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Hariyadarshi Pannu, Dong H. Kim, C. Robyn Seaman, Grace Van Ginhoven, Sanjay Shete and Dianna M. Milewicz

Object

The identification of polymorphisms associated with an increase in the risk of developing disease is integral to the development of genetic biomarkers to identify individuals at risk. Based on reports indicating a role for angiotensin-converting enzyme (ACE) in the pathogenesis of intracranial aneurysms (IAs) as well as hypertension, an independent risk factor for IAs, the authors investigated the association between an insertion/deletion (I/D) polymorphism in the ACE gene and IAs in a Caucasian population in the US.

Methods

The patient population consisted of 162 randomly selected Caucasian patients who underwent surgical repair of an IA at Memorial—Hermann Hospital (Houston, TX) and had no family history of the disease. The ACE I/D polymorphism was typed using polymerase chain reaction amplification of genomic DNA, and allele and genotype frequencies were compared between the patients with IAs and 143 healthy Caucasian volunteers (control group) by performing logistic regression and chi-square tests.

The ACE I/D allele frequencies did not differ significantly between the patient and control populations. There were similar allele and genotype frequencies in male and female study participants in both patient and control populations. The authors found no evidence of an association between the allelic or genotypic distribution of the ACE I/D polymorphism and aneurysmal subarachnoid hemorrhage or unruptured IAs.

Conclusions

Contrary to findings in two European Caucasian populations (one British and one Polish), this polymorphism did not contribute to the risk of developing IAs in a Caucasian population in the US.

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Linna Li, Tony S. Quang, Ed J. Gracely, Ji H. Kim, Jacqueline G. Emrich, Theodore E. Yaeger, Joseph M. Jenrette, Steven C. Cohen, Perry Black and Luther W. Brady

Object

This single-institution Phase II study tests the efficacy of adjuvant radioimmunotherapy with 125I-labeled anti–epidermal growth factor receptor 425 murine monoclonal antibody (125I-mAb 425) in patients with newly diagnosed glioblastoma multiforme (GBM).

Methods

A total of 192 patients with GBM were treated with 125I-mAb 425 over a course of 3 weekly intravenous injections of 1.8 GBq following surgery and radiation therapy. The primary end point was overall survival, and the secondary end point was toxicity. Additional subgroup analyses were performed comparing treatment with 125I-mAb 425 (RIT, 132 patients), 125I-mAb 425 and temozolomide (TMZ+RIT, 60 patients), and a historical control group (CTL, 81 patients).

Results

The median age was 53 years (range 19–78 years), and the median Karnofsky Performance Scale score was 80 (range 60–100). The percentage of patients who underwent debulking surgery was 77.6% and that of those receiving temozolomide was 31.3%. The overall median survival was 15.7 months (95% CI 13.6–17.8 months). The 1- and 2-year survivals were 62.5 and 25.5%, respectively. For subgroups RIT and TMZ+RIT, the median survivals were 14.5 and 20.2 months, respectively. No Grade 3 or 4 toxicity was seen with the administration of 125I-mAb 425. The CTL patients lacked Karnofsky Performance Scale scores, had poorer survival, were older, and were less likely to receive radiation therapy. On multivariate analysis, the hazard ratios for RIT versus CTL, TMZ+RIT versus CTL, and TMZ+RIT versus RIT were 0.49 (p < 0.001), 0.30 (p < 0.001), and 0.62 (p = 0.008), respectively.

Conclusions

In this large Phase II study of 192 patients with GBM treated with anti–epidermal growth factor receptor 125I-mAb 425 radioimmunotherapy, survival was 15.7 months, and treatment was safe and well tolerated.

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Grace H. Kim, David K. Hahn, Christopher P. Kellner, Ricardo J. Komotar, Robert Starke, Matthew C. Garrett, Jiang Yao, Justin Cleveland, Stephan A. Mayer and E. Sander Connolly Jr.

