Sean M. Lew

Tethered Cord Syndrome: An Updated Review

Tethered cord syndrome (TCS) is a diverse clinical entity characterized by symptoms and signs which are caused by excessive tension on the spinal cord. The majority of cases are related to spinal dysraphism. TCS can present in any age group, and presentations differ according to the underlying pathologic condition and age, with pain, cutaneous signs, orthopedic deformities and neurological deficits being the most common. Surgical untethering is indicated in patients with progressive or new onset symptomatology attributable to TCS. The surgical strategy aims to release the tethering structure and thus the chronic tension on the cord. Early operative intervention is associated with improved outcomes. Pain relief is accomplished in almost all cases. Realistic surgical goals include relief of pain and stabilization of neurological function, although improvement in function is often seen. Cord untethering can also halt the progression of scoliosis. The benefits of surgery are debated in asymptomatic patients and patients with normal imaging.

Pediatric blunt carotid injury: a review of the National Pediatric Trauma Registry.

Blunt carotid injury (BCI) is an uncommon yet potentially devastating entity which has received little attention in the pediatric literature. In an attempt to better characterize pediatric BCI, a review of the National Pediatric Trauma Registry was performed. Records were obtained from all children diagnosed with internal or common carotid injury associated with blunt trauma. The incidence of BCI was 0.03% (15 of 57,659 blunt trauma patients). Variables examined included: age, gender, mechanism of injury, associated injuries, various injury severity scores, and outcome. Various injuries were associated with an increase in BCI incidence including chest trauma (4-fold), combined head and chest trauma (6-fold), basilar skull fractures (4-fold), intracranial hemorrhage (6-fold), and clavicle fractures (8-fold). Thirty-three percent of the patients diagnosed with BCI suffered neurological complications directly attributable to their carotid injuries. Current practices regarding screening, diagnosis, and treatment are reviewed.

Photodynamic therapy (PDT) for malignant brain tumors — Where do we stand?

INTRODUCTION What is the current status of photodynamic therapy (PDT) with regard to treating malignant brain tumors? Despite several decades of effort, PDT has yet to achieve standard of care. PURPOSE The questions we wish to answer are: where are we clinically with PDT, why is it not standard of care, and what is being done in clinical trials to get us there. METHOD Rather than a meta-analysis or comprehensive review, our review focuses on who the major research groups are, what their approaches to the problem are, and how their results compare to standard of care. Secondary questions include what the effective depth of light penetration is, and how deep can we expect to kill tumor cells. CURRENT RESULTS A measurable degree of necrosis is seen to a depth of about 5mm. Cavitary PDT with hematoporphyrin derivative (HpD) results are encouraging, but need an adequate Phase III trial. Talaporfin with cavitary light application appears promising, although only a small case series has been reported. Foscan for fluorescence guided resection (FGR) plus intraoperative cavitary PDT results were improved over controls, but are poor compared to other groups. 5-Aminolevulinic acid-FGR plus postop cavitary HpD PDT show improvement over controls, but the comparison to standard of care is still poor. CONCLUSION Continued research in PDT will determine whether the advances shown will mitigate morbidity and mortality, but certainly the potential for this modality to revolutionize the treatment of brain tumors remains. The various uses for PDT in clinical practice should be pursued.

Epilepsy Surgery Outcomes: Quality of Life and Seizure Control

A consecutive, retrospective analysis of seizure control and quality of life was performed among 83 pediatric patients undergoing epilepsy surgery at Childrens Hospital of Wisconsin. Seizure outcomes were generally favorable, with 68.7% class I outcomes; class II, 12%; and class III, 19.3%. Seizure freedom was highest among temporal lobectomies (84.2%) and hemispherectomies (76.2%). Outcomes among hemispherectomies were substantially superior to those of multilobar resections. Cortical dysplasia was associated with lower seizure freedom, at 57.5%. Among age groups, seizure-free outcomes in infants were lowest, at 50%. The lower infant seizure-free rate was likely attributable to frequency of multilobar resections and type of pathology (cortical dysplasia). Quality-of-life measures generally paralleled seizure outcomes. These results indicate that epilepsy surgery in children with intractable epilepsy can result in significant improvements in seizure control, quality of life, and development. Anticipated type of surgery, presumed location of epileptogenic site, absence of a defined lesion on magnetic resonance imaging scan of the brain, and patients age should not prevent surgical evaluations of children with intractable epilepsy.

Outcomes of cranioplasty following decompressive craniectomy in the pediatric population.

