Marvin Bergsneider

Metabolic crisis without brain ischemia is common after traumatic brain injury: a combined microdialysis and positron emission tomography study

Brain trauma is accompanied by regional alterations of brain metabolism, reduction in metabolic rates and possible energy crisis. We hypothesize that microdialysis markers of energy crisis are present during the critical period of intensive care despite the absence of brain ischemia. In all, 19 brain injury patients (mean GCS 6) underwent combined positron emission tomography (PET) for metabolism of glucose (CMRglu) and oxygen (CMRO2) and cerebral microdialysis (MD) at a mean time of 36 h after injury. Microdialysis values were compared with the regional mean PET values adjacent to the probe. Longitudinal MD data revealed a 25% incidence rate of metabolic crisis (elevated lactate/pyruvate ratio (LPR)>40) but only a 2.4% incidence rate of ischemia. Positron emission tomography imaging revealed a 1% incidence of ischemia across all voxels as measured by oxygen extraction fraction (OEF) and cerebral venous oxygen content (CvO2). In the region of the MD probe, PET imaging revealed ischemia in a single patient despite increased LPR in other patients. Lactate/pyruvate ratio correlated negatively with CMRO2 (P<0.001), but not with OEF or CvO2. Traumatic brain injury leads to a state of persistent metabolic crisis as reflected by abnormal cerebral microdialysis LPR that is not related to ischemia.

Antitumor activity of rapamycin in a phase I trial for patients with recurrent PTEN-deficient glioblastoma

Background There is much discussion in the cancer drug development community about how to incorporate molecular tools into early-stage clinical trials to assess target modulation, measure anti-tumor activity, and enrich the clinical trial population for patients who are more likely to benefit. Small, molecularly focused clinical studies offer the promise of the early definition of optimal biologic dose and patient population. Methods and Findings Based on preclinical evidence that phosphatase and tensin homolog deleted on Chromosome 10 (PTEN) loss sensitizes tumors to the inhibition of mammalian target of rapamycin (mTOR), we conducted a proof-of-concept Phase I neoadjuvant trial of rapamycin in patients with recurrent glioblastoma, whose tumors lacked expression of the tumor suppressor PTEN. We aimed to assess the safety profile of daily rapamycin in patients with glioma, define the dose of rapamycin required for mTOR inhibition in tumor tissue, and evaluate the antiproliferative activity of rapamycin in PTEN-deficient glioblastoma. Although intratumoral rapamycin concentrations that were sufficient to inhibit mTOR in vitro were achieved in all patients, the magnitude of mTOR inhibition in tumor cells (measured by reduced ribosomal S6 protein phosphorylation) varied substantially. Tumor cell proliferation (measured by Ki-67 staining) was dramatically reduced in seven of 14 patients after 1 wk of rapamycin treatment and was associated with the magnitude of mTOR inhibition (p = 0.0047, Fisher exact test) but not the intratumoral rapamycin concentration. Tumor cells harvested from the Ki-67 nonresponders retained sensitivity to rapamycin ex vivo, indicating that clinical resistance to biochemical mTOR inhibition was not cell-intrinsic. Rapamycin treatment led to Akt activation in seven patients, presumably due to loss of negative feedback, and this activation was associated with shorter time-to-progression during post-surgical maintenance rapamycin therapy (p < 0.05, Logrank test). Conclusions Rapamycin has anticancer activity in PTEN-deficient glioblastoma and warrants further clinical study alone or in combination with PI3K pathway inhibitors. The short-term treatment endpoints used in this neoadjuvant trial design identified the importance of monitoring target inhibition and negative feedback to guide future clinical development. Trial registration: http://www.ClinicalTrials.gov (#NCT00047073).