Object

Heparin-induced thrombocytopenia Type II (HIT II) is a serious complication that occurs in 0.2–3% of patients treated with heparin and is associated with a high risk of thrombotic events. One center recently reported an incidence of HIT II of 15% in a population of patients with aneurysmal subarachnoid hemorrhage (aSAH). Because these patients are typically exposed to heparin during angiography, controversy exists regarding whether prophylaxis with enoxaparin rather than heparin affords any reduction in the risk of developing HIT II. In this study, the authors investigated the effect of heparin compared with enoxaparin on the incidence of HIT II in patients with aSAH.

Methods

The authors reviewed the medical records of 300 patients treated for aSAH who received thromboprophylaxis with either heparin or enoxaparin, and identified patients who developed HIT II. The incidences of HIT II in the 2 treatment groups were then compared.

Results

One hundred sixty-six patients with aSAH were treated with heparin, and 134 patients were treated with enoxaparin. Sixteen (5.3%) of 300 patients met the diagnostic criteria for HIT II. Of those treated with heparin, 8 (4.8%) of 166 developed HIT II, compared with 8 (6%) of 134 treated with enoxaparin (difference not significant).

Conclusions

The authors report a lower incidence of HIT II in patients with aSAH than has previously been reported. The data also suggest that patients with aSAH who receive heparin are at no greater risk of developing HIT II than those who receive enoxaparin. This finding challenges the merit of choosing enoxaparin rather than heparin for thromboprophylaxis in patients with a SAH.

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Hariyadarshi Pannu, Dong H. Kim, Dongchuan Guo, Terri M. King, Grace Van Ginhoven, Toinette Chin, Katherine Chang, Yuhua Qi, Sanjay Shete and Dianna M. Milewicz

Object

Matrix metalloproteinases (MMPs) are a family of endopeptidases that mediate vascular remodeling by degrading extracellular matrix components, such as collagen and elastin. On the basis of accumulating evidence that implicates increased MMP-2 (gelatinase A) and MMP-9 (gelatinase B) amounts and activity in the pathogenesis of aneurysms, the authors investigated the genetic association between polymorphisms in MMP-2 and MMP-9 and sporadic intracranial aneurysms.

Methods

Eight polymorphisms located in MMP-2 and MMP-9 were genotyped, and the association of these variations with disease was assessed in a Caucasian population consisting of 125 patients with intracranial aneurysms and 234 ethnically matched healthy volunteers.

Polymorphisms in the MMP-2 gene and the haplotypes generated from these polymorphisms were not associated with the occurrence of intracranial aneurysms. However, a polymorphism located in the 3′ untranslated region of MMP-9 showed a significant association with disease in the study population, with individuals carrying the TT genotype at increased risk for developing intracranial aneurysms (odds ratio 1.91, p = 0.005). Haplotypes containing the T allele of this polymorphism also showed a comparable association with disease. Similar results were obtained in an analysis of these polymorphisms in a subgroup of patients who presented with ruptured aneurysms.

Conclusions

The study findings support a role for MMP-9, but not MMP-2, in the pathogenesis of intracranial aneurysms.

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Ricardo J. Komotar, David K. Hahn, Grace H. Kim, Robert M. Starke, Matthew C. Garrett, Maxwell B. Merkow, Marc L. Otten, Robert R. Sciacca and E. Sander Connolly Jr.

Object

Chronic hydrocephalus requiring shunt placement is a common complication following aneurysmal subarachnoid hemorrhage (SAH). Controversy exists over whether microsurgical fenestration of the lamina terminalis during aneurysm surgery affords a reduction in the development of shunt-dependent hydrocephalus. To resolve this debate, the authors performed a systematic review and quantitative analysis of the literature to determine the efficacy of lamina terminalis fenestration in reducing aneurysmal SAH–associated shunt-dependent hydrocephalus.

Methods

A MEDLINE (1950–2007) database search was performed using the following keywords, singly and in combination: “ventriculoperitoneal shunt,” “hydrocephalus,” “subarachnoid hemorrhage,” “aneurysm,” “fenestration,” and “lamina terminalis.” Additional studies were manually singled out by scrutinizing references from identified manuscripts, major neurosurgical journals and texts, and personal files. A recent study from the authors' institution was also incorporated into the review. Data from included studies were analyzed using the chi-square analysis and Student t-test. The Cochran-Mantel-Haenszel test was used to compare overall incidence of shunt-dependent hydrocephalus.