Cranioplasty is routinely performed following decompressive craniectomy in both adult and pediatric populations. In adults, this procedure is associated with higher rates of complications than is elective cranial surgery. This study is a review of the literature describing risk factors for complications after cranioplasty surgery in pediatric patients. A systematic search of PubMed, Cochrane, and SCOPUS databases was undertaken. Articles were selected based on their titles and abstracts. Only studies that focused on a pediatric population were included; case reports were excluded. Studies in which the authors assessed bone flap storage method, timing of cranioplasty, material used (synthetic vs autogenous), skull defect size, and/or complication rates (bone resorption and surgical site infection) were selected for further analysis. Eleven studies that included a total of 441 cranioplasties performed in the pediatric population are included in this review. The findings are as follows: 1) Based on analysis of pooled data, using cryopreserved bone flaps during cranioplasty may lead to a higher rate of bone resorption and lower rate of infection than using bone flaps stored at room temperature. 2) In 3 of 4 articles describing the effect of time between craniectomy and cranioplasty on complication rate, the authors found no significant effect, while in 1 the authors found that the incidence of bone resorption was significantly lower in children who had undergone early cranioplasty. Pooling of data was not possible for this analysis. 3) There are insufficient data to assess the effect of cranioplasty material on complication rate when considering only cranioplasties performed to repair decompressive craniectomy defects. However, when considering cranioplasties performed for any indication, those in which freshly harvested autograft is used may have a lower rate of resorption than those in which stored autograft is used. 4) There is no appreciable effect of craniectomy defect size or patient age on complication rate. There is a paucity of articles describing outcomes and complications following cranioplasty in children and adolescents. However, based on the studies examined in this systematic review, there are reasons to suspect that method of flap preservation, timing of surgery, and material used may be significant. Larger prospective and retrospective studies are needed to shed more light on this important issue.

Synergistic Action of Genistein and Cisplatin on Growth Inhibition and Cytotoxicity of Human Medulloblastoma Cells

Objective: Recent experimental data have shown that dietary soy isoflavones such as genistein can significantly suppress invasiveness and growth of a number of human malignancies. In this study we examined whether genistein, at a concentration typical of plasma levels following soy formula intake, in combination with cisplatin or vincristine exhibited an additive or synergistic inhibitory effect on the growth of medulloblastoma cells. Methods: Three human medulloblastomas cell lines (HTB-186, CRL-8805 and MED-1) were treated with genistein at 6 μM, the maximum reported dietary plasma level in children, combined with cisplatin (0–10 μM) or vincristine (0–1 μM). Monolayer cell growth and cytotoxicity, as measured by colonigenic survival in soft agarose, were then compared in control and drug-treated cultures. Presence of apoptosis, using the DNA ladder assay and laser scanning cytometry, was investigated in all cell lines at those concentrations at which an enhancement of antiproliferative effect of cisplatin and vincristine in presence of genistein was observed. Results: Genistein at 6 μM led to a 2.8-fold increase in the monolayer growth inhibitory effect of cisplatin (0.05 μM) in HTB-186 cells (p = 4.5 × 10–4 by one-tailed t test). Genistein increased colonigenic survival inhibition of HTB-186 2.6-fold at the same cisplatin concentration (p = 1.5 × 10–4). Genistein caused a 1.3-fold increase in antiproliferative effect of cisplatin (0.5 μM) in CRL-8805 cells (p = 3.1 × 10–4). Similarly the inhibition of colonigenic survival was enhanced 2.0-fold in CRL-8805 (p = 1.22 × 10–5). The addition of genistein to 0.5 μM cisplatin led to a 1.7-fold increase in monolayer growth inhibition and 2.4-fold increase in colonigenic survival inhibition of MED-1 cells (p = 8.3 × 10–4 and p = 1.1 × 10–4 respectively). These effects were primarily synergistic but also additive in nature. The combination of genistein and vincristine, as compared to vincristine alone, caused a minimal-to-modest increase in antiproliferative effect on medulloblastoma cells studied here. We were unable to detect apoptosis by two methodologies in any of the medulloblastoma lines when genistein was combined with cisplatin or vincristine. Conclusion: These results indicate that genistein at typical dietary plasma levels can significantly enhance the antiproliferative and cytotoxic action of cisplatin and, to a lesser extent, vincristine. The implication for treatment of medulloblastomas of early childhood may be a reduction in the chemotherapeutic dose recommendations of these agents and subsequently a decrease in the risk of treatment sequelae for these patients.

