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Salvatore Di Maio, Nancy Temkin, Dinesh Ramanathan and Laligam N. Sekhar


The role of surgery and adjuvant radiation therapy for cranial base chordomas is not well established. This meta-analysis measures the relationship of complete resection and type of adjuvant radiation therapy to 5-year progression-free survival (PFS) and overall survival (OS) of cranial base chordomas.


A systematic MEDLINE search (1999–present) yielded 23 observational studies and 807 patients who fit inclusion criteria. The following analyses were performed: 1) Kaplan-Meier 5-year PFS and OS compared based on the extent of resection and type of adjuvant radiation therapy using the log-rank method; 2) a random-effects model comparing 5-year PFS with complete or incomplete resection; and 3) paired z-test comparisons of weighted average 5-year OS and PFS grouped by type of adjuvant radiation therapy.


The weighted average follow-up was 53.6 months. The weighted average 5-year PFS and OS were 50.8% and 78.4%, respectively. Complete resection conferred a higher 5-year PFS than incomplete resection from the random effects model (mean difference in PFS 20.7%; 95% CI 6.57%–34.91%). Patients with incomplete resection were 3.83 times more likely to experience a recurrence (95% CI 1.63–9.00) and 5.85 times more likely to die (95% CI 1.40–24.5) at 5 years versus patients with complete resection. There was no difference in 5-year OS by type of adjuvant radiation, although 5-year PFS was lower in patients receiving Gamma Knife surgery relative to carbon ion radiotherapy (p = 0.042) on paired z-test. No survival difference occurred between radiation therapy techniques on Kaplan-Meier analysis of compiled patient data.


Patients with complete resection of cranial base chordomas have a prolonged 5-year PFS and OS. Adjuvant proton-beam, carbon ion, and modern fractionated photon radiation therapy techniques offered a similar rate of PFS and OS at 5 years.

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Nancy R. Temkin, Richard Holubkov, Joan E. Machamer, H. Richard Winn and Sureyya S. Dikmen

✓ A cohort of 514 hospitalized head-injury survivors was identified based on their injury and 448 (87%) of them were followed for 1 year. Comprehensive neurobehavioral testing was performed 1 month and 1 year after injury.

The authors developed predictions of six neuropsychological and two psychosocial outcomes 1 year after head injury. Prediction trees are presented for verbal IQ, Halstead's Impairment Index, and work status at 1 year. Early predictors of neurobehavioral outcome in survivors are similar to previously reported predictors of mortality. Extent (both depth and length) of coma and age are the medical and demographic variables most predictive of late outcome. Adding 1-month scores substantially improves prediction of neuropsychological variables.

The classification and regression tree is a useful technique for predicting long-term outcome in patients with head injury. The trees are simple enough to be used in a clinical setting and, especially with 1-month scores, predictions are accurate enough for clinical utility.

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J. Paul Elliott, G. Evren Keles, Michael Waite, Nancy Temkin and Mitchel S. Berger

✓ The ventricular system is not infrequently entered during the course of maximum cytoreductive surgery for high-grade supratentorial gliomas. It is unclear if ventricular entry during surgery and/or proximity of the tumor to the ventricular system affects cerebrospinal fluid (CSF) tumor dissemination or the patients' overall survival rate. The authors retrospectively reviewed hospital records and neuroradiological studies of 51 patients operated on at the University of Washington between 1987 and 1991. Inclusion in this study necessitated a pathological diagnosis of malignant glioma and the availability of preoperative and postoperative computerized tomography scans or magnetic resonance images. Patients were excluded from the study if they had radiographic evidence of ventricular entry or CSF tumor dissemination prior to referral to the authors' institution. The index operation was defined as the first operation at the University of Washington or (in those patients with ventricular entry) the operation in which the ventricle was entered. Patients were followed until time of death or, in the case of survivors, until February, 1992. The effect of both ventricular entry and the proximity of the tumor to the ventricular system on CSF tumor dissemination and survival rate was assessed using statistical survival methodology.

