W. Jerry Oakes

Genetic studies in neural tube defects

Neural tube defects (NTD) are one of the most common birth defects and are caused by both environmental and genetic factors. The approach to identifying the genes predisposing to NTD, through linkage analysis and candidate gene analysis, is reviewed along with characteristics of a large, nationally ascertained cohort of families. Results from specific assessments of p53, PAX3 and MTHFR failed to suggest that these genes play a major role in NTD development in these families. Advances in genetic laboratory and statistical techniques have made this a prime opportunity for investigation into the causes of complex disorders, such as NTD. However, traditional approaches may prove to be challenging due to the difficulty of ascertaining samplable multiplex families.

Delayed foreign-body reaction to silk sutures in pediatric neurosurgical patients

Nonabsorbable silk sutures have been a frequently used foreign material in neurosurgery. In general, they are reliable and safe with minimal bio-incompatibility. Three pediatric neurosurgical patients came to clinical attention, however, because of delayed foreign-body reactions to silk sutures. The delayed atypical presentation of these patients delayed appropriate diagnosis and therapy. In two patients, the reaction presented as a delayed inflammation 7 years following surgical suture placement. In the other patient, the reaction caused delayed recurrent shunt failures and surgical wound breakdown. These three cases are used to introduce a discussion of the delayed response of the host to foreign material and its pertinence to neurosurgery.

A multicenter retrospective comparison of conversion from temporary to permanent cerebrospinal fluid diversion in very low birth weight infants with posthemorrhagic hydrocephalus.

OBJECTnThe purpose of this study was to define the incidence of permanent shunt placement and infection in patients who have undergone the 2 most commonly performed temporizing procedures for posthemorrhagic hydrocephalus (PHH) of prematurity: ventriculosubgaleal (VSG) shunt placement and ventricular reservoir placement for intermittent tapping.nnnMETHODSnThe 4 centers of the Hydrocephalus Clinical Research Network participated in a retrospective chart review of infants with PHH who underwent treatment at each institution between 2001 and 2006. Patients were included if they had received a diagnosis of Grade 3 or 4 intraventricular hemorrhage, weighed < 1500 g at birth, and had received surgical intervention. The authors determined the incidence of conversion from a temporizing device to a permanent shunt, the incidence of CSF infection during temporization, and the 6-month CSF infection rate after permanent shunt placement.nnnRESULTSnThirty-one (86%) of 36 patients who received VSG shunts and 61 (69%) of 88 patients who received ventricular reservoirs received permanent CSF diversion with a shunt (p = 0.05). Five patients (14%) in the VSG shunt group had CSF infections during temporization, compared with 11 patients (13%) in the ventricular reservoir group (p = 0.83). The 6-month incidence of permanent shunt infection in the VSG shunt group was 16% (5 of 31), compared with 12% (7 of 61) in the reservoir placement group (p = 0.65). For the first 6 months after permanent shunt placement, infants with no preceding temporizing procedure had an infection rate of 5% (1 of 20 infants) and those who had undergone a temporizing procedure had an infection rate of 13% (12 of 92; p = 0.45).nnnCONCLUSIONSnThe use of intermittent tapping of ventricular reservoirs in this population appears to lead to a lower incidence of permanent shunt placement than the use of VSG shunts. The incidence of infection during temporization and for the initial 6 months after conversion appears comparable for both groups. The apparent difference identified in this pilot study requires confirmation in a more rigorous study.

SURVIVAL AT 5 YEARS OF A COHORT OF NEWBORN INFANTS WITH MYELOMENINGOCELE

Over a nine‐year period, 63 viable newborns with myelomeningocele were consecutively treated, of whom 11 (17%) developed brainstem symptoms assessed to be potentially life‐threatening. All 11 underwent brainstem decompression by cervical laminectomy with stent placement between the fourth ventricle and the spinal subarachnoid space, at a median âge of 8 months. 86% survived to 60 months of age. Those with brainstem dysfunction had a significantly greater mortality than those without, despite aggressive neurosurgical management by brainstem decompression.

Occult spinal dysraphism in patients with anal agenesis

Recent reports have suggested an association between congenital anorectal anomalies and occult spinal dysraphism. Eighty-seven patients with anal agenesis have been treated at this institution over the last 14 years. Two of these patients had spinal cord anomalies recognized at birth (a myelomeningocele and a tethered spinal cord). Two additional patients presented with progressive neurologic deficits in early childhood and were each found to have a tethered spinal cord. To further assess the magnitude of this problem, we have used magnetic resonance imaging (MRI) of the spine to survey prospectively 23 infants with anal agenesis. Twenty-one former patients who were asymptomatic were recalled and also studied. Four of 44 patients (9%) were found to have significant occult spinal dysraphism; each child had undergone neurosurgical operation without morbidity. MRI found each child to have a tethered spinal cord, either as an isolated lesion (2) or in association with a syrinx (1) or lipomyelomeningocele (1). One of these patients had a neurologic deficit detected on careful preoperative evaluation. The other three, two of whom were less than 2 years old, had no detectable deficit. Neither the extent of the anorectal malformation, the absence of associated congenital anomalies, nor the demonstration of normal vertebral anatomy on plain radiographs of the spine precluded the presence of occult spinal dysraphism. Therefore, we recommend that all patients with anorectal anomalies undergo MRI imaging of their spines during initial evaluation to screen for occult spinal dysraphism. In addition, consideration should be given to recalling older patients for MRI evaluation.