Diagnosing idiopathic normal-pressure hydrocephalus

OBJECTIVE:The precise incidence and prevalence of idiopathic normal-pressure hydrocephalus (INPH) is not known, and evidence-based clinical diagnostic criteria have not been developed previously. This report contains evidence-based guidelines for clinical diagnosis of INPH that are intended to facilitate future epidemiological studies of INPH, promote earlier and more accurate diagnosis, and ultimately improve treatment outcome. METHODS:The criteria for the diagnosis of INPH are based on evidence from the medical literature, supplemented as necessary by expert opinion. From 1966 to 2003, 653 publications on “normal-pressure hydrocephalus” were cited in MEDLINE, including 29 articles that met the more stringent criteria of including “idiopathic normal-pressure hydrocephalus” in their title. Additional studies were considered that explicitly identified INPH cases and/or specified the criteria for a diagnosis of INPH. Studies were graded according to the class of evidence and results summarized in evidentiary tables. For issues of clinical relevance that lacked substantive evidence from the medical literature, the opinions of consulting experts were considered and contributed to “Options.” RESULTS:Evidence-based guidelines for the clinical diagnosis of INPH have been developed. A detailed understanding of the range of clinical manifestations of this disorder and adherence to practice guidelines should improve the timely and accurate recognition of this disorder. CONCLUSION:It is recommended that INPH be classified into probable, possible, and unlikely categories. We hope that these criteria will be widely applied in clinical practice and will promote greater consistency in patient selection in future clinical investigations involving INPH.

Intensive insulin therapy reduces microdialysis glucose values without altering glucose utilization or improving the lactate/pyruvate ratio after traumatic brain injury

Objective:To determine that intensive glycemic control does not reduce microdialysis glucose concentration brain metabolism of glucose. Design:Prospective monitoring followed by retrospective data analysis of cerebral microdialysis and global brain metabolism. Setting:Single center, academic neurointensive care unit. Patients:Forty-seven moderate to severe traumatic brain injury patients. Interventions:A nonrandomized, consecutive design was used for glycemic control with loose insulin (n = 33) for the initial 2 yrs or intensive insulin therapy (n = 14) for the last year. Measurements and Main Results:In 14 patients treated with intensive insulin therapy, there was a reduction in microdialysis glucose by 70% of baseline concentration compared with a 15% reduction in 33 patients treated with a loose insulin protocol. Despite this reduction in microdialysis glucose, the global metabolic rate of glucose did not change. However, intensive insulin therapy was associated with increased incidence of microdialysis markers of cellular distress, namely elevated glutamate (38 ± 37% vs. 10 ± 17%, p < .01), elevated lactate/pyruvate ratio (38 ± 37% vs. 19 ± 26%, p < .03) and low glucose (26 ± 17% vs. 11 ± 15%, p < .05, and increased global oxygen extraction fraction. Mortality was similar in the intensive and loose insulin treatment groups (14% vs. 15%, p = .9), as was 6-month clinical outcome (p = .3). Conclusions:Intensive insulin therapy results in a net reduction in microdialysis glucose and an increase in microdialysis glutamate and lactate/pyruvate without conveying a functional outcome advantage.

Persistently low extracellular glucose correlates with poor outcome 6 months after human traumatic brain injury despite a lack of increased lactate: a microdialysis study.

Disturbed glucose brain metabolism after brain trauma is reflected by changes in extracellular glucose levels. The authors hypothesized that posttraumatic reductions in extracellular glucose levels are not due to ischemia and are associated with poor outcome. Intracerebral microdialysis, electroencephalography, and measurements of brain tissue oxygen levels and jugular venous oxygen saturation were performed in 30 patients with traumatic brain injury. Levels of glucose, lactate, pyruvate, glutamate, and urea were analyzed hourly. The 6-month Glasgow Outcome Scale extended (GOSe6) score was assessed for each patient. In regions of increased glucose utilization defined by positron emission tomography, the extracellular glucose concentration was less than 0.2 mmol/l. Extracellular glucose values were less than 0.2 mmol during postinjury days 0 to 7 in 19% to 30% of hourly samples on each day. Transient decreases in glucose levels occurred with electrographic seizures and nonischemic reductions in cerebral perfusion pressure and jugular venous oxygen saturation. Glutamate levels were elevated in the majority of low-glucose samples, but the lactate/pyruvate ratio did not indicate focal ischemia. Terminal herniation resulted in reductions in glucose with increases in the lactate/pyruvate ratio but not in lactate concentration alone. GOSe6 scores correlated with persistently low glucose levels, combined early low glucose levels and low lactate/glucose ratio, and with the overall lactate/glucose ratio. These results suggest that the level of extracellular glucose is typically reduced after traumatic brain injury and associated with poor outcome, but is not associated with ischemia.