Results

The literature search revealed 19 studies, but only 11 were included in this review, involving 1973 patients. The fenestrated and nonfenestrated cohorts (combined from the various studies) differed significantly with regard to patient sex, age, and clinical grade as well as aneurysm location (p = 0.0065, 0.0028, 0.0003, and 0.017, respectively). The overall incidence of shunt-dependent hydrocephalus in the fenestrated cohort was 10%, as compared with 14% in the nonfenestrated cohort (p = 0.089). The relative risk of shunt-dependent hydrocephalus in the fenestrated cohort was 0.88 (95% CI 0.62–1.24).

Conclusions

This systematic review revealed no significant association between lamina terminalis fenestration and a reduced incidence of shunt-dependent hydrocephalus. The interpretation of these results, however, is restricted by unmatched cohort differences as well as other inherent study limitations. Although the overall literature supports lamina terminalis fenestration, a number of authors have questioned the technique's benefits, thus rendering its efficacy in reducing shunt-dependent hydrocephalus unclear. A well-designed, multicenter, randomized controlled trial is needed to definitively address the efficacy of this microsurgical technique.

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William J. Mack, Christopher P. Kellner, Daniel H. Sahlein, Andrew F. Ducruet, Grace H. Kim, J Mocco, Joseph Zurica, Ricardo J. Komotar, Raqeeb Haque, Robert Sciacca, Donald O. Quest, Robert A. Solomon, E. Sander Connolly Jr. and Eric J. Heyer

Object

Recent data from both experimental and clinical studies have supported the use of intravenous magnesium as a potential therapy in the setting of cerebral ischemia. This study assessed whether intraoperative magnesium therapy improves neuropsychometric testing (NPT) following carotid endarterectomy (CEA).

Methods

One hundred eight patients undergoing CEA were randomly assigned to receive placebo infusion or 1 of 3 magnesium-dosing protocols. Neuropsychometric testing was performed 1 day after surgery and compared with baseline performance. Assessment was also performed on a set of 35 patients concurrently undergoing lumbar laminectomy to serve as a control group for NPT. A forward stepwise logistic regression analysis was performed to evaluate the impact of magnesium therapy on NPT. A subgroup analysis was then performed, analyzing the impact of each intraoperative dose on NPT.

Results

Patients treated with intravenous magnesium infusion demonstrated less postoperative neurocognitive impairment than those treated with placebo (OR 0.27, 95% CI 0.10–0.74, p = 0.01). When stratified according to dosing bolus and intraoperative magnesium level, those who were treated with low-dose magnesium had less cognitive decline than those treated with placebo (OR 0.09, 95% CI 0.02–0.50, p < 0.01). Those in the high-dose magnesium group demonstrated no difference from the placebo-treated group.

Conclusions

Low-dose intraoperative magnesium therapy protects against neurocognitive decline following CEA.

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J Mocco, William J. Mack, Grace H. Kim, Alan P. Lozier, Ilya Laufer, Kurt T. Kreiter, Robert R. Sciacca, Robert A. Solomon, Stephan A. Mayer and E. Sander Connolly Jr.

Object. Proinflammatory adhesion molecule expression has been demonstrated to be elevated in patients with aneurysmal subarachnoid hemorrhage (SAH). Recent studies have shown that elevations in soluble intercellular adhesion molecule—1 (ICAM-1) may be predictive of poor outcome in patients with good grade (Hunt and Hess Grades 1–2) aneurysmal SAH at delayed time points that correspond with the risk period for cerebral vasospasm. In addition, ICAM-1 is upregulated in experimental models of vasospasm. Unfortunately, the relationship of adhesion molecule expression to human vasospasm remains unclear. The authors hypothesized that the delayed elevation of soluble ICAM-1 in patients with aneurysmal SAH is associated with the development of cerebral vasospasm.