There was no significant difference in time from diagnosis to the index operation between groups compared (Mann-Whitney U-test, p > 0.40). Cerebrospinal fluid dissemination was radiographically documented in 18 patients (35%) following the index operation. This occurrence was not significantly influenced by either ventricular entry during surgery (Mantel-Cox test, p = 0.13), the proximity of the tumor to the ventricular system (p = 0.63), or these two variables combined (p = 0.28). Survival rate following the index operation was not significantly affected by ventricular entry (p = 0.66), proximity of the tumor to the ventricular system (p = 0.61), or these two variable considered in combination (p = 0.44). However, survival rate was significantly decreased once CSF tumor dissemination had occurred (Cox model, p = 0.03).

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Alan M. Haltiner, David W. Newell, Nancy R. Temkin, Sureyya S. Dikmen and H. Richard Winn

Object. The goals of this study were to determine if the use of phenytoin to prevent early posttraumatic seizures following head injury was associated with significant adverse side effects and also to determine if the reduction in early posttraumatic seizures after phenytoin administration was associated with a change in mortality rates in head-injured patients.

Methods. The authors performed a secondary analysis of the data obtained in a prospective double-blind placebo-controlled study of 404 patients who were randomly assigned to receive phenytoin or placebo for the prevention of early and late posttraumatic seizures. The incidence of adverse drug effects during the first 2 weeks of treatment, however, was low and not significantly different between the treated and placebo groups. Hypersensitivity reactions occurred in 0.6% of the patients in the phenytoin-treated group compared with 0% in the placebo group (p = 1.0) during week 1, and in 2.5% of phenytoin-treated compared with 0% of placebo-treated patients (p = 0.12) for the first 2 weeks of treatment. Mortality rates were also similar in both groups. Although the mortality rate was higher in patients who developed seizures, this increase was related to the greater severity of the injuries sustained by these patients at the time of the original trauma.

Conclusions. The results of this study indicate that the incidence of early posttraumatic seizure can be effectively reduced by prophylactic administration of phenytoin for 1 or 2 weeks without a significant increase in drug-related side effects. Reduction in posttraumatic seizure during the 1st week, however, was not associated with a reduction in the mortality rate.

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Aziz S. Alali, Nancy Temkin, Jason Barber, Jim Pridgeon, Kelley Chaddock, Sureyya Dikmen, Peter Hendrickson, Walter Videtta, Silvia Lujan, Gustavo Petroni, Nahuel Guadagnoli, Zulma Urbina and Randall M. Chesnut


While existing guidelines support the treatment of intracranial hypertension in severe traumatic brain injury (TBI), it is unclear when to suspect and initiate treatment for high intracranial pressure (ICP). The objective of this study was to derive a clinical decision rule that accurately predicts intracranial hypertension.


Using Delphi methods, the authors identified a set of potential predictors of intracranial hypertension and a clinical decision rule a priori by consensus among a group of 43 neurosurgeons and intensivists who have extensive experience managing severe TBI without ICP monitoring. To validate these predictors, the authors used data from a Latin American trial (n = 150; BEST TRIP). To report on the performance of the rule, they calculated sensitivity, specificity, and positive and negative predictive values with 95% confidence intervals. In a secondary analysis, the rule was validated using data from a North American trial (n = 131; COBRIT).


The final predictors and the clinical decision rule were approved by 97% of participants in the consensus working group. The predictors are divided into major and minor criteria. High ICP would be considered suspected in the presence of 1 major or ≥ 2 minor criteria. Major criteria are: compressed cisterns (CT classification of Marshall diffuse injury [DI] III), midline shift > 5 mm (Marshall DI IV), or nonevacuated mass lesion. Minor criteria are: Glasgow Coma Scale (GCS) motor score ≤ 4, pupillary asymmetry, abnormal pupillary reactivity, or Marshall DI II. The area under the curve for the logistic regression model that contains all the predictors was 0.86. When high ICP was defined as > 22 mm Hg, the decision rule performed with a sensitivity of 93.9% (95% CI 85.0%–98.3%), a specificity of 42.3% (95% CI 31.7%–53.6%), a positive predictive value of 55.5% (95% CI 50.7%–60.2%), and a negative predictive value of 90% (95% CI 77.1%–96.0%). The sensitivity of the clinical decision rule improved with higher ICP cutoffs up to a sensitivity of 100% when intracranial hypertension was defined as ICP > 30 mm Hg. Similar results were found in the North American cohort.


