The DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) inhibits the killing of tumor cells by alkylating agents. MGMT activity is controlled by a promoter; methylation of the promoter silences the gene in cancer, and the cells no longer produce MGMT. We examined gliomas to determine whether methylation of the MGMT promoter is related to the responsiveness of the tumor to alkylating agents. METHODS: We analyzed the MGMT promoter in tumor DNA by a methylation-specific polymerase-chain-reaction assay. The gliomas were obtained from patients who had been treated with carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea, or BCNU). The molecular data were correlated with the clinical outcome. RESULTS: The MGMT promoter was methylated in gliomas from 19 of 47 patients (40 percent). This finding was associated with regression of the tumor and prolonged overall and disease-free survival. It was an independent and stronger prognostic factor than age, stage, tumor grade, or performance status. CONCLUSIONS: Methylation of the MGMT promoter in gliomas is a useful predictor of the responsiveness of the tumors to alkylating agents.
Michael F. Stiefel and M. Sean Grady
Michael F. Stiefel and Anthony Marmarou
Object. Disruption of ionic homeostasis during ischemia is a well-characterized event and is identified by a rise in the concentration of extracellular potassium [K+]e, with a concomitant reduction in the concentration of extracellular sodium [Na+]e. Results of clinical studies in which microdialysis has been used, however, have shown only modest changes in the levels of extracellular ions. The object of this study was to measure [K+]e and [Na+]e by using ion-selective electrodes (ISEs) and to compare these measurements with those obtained using the well-established method of microdialysis.
Methods. Fifteen Sprague—Dawley rats were separated into three groups. Five animals were subjected to a 15-minute period of ischemia, and another five animals to a 60-minute period of ischemia; animals in both of these groups received K+-free microdialysis perfusate. The third group of five rats underwent a 60-minute period of ischemia and received a reduced-Na+ microdialysis perfusate. Transient forebrain ischemia was produced by bilateral carotid artery occlusion combined with hypotension. A custom-fabricated glass Na+ electrode and a flexible plastic K+ and reference electrodes were used to monitor extracellular ion transients. Microdialysis samples were obtained with the aid of a 2-mm microdialysis probe that was perfused with K+-free mock cerebrospinal fluid at a rate of 2 µl/minute.
Baseline measurements of [K+]e and [Na+]e, obtained using ISEs, were 3.41 ± 0.09 mM and 145 ± 7.75 mM, respectively. Ischemia resulted in a rapid accumulation of [K+]e (in animals subjected to 15 minutes of ischemia, the concentration was 41.9 ± 13.7 mM; and in animals subjected to 60 minutes of ischemia, the concentration was 66.9 ± 11.5 mM), with a concomitant decrease in [Na+]e (in animals subjected to 15 minutes of ischemia, the concentration was 71.7 ± 2.9 mM; and in animals subjected to 60 minutes of ischemia, the concentration was 74.7 ± 1.9 mM). A comparison of microdialysis and ISE methods revealed that microdialysis underestimated the [K+]e changes and was insensitive to concomitant [Na+]e alterations that occur during ischemia.
Conclusions. Our results indicate that the flexible ISE is a reliable and accurate tool for monitoring ionic dysfunction that accompanies brain injury.
Michael F. Stiefel, Gregory G. Heuer, Michelle J. Smith, Stephanie Bloom, Eileen Maloney-Wilensky, Vincente H. Gracias, M. Sean Grady and Peter D. Leroux
Object. Medically intractable intracranial hypertension is a major cause of morbidity and mortality after severe brain injury. One potential treatment for intracranial hypertension is decompressive hemicraniectomy (DCH). Whether and when to use DCH, however, remain unclear. The authors therefore studied the effects of DCH on cerebral O2 to develop a better understanding of the effects of this treatment on the recovery from injury and disease.
Methods. The study focused on seven patients (mean age 30.6 ± 9.7 years) admitted to the hospital after traumatic brain injury (five patients) or subarachnoid hemorrhage (two patients) as part of a prospective observational database at a Level I trauma center. At admission the Glasgow Coma Scale (GCS) score was 6 or less in all patients. Patients received continuous monitoring of intracranial pressure (ICP), cerebral perfusion pressure (CPP), blood pressure, and arterial O2 saturation. Cerebral oxygenation was measured using the commercially available Licox Brain Tissue Oxygen Monitoring System manufactured by Integra NeuroSciences. A DCH was performed when the patient's ICP remained elevated despite maximal medical management.