Further evidence for a maternal genetic effect and a sex-influenced effect contributing to risk for human neural tube defects.

BACKGROUNDnNeural tube defects (NTDs), including spina bifida and anencephaly, are the second most common birth defect with an incidence of 1/1000. Genetic factors are believed to contribute to NTD risk and family-based studies can be useful for identifying such risk factors.nnnMETHODSnWe ascertained 1066 NTD families (1467 affected patients), including 307 multiplex NTD families. We performed pedigree analysis to describe the inheritance patterns, pregnancy outcomes, and recurrence risks to relatives of various types.nnnRESULTSnMyelomeningocele or spina bifida (66.9%) and cranial defects (17.7%) were the most common NTD subtypes observed. The overall male:female ratio for affected individuals was 0.82, and there were even fewer males among individuals with an upper level NTD (0.62). Among twins, 2 of the 5 monozygotic twins and only 3 of 35 dizygotic twins were concordant, while 27% of the same sex twins were concordant, but none of the different sex twins. The estimated 6.3% recurrence risk to siblings (CI 0.04-0.08) is consistent with previous reports. Families with two or more affected individuals show a higher proportion of female transmitters (p = 0.0002). Additionally, the number of affected relatives in maternal compared to paternal lineages was more than double (p = 0.006). There were significantly more miscarriages, infant deaths, and stillborn pregnancies of the maternal aunts and uncles (p < 0.0001) and of first cousins (p = 0.04).nnnCONCLUSIONSnOur data provide several lines of evidence consistent with a maternal effect, as well as a sex-influenced effect, in the etiology of NTDs.

Updated investigations of the role of methylenetetrahydrofolate reductase in human neural tube defects

Folate supplementation appears to reduce the risk for neural tube defects (NTDs). Methylenetetrahydrofolate reductase (MTHFR) is a candidate gene in the folate metabolism pathway that has been extensively studied in different human populations. We examined the risk associated with having the thermolabile variant (TT) of MTHFR in a study of 175 American Caucasians with NTDs and their families. We found a significant association in patients compared with 195 unrelated controls [odds ratio (OR)u2003=u20032.13, 95% confidence interval (95% CI)u2003= 1.11–4.09)], but not in mothers (ORu2003=u20031.29, 95% CIu2003=u20030.622–2.67) or in fathers (ORu2003=u20031.45, 95% CIu2003=u20030.681–3.09). We found no evidence for unequal transmission from parents to an affected child (p >u200a0.10). We failed to find a previously reported association for a combined haplotype for MTHFR and cystathionine β‐synthase, except in subjects with NTDs compared with 559 pooled controls (ORu2003=u20032.87, 95% CIu2003= 1.03–8.03). We found no evidence for an association for a novel CA‐repeat polymorphism identified in a gene closely linked to MTHFR (p >u200a0.10). Our studies continue to suggest that additional candidate genes other than MTHFR may be responsible for an increased risk to NTD in some American Caucasian families.u2003

Leptomeningeal Dissemination of Optic Pathway Gliomas in Three Children

We treated three children with optic pathway gliomas who had progressive disease associated with metastatic spread to the leptomeninges. One patient had radiographic resolution of leptomeningeal disease after treatment with intravenous carmustine and oral mercaptopurine but died of progressive pulmonary fibrosis. The second patient was treated with intravenous thiotepa, and the leptomeningeal disease remained stable. The third patient was treated with intravenous vincristine sulfate, cyclophosphamide, cisplatin, and etoposide and had a significant size reduction of the leptomeningeal lesion. Although leptomeningeal dissemination is a seemingly rare event, it is important that all children with optic pathway gliomas be considered for this possibility, particularly after the onset of new, atypical neurologic symptoms.

Reversal of radiation‐induced neutropenia by granulocyte colony‐stimulating factor

Myelosuppression is a common sequelae of radiotherapy, occasionally delaying the completion of treatment. In this report, we describe successful reversal of radiation-induced neutropenia in a child receiving craniospinal irradiation by granulocyte colony-stimulating factor (G-CSF). We suggest that G-CSF be considered as supportive care in patients in whom neutropenia develops during radiotherapy.

The chemotherapy of posterior Fossa tumors in childhood

Conventional therapy for brain tumors, consisting of neurosurgical intervention and radiotherapy, has not resulted in the successes achievable in other childhood malignancies. The role of adjuvant chemotherapy, well defined in many childhood cancers, has not yet contributed significantly to the treatment of children with brain tumors. Chemotherapy of recurrent tumors has produced regressions but no cures. The most active agents identified to date in the treatment of recurrent posterior fossa tumors include cisplatinum, cyclophosphamide and methotrexate. Future efforts will need to focus on the rational selection of drugs for study in limited agent histology-stratified phase II trials, with advancement of active agents into large randomized phase III adjuvant therapy trials.