a recurrence has not been established. To answer these questions, we have reviewed the charts of 23 patients with benign cerebellar astrocytomas treated at Childrens Hospital of Los Angeles over a 10-year period (1977-1987). Of the 23 tumors, 15 were pilocytic and 8 were diffuse. All patients underwent an attempted gross total surgical removal of the tumor, and all patients had a postoperative computed tomographic (CT) scan with and without intravenously administered contrast material performed within 72 hours of the operation. Based on the postoperative CT scan, 12 patients had residual tumors. Seven of the subtotally resected tumors were pilocytic (7 of 15), and 5 were diffuse (5 of 8). Interestingly, the surgeon believed that a gross total resection had been obtained in 9 of these patients. There have been 4 recurrences in these 23 patients, with a mean follow-up of 4.9 years. All recurrences were in patients with subtotal resections. Of the 11 patients with a total resection of the tumor, 7 developed a small rim of enhancement on subsequent scans an average of 5 months after the operation.(ABSTRACT TRUNCATED AT 250 WORDS)

Absence of p53 Mutations in Childhood Central Nervous System Primitive Neuroectodermal Tumors

The primitive neuroectodermal tumor of the central nervous system is one of a number of tumors in which deletions on chromosome 17p have been identified. The tumor suppressor gene, p53, is located in the region of the deletion. To determine if the p53 gene is involved in the development of primitive neuroectodermal tumors, deoxyribonucleic acid (DNA) blot analysis, ribonucleic acid blot analysis, and p53 complementary DNA sequencing were performed on 34 primitive neuroectodermal tumors removed from children. No rearrangement in the gene was detected in 21 tumors. The p53 messenger ribonucleic acid was of the expected size in all 18 tumors for which ribonucleic acid was available. Sequencing of p53 Exons 5 through 9 revealed a mutation in the cell line DAOY and in only 1 of 14 tumors examined. A DNA rearrangement was detected in the DNA from one tumor with a probe mapping to the distal portion of 17p. Taken together, these data suggest that the p53 gene is not involved in the development of most primitive neuroectodermal tumors. In addition, a gene of interest may be present on distal 17p.

The lack of a role for p53 in astrocytomas in pediatric patients.

Mutations in the p53 gene, which codes for a cell division regulatory protein, have been identified in approximately one-third of adult astrocytomas. We evaluated 35 astrocytic tumors (17 pilocytic, 4 diffuse low grade, 12 anaplastic, and 2 glioblastoma) in pediatric patients for p53 mutations, using polymerase chain reaction-single-stranded conformation polymorphism analysis as a screening technique. Additionally, those tumors identified with homozygosity in the area of the p53 gene on chromosome 17 by Southern blotting were sequenced to look for p53 mutations. No tumors were identified with polymerase chain reaction-single-stranded conformation polymorphism analysis shifts indicative of mutations in the p53 gene. Five of 21 tumors were homozygous in the region of the p53 gene on chromosome 17; no mutations in exons 5 to 8 were found in any of these tumors. The frequency of p53 mutation in pediatric astrocytomas is significantly less than the frequency for adult tumors, regardless of tumor grade. Furthermore, the frequency of p53 mutations in high-grade astrocytomas is significantly lower in pediatric tumors than in adult tumors. These results suggest that p53 is not important in the oncogenesis of pediatric astrocytomas. Oncogenesis in pediatric astrocytomas may occur by different mechanisms than those of similar tumors in adults.

Treatment of Spinal Cord Compression by Epidural Malignancy in Childhood

Epidural spinal cord compression by a malignant tumor is a rare occurrence in children. Both the tumors involved and the extent of involvement of the vertebral column are different in children and adults. Often, the epidural tumor in a child is identified before significant spinal canal compromise has occurred, and these children frequently can be managed by radiation therapy and/or chemotherapy. There is a group of children, however, who have severe spinal canal encroachment by a tumor, as evidenced by a near complete or complete block on myelography. In this study, we report a group of patients with severe spinal cord compression, as documented by imaging studies. We compared the results of a decompressive laminectomy and subtotal tumor resection followed by adjuvant therapy with the results obtained with radiation therapy and/or chemotherapy alone. Thirty-three patients met the criteria for inclusion in the study. Twenty-six were treated with a laminectomy and adjuvant therapy, and 7 were treated without surgical intervention. With surgical therapy, 25 of 26 epidurals were either improved or stable, whereas 4 of 7 nonsurgical patients deteriorated. Especially notable was a decrease in pain in the operative patients immediately after their procedure. There was no surgical mortality or morbidity. The results of this study indicate that children with severe spinal cord compression as evidenced by a near complete or complete block on myelography or filling of 50% or more of the spinal canal on magnetic resonance imaging are best treated by a combination of surgical decompression and tumor removal followed by adjuvant therapy.

Management of symptomatic chronic extra-axial fluid collections in pediatric patients.