Equivalence of fusion rates after rigid internal fixation of the occiput to C-2 with or without C-1 instrumentation

OBJECT The object of this study was to assess a multiinstitutional experience with pediatric occipitocervical constructs to determine whether a difference exists between the fusion and complication rates of constructs with or without direct C-1 instrumentation. METHODS Seventy-seven cases of occiput-C2 instrumentation and fusion, performed at 9 childrens hospitals, were retrospectively analyzed. Entry criteria included atlantooccipital instability with or without atlantoaxial instability. Any case involving subaxial instability was excluded. Constructs were divided into 3 groups based on the characteristics of the anchoring spinal instrumentation: Group 1, C-2 instrumentation; Group 2, C-1 and C-2 instrumentation without transarticular screw (TAS) placement; and Group 3, any TAS placement. Groups were compared based on rates of fusion and perioperative complications. RESULTS Group 1 consisted of 16 patients (20.8%) and had a 100% rate of radiographically demonstrated fusion. Group 2 included 22 patients (28.6%), and a 100% fusion rate was achieved, although 2 cases were lost to follow-up before documented fusion. Group 3 included 39 patients (50.6%) and demonstrated a 100% radiographic fusion rate. Complication rates were 12.5, 13.7, and 5.1%, respectively. There were 3 vertebral artery injuries, 1 (4.5%) in Group 2 and 2 (5.1%) in Group 3. CONCLUSIONS High fusion rates and low complication rates were achieved with each configuration examined. There was no difference in fusion rates between the group without (Group 1) and those with (Groups 2 and 3) C-1 instrumentation. These findings indicated that in the pediatric population, excellent occipitocervical fusion rates can be accomplished without directly instrumenting C-1.

Complement depletion does not reduce brain injury in a rabbit model of thromboembolic stroke

The contribution of the complement system to cerebral ischemic and ischemia/reperfusion injury was examined in a rabbit model of thromboembolic stroke by delivery of an autologous clot embolus to the intracranial circulation via the internal carotid artery. A two-by-two factorial design was employed to study the impact of complement depletion via pretreatment with cobra venom factor (CVF, 100 U/kg i.v.) in the setting of permanent (without tissue plasminogen activator; t-PA) and transient (with t-PA) cerebral ischemia. Thirty-two New Zealand white rabbits were assigned to one of four groups (n=8, each group): control without t-PA, control with t-PA, CVF without t-PA and CVF with t-PA. In the complement intact animals, t-PA administration resulted in an approximate 30% reduction in infarct size when compared to the group not receiving t-PA (20.4+/-6.6% of hemisphere area vs. 30.1+/-7.2%; mean+/-SEM). However, infarct sizes in the complement depleted rabbits, with (30.7+/-8.2%) or without (30.2+/-7.9%) t-PA, were no different from the control group receiving no therapy. Similarly, no difference in regional cerebral blood flow or final intracranial pressure values was noted between any of the four groups. Complement activation does not appear to be a primary contributor to brain injury in acute thromboembolic stroke.

Brain tumor invasion rate measured in vitro does not correlate with Ki-67 expression.

The need for more accurate prediction of the biological behavior of brain tumors has lead to the use of immunohistochemical methods for assessment of proliferating cell nuclear antigens such as Ki-67. There is a variable association of glioma Ki-67 labeling index with patient survival. Brain invasion by individual tumor cells also defines biological aggressiveness, and can be assessed in vitro. Further, proliferation and migration seem to be mutually exclusive behaviors for a given cell at a point in time. We studied the relationship between Ki-67 labeling index and invasion rate in a group of 10 gliomas, and 2 meningiomas. Human tumor spheroids obtained from operative speciments were co-cultured with fetal rat brain aggregates, and invasion rate was measured by confocal microscopic observation. There was no correlation between two measures of invasion and Ki-67 labeling. This finding supports the dichotomous nature of glioma proliferation and invasion, and may in part explain the limited usefulness of proliferation marker labeling.

3D visualization of subdural electrode shift as measured at craniotomy reopening

PURPOSE Subdural electrodes are implanted for recording intracranial EEG (iEEG) in cases of medically refractory epilepsy as a means to locate cortical regions of seizure onset amenable to surgical resection. Without the aid of imaging-derived 3D electrode models for surgical planning, surgeons have relied on electrodes remaining stationary from the time between placement and follow-up resection. This study quantifies electrode shift with respect to the cortical surface occurring between electrode placement and subsequent reopening. METHODS CT and structural MRI data were gathered following electrode placement on 10 patients undergoing surgical epilepsy treatment. MRI data were used to create patient specific post-grid 3D reconstructions of cortex, while CT data were co-registered to the MRI and thresholded to reveal electrodes only. At the time of resective surgery, the craniotomy was reopened and electrode positions were determined using intraoperative navigational equipment. Changes in position were then calculated between CT coordinates and intraoperative electrode coordinates. RESULTS Five out of ten patients showed statistically significant overall magnitude differences in electrode positions (mean: 7.2mm), while 4 exhibited significant decompression based shift (mean: 4.7mm), and 3 showed significant shear displacement along the surface of the brain (mean: 7.1mm). DISCUSSION Shift in electrode position with respect to the cortical surface has never been precisely measured. We show that in 50% of our cases statistically significant shift occurred. These observations demonstrate the potential utility of complimenting electrode position measures at the reopening of the craniotomy with 3D electrode and brain surface models derived from post-implantation CT and MR imaging for better definition of surgical boundaries.