Conclusions. All patients tolerated DCH without complications. Before the operation, the mean ICP was elevated in all patients (26 ± 4 mm Hg), despite maximal medical management. After surgery, there was an immediate and sustained decrease in ICP (19 ± 11 mm Hg) and an increase in CPP (81 ± 17 mm Hg). Following DCH, cerebral oxygenation improved from a mean of 21.2 ± 13.8 mm Hg to 45.5 ± 25.4 mm Hg, a 114.8% increase. The change in brain tissue O2 and the change in ICP after DCH demonstrated only a modest relationship (r2 = 0.3). These results indicate that the use of DCH in the treatment of severe brain injury is associated with a significant improvement in brain O2.
Michael F. Stiefel, Gregory G. Heuer, John M. Abrahams, Stephanie Bloom, Michelle J. Smith, Eileen Maloney-Wilensky, M. Sean Grady and Peter D. Leroux
Object. Nimodipine has been shown to improve neurological outcome after subarachnoid hemorrhage (SAH); the mechanism of this improvement, however, is uncertain. In addition, adverse systemic effects such as hypotension have been described. The authors investigated the effect of nimodipine on brain tissue PO2.
Methods. Patients in whom Hunt and Hess Grade IV or V SAH had occurred who underwent aneurysm occlusion and had stable blood pressure were prospectively evaluated using continuous brain tissue PO2 monitoring. Nimodipine (60 mg) was delivered through a nasogastric or Dobhoff tube every 4 hours. Data were obtained from 11 patients and measurements of brain tissue PO2, intracranial pressure (ICP), mean arterial blood pressure (MABP), and cerebral perfusion pressure (CPP) were recorded every 15 minutes.
Nimodipine resulted in a significant reduction in brain tissue PO2 in seven (64%) of 11 patients. The baseline PO2 before nimodipine administration was 38.4 ± 10.9 mm Hg. The baseline MABP and CPP were 90 ± 20 and 84 ± 19 mm Hg, respectively. The greatest reduction in brain tissue PO2 occurred 15 minutes after administration, when the mean pressure was 26.9 ± 7.7 mm Hg (p < 0.05). The PO2 remained suppressed at 30 minutes (27.5 ± 7.7 mm Hg [p < 0.05]) and at 60 minutes (29.7 ± 11.1 mm Hg [p < 0.05]) after nimodipine administration but returned to baseline levels 2 hours later. In the seven patients in whom brain tissue PO2 decreased, other physiological variables such as arterial saturation, end-tidal CO2, heart rate, MABP, ICP, and CPP did not demonstrate any association with the nimodipine-induced reduction in PO2. In four patients PO2 remained stable and none of these patients had a significant increase in brain tissue PO2.
Conclusions. Although nimodipine use is associated with improved outcome following SAH, in some patients it can temporarily reduce brain tissue PO2.
Michael F. Stiefel, Yoshiyuki Tomita and Anthony Marmarou
Object. It is well established that posttraumatic secondary ischemia contributes to poor outcome. Ion dysfunction leading to cytotoxic edema is a primary force in the formation of ischemic brain edema and is a principal component of traumatic brain swelling. Because cell swelling is the result of net ion and water movement, it is crucial to have a thorough understanding of these transient phenomena. The purpose of this study was to characterize the effects of secondary ischemia following traumatic brain injury (TBI) on the ability to restore ion homeostasis.
Methods. Twenty-four Sprague—Dawley rats were divided into four groups of six animals each. The rats underwent transient forebrain ischemia via bilateral carotid artery occlusion combined with hypotension: 15 minutes of forebrain ischemia (Group 1); 60 minutes of forebrain ischemia (Group 2); impact acceleration/TBI (Group 3); and impact acceleration/TBI followed by 15 minutes of ischemia (Group 4).