The Value of Supplemental Prognostic Tests for the Preoperative Assessment of Idiopathic Normal-pressure Hydrocephalus

OBJECTIVE:The diagnosis and management of idiopathic normal-pressure hydrocephalus (INPH) remains unclear. Moreover, the value of supplementary tests to predict which patients would benefit from placement of a shunt has not been established. This report develops evidence-based guidelines for the use of supplementary tests as an aid in prognosis. METHODS:MEDLINE searches from 1966 to the present were undertaken by use of the query NPH, normal-pressure hydrocephalus, lumbar drain, CSF [cerebrospinal fluid] tap test, and external CSF drainage in humans. This resulted in 242 articles. To provide a scientific, evidence-based review, we have chosen to restrict our analysis to clinically relevant studies usually consisting of large numbers of shunted NPH patients. Studies that did not specify INPH or secondary NPH were considered in a separate evidentiary table. RESULTS:Evidence-based guidelines for use in supplementary tests have been developed. A positive response to a 40- to 50-ml tap test has a higher degree of certainty for a favorable response to shunt placement than can be obtained by clinical examination. However, the tap test cannot be used as an exclusionary test because of its low sensitivity (26–61%). Determination of the CSF outflow resistance via an infusion test carries a higher sensitivity (57–100%) compared with the tap test and a similar positive predictive value of 75 to 92%. Prolonged external lumbar drainage in excess of 300 ml is associated with high sensitivity (50–100%) and high positive predictive value (80–100%). CONCLUSION:To date, a single standard for the prognostic evaluation of INPH patients is lacking. However, supplemental tests can increase predictive accuracy for prognosis to greater than 90%. Additional multicenter prospective randomized clinical trials are needed.

Energy dysfunction as a predictor of outcome after moderate or severe head injury: indices of oxygen, glucose, and lactate metabolism.

The purpose of this study was to determine if the relationship between abnormalities in glucose, lactate, and oxygen metabolism were predictive of neurologic outcome after moderate or severe head injury, relative to other known prognostic factors. Serial assessments of the cerebral metabolic rates for glucose, lactate, and oxygen were performed using a modified Kety-Schmidt method. In total, 31 normal control subjects were studied once, and 49 TBI patients (mean age 36±16 years, median GCS 7) were studied five times median per patient from postinjury days 0 to 9. Univariate and multivariate analyses were performed. Univariate analysis showed that the 6-month postinjury Glasgow Outcome Scale (GOS) was most strongly associated with the mean cerebral metabolic rate of oxygen (CMRO2) (P = 0.0001), mean arterial lactate level (P = 0.0001), mean arterial glucose (P = 0.0008), mean cerebral blood flow (CBF), (P = 0.002), postresuscitation GCS (P = 0.003), and pupillary status (P = 0.004). Brain lactate uptake was observed in 44% of all metabolic studies, and 76% of patients had at least one episode of brain lactate uptake. By dichotomized GOS, patients achieving a favorable outcome (GOS 4-5) were distinguished from those with an unfavorable outcome (GOS1-3) by having a higher CMRO2 (P = 0.003), a higher rate of abnormal brain lactate uptake relative to arterial lactate levels (P = 0.04), and lesser degrees of blood-brain barrier damage based on CT findings (P = 0.03). Conclusions: During the first 6 days after moderate or severe TBI, CMRO2 and arterial lactate levels are the strongest predictors of neurologic outcome. However, the frequent occurrence of abnormal brain lactate uptake despite only moderate elevations in arterial lactate levels in the favorable outcome patients suggests the brains ability to use lactate as a fuel may be another key outcome predictor. Future studies are needed to determine to what degree nonglycolytic energy production from alternative fuels such as lactate occurs after TBI and whether alternative fuel administration is a viable therapy for TBI patients.

Phase II Pilot Study of Bevacizumab in Combination with Temozolomide and Regional Radiation Therapy for Up-Front Treatment of Patients With Newly Diagnosed Glioblastoma Multiforme: Interim Analysis of Safety and Tolerability