A simple clinical decision rule based on a combination of clinical and imaging findings was found to be highly sensitive in distinguishing patients with severe TBI who would suffer intracranial hypertension. It could be used to identify patients who require ICP monitoring in high-resource settings or start ICP-lowering treatment in environments where resource limitations preclude invasive monitoring.

Clinical trial registration no.: NCT02059941 (

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Michael R. Levitt, Brent R. O'Neill, Gisele E. Ishak, Paritosh C. Khanna, Nancy R. Temkin, Richard G. Ellenbogen, Jeffrey G. Ojemann and Samuel R. Browd


Cerebrospinal fluid shunt placement has a high failure rate, especially in patients with small ventricles. Frameless stereotactic electromagnetic image guidance can assist ventricular catheter placement. The authors studied the effects of image guidance on catheter accuracy and shunt survival in children.


Pediatric patients who underwent placement or revision of a frontal ventricular CSF shunt were retrospectively evaluated. Catheters were placed using either anatomical landmarks or image guidance. Preoperative ventricular size and postoperative catheter accuracy were quantified. Outcomes of standard and image-guided groups were compared.


Eighty-nine patients underwent 102 shunt surgeries (58 initial, 44 revision). Image guidance was used in the placement of 56 shunts and the standard technique in 46. Shunt failure rates were not significantly different between the standard (22%) and image-guided (25%) techniques (p = 0.21, log-rank test). Ventricular size was significantly smaller in patients in the image-guided group (p < 0.02, Student t-test) and in the surgery revision group (p < 0.01). Small ventricular size did not affect shunt failure rate, even when controlling for shunt insertion technique. Despite smaller average ventricular size, the accuracy of catheter placement was significantly improved with image guidance (p < 0.01). Shunt accuracy did not affect shunt survival.


The use of image guidance improved catheter tip accuracy compared with a standard technique, despite smaller ventricular size. Failure rates were not dependent on shunt insertion technique, but an observed selection bias toward using image guidance for more at-risk catheter placements showed failure rates similar to initial surgeries.

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Nancy R. Temkin, Sureyya S. Dikmen, Gail D. Anderson, Alan J. Wilensky, Mark D. Holmes, Wendy Cohen, David W. Newell, Pamela Nelson, Asaad Awan and H. Richard Winn

Object. Seizures frequently accompany moderate to severe traumatic brain injury. Phenytoin and carbamazepine are effective in preventing early, but not late, posttraumatic seizures. In this study the authors compare the safety and effectiveness of valproate with those of short-term phenytoin for prevention of seizures following traumatic brain injury.

Methods. The study was a randomized, double-blind, single-center, parallel-group clinical trial. Treatment began within 24 hours of injury. One hundred thirty-two patients at high risk for seizures were assigned to receive a 1-week course of phenytoin, 120 were assigned to receive a 1-month course of valproate, and 127 were assigned to receive a 6-month course of valproate. The cases were followed for up to 2 years.

The rates of early seizures were low and similar when using either valproate or phenytoin (1.5% in the phenytoin treatment group and 4.5% in the valproate arms of the study; p = 0.14, relative risk [RR] = 2.9, 95% confidence interval [CI] 0.7–13.3). The rates of late seizures did not differ among treatment groups (15% in patients receiving the 1-week course of phenytoin, 16% in patients receiving the 1-month course of valproate, and 24% in those receiving the 6-month course of valproate; p = 0.19, RR = 1.4, 95% CI 0.8–2.4). The rates of mortality were not significantly different between treatment groups, but there was a trend toward a higher mortality rate in patients treated with valproate (7.2% in patients receiving phenytoin and 13.4% in those receiving valproate; p = 0.07, RR = 2.0, 95% CI 0.9–4.1). The incidence of serious adverse events, including coagulation problems and liver abnormalities, was similar in phenytoin- and valproate-treated patients.

Conclusions. Valproate therapy shows no benefit over short-term phenytoin therapy for prevention of early seizures and neither treatment prevents late seizures. There was a trend toward a higher mortality rate among valproate-treated patients. The lack of additional benefit and the potentially higher mortality rate suggest that valproate should not be routinely used for the prevention of posttraumatic seizures.

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