Carl E. Johnson

Extent of Microstructural White Matter Injury in Postconcussive Syndrome Correlates with Impaired Cognitive Reaction Time: A 3T Diffusion Tensor Imaging Study of Mild Traumatic Brain Injury

BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) may be a useful index of microstructural changes implicated in diffuse axonal injury (DAI) linked to persistent postconcussive symptoms, especially in mild traumatic brain injury (TBI), for which conventional MR imaging techniques may lack sensitivity. We hypothesized that for mild TBI, DTI measures of DAI would correlate with impairments in reaction time, whereas the number of focal lesions on conventional 3T MR imaging would not. MATERIALS AND METHODS: Thirty-four adult patients with mild TBI with persistent symptoms were assessed for DAI by quantifying traumatic microhemorrhages detected on a conventional set of T2*-weighted gradient-echo images and by DTI measures of fractional anisotropy (FA) within a set of a priori regions of interest. FA values 2.5 SDs below the region average, based on a group of 26 healthy control adults, were coded as exhibiting DAI. RESULTS: DTI measures revealed several predominant regions of damage including the anterior corona radiata (41% of the patients), uncinate fasciculus (29%), genu of the corpus callosum (21%), inferior longitudinal fasciculus (21%), and cingulum bundle (18%). The number of damaged white matter structures as quantified by DTI was significantly correlated with mean reaction time on a simple cognitive task (r = 0.49, P = .012). In contradistinction, the number of traumatic microhemorrhages was uncorrelated with reaction time (r = −0.08, P = .71). CONCLUSION: Microstructural white matter lesions detected by DTI correlate with persistent cognitive deficits in mild TBI, even in populations in which conventional measures do not. DTI measures may thus contribute additional diagnostic information related to DAI.

Diagnostic Accuracy of CT Angiography and CT Perfusion for Cerebral Vasospasm: A Meta-Analysis

BACKGROUND AND PURPOSE: In recent years, the role of CTA and CTP for vasospasm diagnosis in the setting of ASAH has been the subject of many research studies. The purpose of this study was to perform a meta-analysis of the diagnostic performance of CTA and CTP for vasospasm in patients with ASAH by using DSA as the criterion standard. MATERIALS AND METHODS: The search strategy for research studies was based on the Cochrane Handbook for Systematic Reviews, including literature data bases (PubMed, Embase, Cochrane Database of Systematic Reviews, and the Web of Science) and reference lists of manuscripts published from January 1996 to February 2009. The inclusion criteria were the following: 1) published manuscripts, 2) original research studies with prospective or retrospective data, 3) patients with ASAH, 4) CTA or CTP as the index test, and 5) DSA as the reference standard. Three reviewers independently assessed the quality of these research studies by using the QUADAS tool. Pooled estimates of sensitivity, specificity, LR+, LR−, DOR, and the SROC curve were determined. RESULTS: CTA and CTP searches yielded 505 and 214 manuscripts, respectively. Ten research studies met inclusion criteria for each CTA and CTP search. Six CTA and 3 CTP studies had sufficient data for statistical analysis. CTA pooled estimates had 79.6% sensitivity (95%CI, 74.9%–83.8%), 93.1%specificity (95%CI, 91.7%–94.3%), 18.1 LR+ (95%CI, 7.3–45.0), and 0.2 LR− (95%CI, 0.1–0.4); and CTP pooled estimates had 74.1% sensitivity (95%CI, 58.7%- 86.2%), 93.0% specificity (95% CI, 79.6%–98.7%), 9.3 LR+ (95%CI, 3.4–25.9), and 0.2 LR− (95%CI, 0.04–1.2). Overall DORs were 124.5 (95%CI, 28.4–546.4) for CTA and 43.0 (95%CI, 6.5–287.1) for CTP. Area under the SROC curve was 98 ± 2.0%for CTA and 97 ± 3.0% for CTP. CONCLUSIONS: The high diagnostic accuracy determined for both CTA and CTP in this meta-analysis suggests that they are potentially valuable techniques for vasospasm diagnosis in ASAH. Awareness of these results may impact patient care by providing supportive evidence for more effective use of CTA and CTP imaging in ASAH.