Methods. Eighty-nine patients with aneurysmal SAH were prospectively enrolled in a study and stratified according to the presence or absence of vasospasm, as evidenced by daily monitoring of transcranial Doppler (TCD) velocities (presence, > 200 cm/second; absence, ≤ 120 cm/second). Levels of soluble ICAM-1 were determined using enzyme-linked immunosorbent assay every other day for 12 days post-SAH. An analysis of covariance model was used to evaluate trends in soluble ICAM-1 levels from 2 days prior to 6 days after the occurrence of documented vasospasm. Two groups of patients, matched for admission admission Hunt and Hess grade, were compared: nine patients with TCD velocities greater than 200 cm/second and nine patients with TCD velocities less than 120 cm/second. From among the patients with TCD velocities greater than 200 cm/second six patients with angiographically documented vasospasm were selected. Patients with TCD velocities less than 120 cm/second and matched admission Hunt and Hess grades but without angiographically documented vasospasm were selected. Patients with TCD-demonstrated vasospasm showed a significant mean rate of rise (p < 0.01) in soluble ICAM-1 levels during the perivasospasm period, but admission Hunt and Hess grade—matched control patients did not (p = not significant [NS]). There was a significant difference between these groups' rates of soluble ICAM increase (p < 0.01). Patients with both TCD- and angiographically demonstrated vasospasm likewise showed a highly significant mean rate of increase in soluble ICAM-1 levels during the perivasospasm period (p < 0.01), whereas admission Hunt and Hess grade—matched controls did not (p = NS). The difference beween these groups' rates of increase was highly significant (p < 0.001).

Conclusions. These data suggest a role for ICAM-1 in the pathophysiology of cerebral vasospasm or its ischemic sequelae. As this relationship is further elucidated, adhesion molecules such as ICAM-1 may provide novel therapeutic targets in the prevention of vasospasm or its ischemic consequences.

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Grace H. Kim, Christopher P. Kellner, David K. Hahn, Brianna M. Desantis, Muhith Musabbir, Robert M. Starke, Michal Rynkowski, Ricardo J. Komotar, Marc L. Otten, Robert Sciacca, J. Michael Schmidt, Stephan A. Mayer and E. Sander Connolly Jr.

Object

Despite efforts to elucidate both the molecular mechanism and the clinical predictors of vasospasm after aneurysmal subarachnoid hemorrhage (ASAH), its pathogenesis remains unclear. Monocyte chemoattractant protein–1 (MCP-1) is a chemokine that has been firmly implicated in the pathophysiology of vasospasm and in neural tissue injury following focal ischemia in both animal models and human studies. The authors hypothesized that MCP-1 would be found in increased concentrations in the blood and cerebrospinal fluid (CSF) of patients with ASAH and would correlate with both outcome and the occurrence of vasospasm.

Methods

Seventy-seven patients who presented with ASAH were prospectively enrolled in this study between July 2001 and May 2002. Using an enzyme-linked immunosorbent assay, MCP-1 levels were measured in serum daily and in CSF when available. The mean serum and CSF MCP-1 concentrations were calculated for each patient throughout the entire hospital stay. Neurological outcome was evaluated at discharge or 14 days posthemorrhage using the modified Rankin Scale. Vasospasm was evaluated on angiography.

Results

The serum MCP-1 concentrations correlated with negative outcome such that a 10% increase in concentration predicted a 25% increase in the probability of a poor outcome, whereas the serum MCP-1 levels did not correlate with vasospasm. Concentrations of MCP-1 in the CSF, however, proved to be significantly higher in patients with angiographically demonstrated vasospasm.

Conclusions

These findings suggest a role for MCP-1 in neurological injury and imply that it may act as a biomarker of poor outcome in the serum and of vasospasm in the CSF.

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Linda S. Aglio, Muhammad M. Abd-El-Barr, Vwaire Orhurhu, Grace Y. Kim, Jie Zhou, Laverne D. Gugino, Lisa J. Crossley, James L. Gosnell, John H. Chi and Michael W. Groff

OBJECTIVE

Preemptive administration of analgesic medication is more effective than medication given after the onset of the painful stimulus. The efficacy of preoperative or preemptive pain relief after thoracolumbosacral spine surgery has not been well studied. The present study was a double-blind, placebo-controlled randomized trial of preemptive analgesia with a single-shot epidural injection in adult patients undergoing spine surgery.