The records of 103 pediatric patients having symptomatic chronic extra-axial fluid collections treated at Childrens Hospital of Los Angeles from 1977 to 1988 were reviewed. Patients were treated with observation, serial percutaneous needle drainage, drainage through burr holes, drainage into a closed external drainage system, or subdural to peritoneal shunt. If the initial treatment was not effective, additional forms of treatment were instituted. Shunts, ultimately used in 73% of the patients, proved to be the most effective treatment. Of the group with shunts, the extra-axial fluid was unilateral in 20% and bilateral in 80%. In those patients with bilateral effusions, no difference in efficacy of shunts was seen in patients treated with bilateral versus unilateral shunts. Of the 75 patients with shunts, 12% required a shunt revision for progressive or recurrent symptoms. Shunt infections occurred in 3% of the patients, necessitating removal of the shunt and treatment with antibiotics. Eosinophilia in the subdural fluid was associated with shunt obstruction requiring revision. The shunt was never removed in 51% of patients with no untoward effects. This study demonstrates that the most efficacious treatment of symptomatic chronic extra-axial fluid collections in children is a unilateral subdural to peritoneal shunt. The shunt need not be removed after resolution of the fluid collections.

Surveillance Imaging in Children with Primitive Neuroectodermal Tumors

Controversy surrounds the benefits of routine surveillance magnetic resonance or computed tomographic imaging for monitoring children after resection of primitive neuroectodermal tumors. A recent study suggested that serial imaging studies detect only a small minority of tumor recurrences in patients with symptoms. The authors concluded that even in patients with recurrence documented by imaging, no patient with a recurrence survived long (average, 5 mo) and that surveillance scanning is of little clinical value in children with primitive neuroectodermal tumors. We reviewed our experience with 25 patients (28% of our total series) who presented to the Childrens Hospital Los Angeles, Los Angeles, CA, from 1985 to 1993 with recurrent tumors after surgery and adjuvant therapy. Recurrent tumors were detected on routine imaging in 19 asymptomatic patients (76%) and in 6 symptomatic patients (24%). Recurrences were documented 15 months (mean) after the initial diagnosis in asymptomatic children and 5 months (mean) after the initial diagnosis in children with symptoms of recurrent tumor (P < or = 0.01). Asymptomatic patients with recurrence documented on serial imaging had prolonged survival when compared with those who were symptomatic (P < or = 0.05). The surviving patients with recurrence remained alive for more than 24 months after documentation of recurrence. Early detection of local tumor recurrence by surveillance scanning may provide a critical therapeutic window for successful treatment with aggressive or novel therapies.

Acrylic Cranioplasty with Alginate Molding: Technical Note

OBJECTIVEnAcrylic cranioplasty for cranial defects is a common neurosurgical procedure that is performed when the original bone flap becomes infected or is unusable for other reasons. We developed a simple technique to produce a complete copy of the original bone flap from acrylic, using alginate impression material as a mold.nnnMETHODSnAlginate impression material was used to form a mold of the patients original bone flap. Methylmethacrylate was then placed inside the mold to create an exact duplicate of the bone flap. The acrylic flap was sterilized with gamma irradiation and used for cranioplasty. Two patients who had cranial defects secondary to infections of their craniotomy bone flaps underwent cranioplasty with this technique.nnnRESULTS AND CONCLUSIONnA perfect copy of the patients original bone flap was easily and quickly created with this technique, and excellent cosmetic results were obtained. Operative time was shortened because the prosthesis was preformed before the operation. This technique can also be used to mold large or complex cranial defects as long as the original bone flap is available and there is no major cranial remodeling around the defect.

The multiple tumor suppressor 1/cyclin-dependent kinase inhibitor 2 gene in human central nervous system primitive neuroectodermal tumor

The recently described multiple tumor suppressor 1/cyclin-dependent kinase inhibitor 2 (MTS1/CDKN2) gene, encoding the cyclin-dependent kinase 4 inhibitor p16, is mutated in a wide variety of tumor cell lines, including gliomas. To investigate the possible role of this gene in the genesis of the central nervous system primitive neuroectodermal tumor (PNET), four established PNET cell lines and 18 PNET surgical specimens were studied for deletions and mutations of the MTS1/CDKN2 gene. One of the four cell lines had homozygous deletion of the gene. No mutation in any of the three MTS1/CDKN2 exons was detected in the other three cell lines by single strand conformational polymorphism analysis. Eighteen surgical PNET specimens were studied for allelic and homozygous deletion at chromosome 9p21, the location of the MTS1/CDKN2 gene. No loss of heterozygosity was noted in 11 of the tumors, and no homozygous loss was noted in any tumor. Single strand conformational polymorphism analysis of the entire coding region of the MTS1/CDKN2 gene revealed no mutation within MTS1/CDKN2 in any tumor. Although deletion of MTS1/CDKN2 may occur in some PNET cell lines, neither deletion nor mutation of the gene is found in tumors before culture. The genesis of the human central nervous system PNET does not involve deletion or mutation of the MTS1/CDKN2 gene.