Ischemia resulted in a rapid accumulation of [K+]e: 41.94 ± 13.65 and 66.33 ± 6.63 mM, respectively, in Groups 1 and 2, with a concomitant decrease of [Na+]e: 64 ± 18 mM and 72 ± 11 mM in Groups 1 and 2. Traumatic brain injury resulted in a less severe although identical trend in ion dysfunction ([K+]e 30.42 ± 11.67 mM and [Na+]e 63 ± 33 mM). Secondary ischemia resulted in prolonged and sustained ion dysfunction with a concomitant elevation of intracranial pressure (ICP).
Conclusions. Analysis of these results indicates that ischemia and TBI are sublethal in isolation; however, when TBI is associated with secondary ischemia, ion dysfunction is sustained and is associated with elevated ICP.
Michael F. Stiefel, Alejandro Spiotta, Vincent H. Gracias, Alicia M. Garuffe, Oscar Guillamondegui, Eileen Maloney-Wilensky, Stephanie Bloom, M. Sean Grady and Peter D. LeRoux
Object. An intracranial pressure (ICP) monitor, from which cerebral perfusion pressure (CPP) is estimated, is recommended in the care of severe traumatic brain injury (TBI). Nevertheless, optimal ICP and CPP management may not always prevent cerebral ischemia, which adversely influences patient outcome. The authors therefore determined whether the addition of a brain tissue oxygen tension (PO2) monitor in the treatment of TBI was associated with an improved patient outcome.
Methods. Patients with severe TBI (Glasgow Coma Scale [GCS] score < 8) who had been admitted to a Level I trauma center were evaluated as part of a prospective observational database. Patients treated with ICP and brain tissue PO2 monitoring were compared with historical controls matched for age, pathological features, admission GCS score, and Injury Severity Score who had undergone ICP monitoring alone. Therapy in both patient groups was aimed at maintaining an ICP less than 20 mm Hg and a CPP greater than 60 mm Hg. Among patients whose brain tissue PO2 was monitored, oxygenation was maintained at levels greater than 25 mm Hg. Twenty-five patients with a mean age of 44 ± 14 years were treated using an ICP monitor alone. Twenty-eight patients with a mean age of 38 ± 18 years underwent brain tissue PO2-directed care. The mean daily ICP and CPP levels were similar in each group. The mortality rate in patients treated using conventional ICP and CPP management was 44%. Patients who also underwent brain tissue PO2 monitoring had a significantly reduced mortality rate of 25% (p < 0.05).
Conclusions. The use of both ICP and brain tissue PO2 monitors and therapy directed at brain tissue PO2 is associated with reduced patient death following severe TBI.
Michael F. Stiefel, Joshua D. Udoetuk, Phillip B. Storm, Leslie N. Sutton, Heakyung Kim, Troy E. Dominguez, Mark A. Helfaer and Jimmy W. Huh
Intracranial pressure (ICP) and cerebral perfusion pressure (CPP) monitoring are fundamental to the management of severe traumatic brain injury (TBI). In adults, brain tissue oxygen monitoring (specifically PO2) and treatment have been shown to be safe additions to conventional neurocritical care and are associated with improved outcome. Brain tissue oxygen monitoring, however, has not been described in pediatric patients with TBI. In this report, the authors present preliminary experience with the use of ICP and PO2 monitoring in this population.
Pediatric patients (age <18 years) with severe TBI (Glasgow Coma Scale score <8) admitted to a Level 1 trauma center who underwent ICP and PO2 monitoring were evaluated. Therapy was directed at maintaining ICP below 20 mm Hg and age-appropriate CPP (≥ 40 mm Hg).
Data obtained in six patients (two girls and four boys ranging in age from 6–16 years) were analyzed. Brain tissue oxygen levels were significantly higher (p <0.01) at an ICP of less than 20 mm Hg (PO2 29.29 ± 7.17 mm Hg) than at an ICP of greater than or equal to 20 mm Hg (PO2 22.83 ± 13.85 mm Hg). Significant differences (p <0.01) were also measured when CPP was less than 40 mm Hg (PO2 2.53 ± 7.98 mm Hg) and greater than or equal to 40 mm Hg (PO2 28.97 ± 7.85 mm Hg).