METHODS

Ninety-nine adult patients undergoing thoracolumbosacral operations via a posterior approach were randomized to receive a single shot of either epidural placebo (group 1), hydromorphone alone (group 2), or bupivacaine with hydromorphone (group 3) before surgery at the preoperative holding area. The primary outcome was the presence of opioid sparing and rescue time—defined as the time interval from when a patient was extubated to the time pain medication was first demanded during the postoperative period. Secondary outcomes include length of stay at the postanesthesia care unit (PACU), pain score at the PACU, opioid dose, and hospital length of stay.

RESULTS

Of the 99 patients, 32 were randomized to the epidural placebo group, 33 to the hydromorphone-alone group, and 34 to the bupivacaine with hydromorphone group. No significant difference was seen across the demographics and surgical complexities for all 3 groups. Compared to the control group, opioid sparing was significantly higher in group 2 (57.6% vs 15.6%, p = 0.0007) and group 3 (52.9% vs 15.6%, p = 0.0045) in the first demand of intravenous hydromorphone as a supplemental analgesic medication. Compared to placebo, the rescue time was significantly higher in group 2 (187 minutes vs 51.5 minutes, p = 0.0014) and group 3 (204.5 minutes vs 51. minutes, p = 0.0045). There were no significant differences in secondary outcomes.

CONCLUSIONS

The authors’ study demonstrated that preemptive analgesia in thoracolumbosacral surgeries can significantly reduce analgesia requirements in the immediate postoperative period as evidenced by reduced request for opioid medication in both analgesia study groups who received a preoperative analgesic epidural. Nonetheless, the lack of differences in pain score and opioid dose at the PACU brings into question the role of preemptive epidural opioids in spine surgery patients. Further work is necessary to investigate the long-term effectiveness of preemptive epidural opioids and their role in pain reduction and patient satisfaction.

Clinical trial registration no.: NCT02968862 (clinicaltrials.gov)

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Jack M. Fletcher, Kim Copeland, Jon A. Frederick, Susan E. Blaser, Larry A. Kramer, Hope Northrup, H. Julia Hannay, Michael E. Brandt, David J. Francis, Grace Villarreal, James M. Drake, John P. Laurent, Irene Townsend, Susan Inwood, Amy Boudousquie and Maureen Dennis

Object. The aim of this study was to evaluate whether the level of a spinal lesion is associated with variations in anomalous brain development and neurobehavioral outcomes in children suffering from the meningomyelocele form of spina bifida and hydrocephalus (SBM-H).

Methods. Two hundred sixty-eight children with SBM-H were divided into upper (T-12 and above; 82 patients) and lower (L-1 and below; 186 patients) lesion-level groups. Magnetic resonance images were qualitatively coded by radiologists and quantitatively segmented for cerebrum and cerebellum volumes. Psychometric assessments of handedness, intelligence, academic skills, and adaptive behavior were compared between lesion-level groups and also used to determine the number of children who met research-based criteria for mental retardation, attention deficit hyperactivity disorder, and learning disabilities.

The magnetic resonance images obtained in children with upper-level spinal lesions demonstrated more qualitative abnormalities in the midbrain and tectum, pons, and splenium, although not in the cerebellum, compared with images obtained in children with lower-level spinal lesions. Upper-level lesions were also associated with reductions in cerebrum and cerebellum volumes, lower scores on measures of intelligence, academic skills, and adaptive behavior, and with a higher frequency of individuals meeting the criteria for mental retardation. Hispanic children (who were also more economically disadvantaged) were more likely to have upper-level lesions and poorer neurobehavioral outcomes, but lesion-level effects were generally independent of ethnicity.

Conclusions. A higher level of spinal lesion in SBM-H is a marker for more severe anomalous brain development, which is in turn associated with poorer neurobehavioral outcomes in a wide variety of domains that determine levels of independent functioning for these children at home and school.