PURPOSE To assess interim safety and tolerability of a 10-patient, Phase II pilot study using bevacizumab (BV) in combination with temozolomide (TMZ) and regional radiation therapy (RT) in the up-front treatment of patients with newly diagnosed glioblastoma. METHODS AND MATERIALS All patients received standard external beam regional RT of 60.0 Gy in 30 fractions started within 3 to 5 weeks after surgery. Concurrently TMZ was given daily at 75 mg/m(2) for 42 days during RT, and BV was given every 2 weeks at 10 mg/kg starting with the first day of RT/TMZ. After a 2-week interval upon completion of RT, the post-RT phase commenced with resumption of TMZ at 150 to 200 mg/m(2) for 5 days every 4 weeks and continuation of BV every 2 weeks. RESULTS For these 10 patients, toxicities were compiled until study discontinuation or up to approximately 40 weeks from initial study treatment for those remaining on-study. In terms of serious immediate or delayed neurotoxicity, 1 patient developed presumed radiation-induced optic neuropathy. Among the toxicities that could be potentially treatment related, relatively high incidences of fatigue, myelotoxicity, wound breakdown, and deep venous thrombosis/pulmonary embolism were observed. CONCLUSION The observed toxicities were acceptable to continue enrollment toward the overall target group of 70 patients. Preliminary efficacy analysis shows encouraging mean progression-free survival. At this time data are not sufficient to encourage routine off-label use of BV combined with TMZ/RT in the setting of newly diagnosed glioblastoma without longer follow-up, enrollment of additional patients, and thorough efficacy assessment.

Metabolic recovery following human traumatic brain injury based on FDG-PET: time course and relationship to neurological disability.

Objective:Utilizing [18F]fluorodeoxyglucose positron emission tomography (FDG-PET), we assessed the temporal pattern and the correlation of functional and metabolic recovery following human traumatic brain injury. Design and Subjects:Fifty-four patients with injury severity ranging from mild to severe were studied. Thirteen of these patients underwent both an acute and delayed FDG-PET study. Results:Analysis of the pooled global cerebral metabolic rate of glucose (CMRglc) values revealed that the intermediate metabolic reduction phase begins to resolve approximately one month following injury, regardless of injury severity. The correlation, in the 13 patients studied twice, between the extent of change in neurologic disability, assessed by the Disability Rating Scale (DRS), and the change in CMRglc from the early to late period was modest (r = −0.42). Potential explanations for this rather poor correlation are discussed. A review of the pertinent literature regarding the use of PET and related imaging modalities, including single photon emission tomography (SPECT) for the assessment of patients following traumatic brain injury is given. Conclusion:The dynamic profile of CMRglc that changes following traumatic brain injury is seemingly stereotypic across a broad range and severity of injury types. Quantitative FDG-PET cannot be used as a surrogate technique for estimating degree of global functional recovery following traumatic brain injury.

Surgical management of idiopathic normal-pressure hydrocephalus.

OBJECTIVE:To develop evidence-based guidelines for surgical management of idiopathic normal-pressure hydrocephalus (INPH). Compared with the diagnostic phase, the surgical management of INPH has received less scientific attention. The quality of much of the literature concerning the surgical management has been limited by many factors. These include retrospective analysis, small patient numbers, analysis of a mixed NPH population, and sometimes a lack of detail as to what type of shunt system was used. Many earlier studies predated our current understanding of the hydrodynamics of cerebrospinal fluid shunts, and therefore, the conclusions drawn may no longer be valid. METHODS:A MEDLINE and PubMed search from 1966 to the present was conducted using the following key terms: normal-pressure hydrocephalus and idiopathic adult-onset hydrocephalus. Only English-language literature in peer-reviewed journals was reviewed. The search was further limited to articles that described the method of treatment and outcome selectively for INPH patients. Finally, only studies that included 20 or more INPH patients were considered with respect to formulating the recommendations in these Guidelines (27 articles). RESULTS:For practical reasons, it is important to identify probable shunt responders diagnosed with INPH. If the patient is an acceptable candidate for anesthesia, then an INPH-specific risk-benefit analysis should be determined. In general, patients exhibiting negligible symptoms may not be suitable candidates for surgical management, given the known risks and complications associated with shunting INPH. The choice of valve type and setting should be based on empirical reasoning and a basic understanding of shunt hydrodynamics. The most conservative choice is a valve incorporating an antisiphon device, with the understanding that underdrainage (despite a low opening pressure) may occur in a small percentage of patients because of the antisiphon device. On the basis of retrospective studies, the use of an adjustable valve seems to be beneficial in the management of INPH. CONCLUSION:The treatment of INPH should not be considered lightly, given the seriousness of the potential complications. Within these limitations and the available evidence, guidelines for surgical management were developed.