Brain tissue oxygen monitoring may be a safe and useful addition to ICP monitoring in the treatment of pediatric patients with severe TBI.
Michael F. Stiefel, Joshua D. Udoetuk, Alejandro M. Spiotta, Vicente H. Gracias, Aaron Goldberg, Eileen Maloney-Wilensky, Stephanie Bloom and Peter D. Le Roux
Control of intracranial pressure (ICP) and cerebral perfusion pressure (CPP) is the foundation of traumatic brain injury (TBI) management. In this study, the authors examined whether conventional ICP- and CPP-guided neurocritical care ensures adequate brain tissue O2 in the first 6 hours after resuscitation.
Resuscitated patients with severe TBI (Glasgow Coma Scale score ≤ 8 and Injury Severity Scale score ≥ 16) who were admitted to a Level I trauma center and who underwent brain tissue O2 monitoring within 6 hours of injury were evaluated as part of a prospective observational database. Therapy was directed to maintain an ICP of 25 mm Hg or less and a CPP of 60 mm Hg or higher.
Data from a group of 25 patients that included 19 men and six women (mean age 39 ± 20 years) were examined. After resuscitation, ICP was 25 mm Hg or less in 84% and CPP was 60 mm Hg or greater in 88% of the patients. Brain O2 probes were allowed to stabilize; the initial brain tissue O2 level was 25 mm Hg or less in 68% of the patients, 20 mm Hg or less in 56%, and 10 mm Hg or less in 36%. Nearly one third (29%) of patients with ICP readings of 25 mm Hg or less and 27% with CPP levels of 60 mm Hg or greater had severe cerebral hypoxia (brain tissue O2 ≤10 mm Hg). Nineteen patients had both optimal ICP (≤25 mm Hg) and CPP (> 60 mm Hg); brain tissue O2 was 20 mm Hg or less in 47% and 10 mm Hg or less in 21% of these patients. The mortality rate was higher in patients with reduced brain tissue O2.
Brain resuscitation based on current neurocritical care standards (that is, control of ICP and CPP) does not prevent cerebral hypoxia in some patients. This finding may help explain why secondary neuronal injury occurs in some patients with adequate CPP and suggests that the definition of adequate brain resuscitation after TBI may need to be reconsidered.
Gregory G. Heuer, Kareem A. Zaghloul, Richard Roberts, Michael F. Stiefel and Phillip B. Storm
✓ Coil migration is a rare but potentially serious complication of endovascular procedures. Occasionally coils can be retrieved via endovascular techniques. The authors describe the microsurgical management of a case in which endovascular techniques failed. A 2-year-old girl with pulmonary atresia and a Blalock–Taussig shunt underwent attempted endovascular closure of the shunt with Gianturco steel coils. During deployment, a coil was lost in the aorta and an angiogram showed that it had lodged in the proximal M1 segment of the middle cerebral artery. The coil could not be retrieved by endovascular techniques, and the patient was taken to the operating room to undergo a craniotomy. After the sylvian fissure was split, the coil was visible through the vessel wall. Temporary clips were placed on the proximal M1 and the proximal M2 segments, trapping the coil. A small arteriotomy was performed, the coil was removed, and the arteriotomy was closed. A cerebral angiogram showed excellent perfusion with no dissections. The patient’s motor examination demonstrated a mild hemiparesis on the left with no tremulousness. Coil migration can be treated by microsurgical techniques in pediatric patients with a good clinical outcome.
Report of two cases and review of the literature
Gregory G. Heuer, Michael F. Stiefel, Robert L. Bailey and James M. Schuster
✓Spinal ependymomas are a common type of primary spinal cord neoplasm that frequently occurs in the lumbar spine. The authors report on two patients who presented with acute neurological decline after hemorrhage into ependymomas of the filum terminale. Both were transferred to the authors' institution because of diagnostic uncertainty and a concern about possible intradural vascular abnormalities. Both patients underwent lumbar laminectomies for tumor resection. The pathological finding in each case was myxopapillary ependymoma. Both patients made a significant recovery and were ambulatory and continent at follow-up review. These cases illustrate the rare but clinically significant incidence of acute neurological decline caused by hemorrhagic cauda equina ependymomas, including the potential for delayed diagnosis and treatment.