Using Quantitative CT Perfusion for Evaluation of Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage

BACKGROUND AND PURPOSE: DCI is a serious complication following aneurysmal SAH leading to permanent neurologic deficits, infarction, and death. Our aim was to prospectively evaluate the diagnostic accuracy of CTP and to determine a quantitative threshold for DCI in aneurysmal SAH. MATERIALS AND METHODS: Patients with SAH were prospectively enrolled in a protocol approved by the institutional review board. CTP was performed during the typical time period for DCI, between days 6 and 8 following SAH. Quantitative CBF, CBV, and MTT values were obtained by using standard region-of-interest placement sampling of gray matter. The reference standard for DCI is controversial and consisted of clinical and imaging criteria in this study. In a subanalysis of vasospasm, DSA was used as the reference standard. ROC curves determined the diagnostic accuracy by using AUC. Optimal threshold values were calculated by using the patient population utility method. RESULTS: Ninety-seven patients were included; 41% (40/97) had DCI. Overall diagnostic accuracy was 93% for CBF, 88% for MTT, and 72% for CBV. Optimal threshold values were 35 mL/100 g/min (90% sensitivity, 68% specificity) for CBF and 5.5 seconds (73% sensitivity, 79% specificity) for MTT. In the subanalysis (n = 57), 63% (36/57) had vasospasm. Overall diagnostic accuracy was 94% for CBF, 85% for MTT, and 72% for CBV. Optimal threshold values were 36.5 mL/100 g/min (95% sensitivity, 70% specificity) for CBF and 5.4 seconds (78% sensitivity, 70% specificity) for MTT. CONCLUSIONS: CBF and MTT have the highest overall diagnostic accuracy. Threshold values of 35 mL/100 g/min for CBF and 5.5-second MTT are suggested for DCI on the basis of the patient population utility method. Absolute threshold values may not be generalizable due to differences in scanner equipment and postprocessing methods.

Natural Suppression of Human Immunodeficiency Virus Type 1 Replication Is Mediated by Transitional Memory CD8+ T Cells

ABSTRACT HIV replication is suppressed in vitro by a CD8+ cell noncytotoxic antiviral response (CNAR). This activity directly correlates with an asymptomatic clinical state. The objective of this study was to identify the phenotype of CD8+ cell subsets having strong CNAR activity. CD8+ cell subset frequencies and CNAR levels were measured for human immunodeficiency virus (HIV)-uninfected individuals and three groups of HIV type 1 (HIV-1)-infected individuals: asymptomatic individuals with low-level viremia (vHIV), antiretroviral-drug-treated subjects with undetectable virus levels (TxHIV), and therapy-naïve aviremic elite controllers (EC). CD8+ cells from the vHIV individuals exhibited the highest HIV-suppressing activity and had elevated frequencies of CD45RA− CD27+ and PD-1+ (CD279+) cells. Functional assessments of CD8+ cells sorted into distinct subsets established that maximal CNAR activity was mediated by CD45RA− CCR7− CD27+ and PD-1+ CD8+ cells. T cell receptor (TCR) repertoire profiles of CD8+ cell subsets having strong CNAR activity exhibited increased perturbations in comparison to those of inactive subsets. Together, these studies suggest that CNAR is driven by HIV replication and that this antiviral activity is associated with oligoclonally expanded activated CD8+ cells expressing PD-1 and having a transitional memory cell phenotype. The findings better describe the identity of CD8+ cells showing CNAR and should facilitate the evaluation of this important immune response in studies of HIV pathogenesis, resistance to infection, and vaccine development.

Evaluating CT perfusion using outcome measures of delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage

Ninety-six patients with SAH were evaluated with CT perfusion for cortical deficits and these were correlated with primary (permanent neurologic deficits and infarctions) and secondary (delayed cerebral ischemia manifesting as clinical deterioration) outcome measures. One-third of patients developed permanent neurologic deficits (78% showed CT perfusion defects), infarctions developed in 18% (88% had perfusion defects), and delayed cerebral ischemia was found in 50% (81% had perfusion defects). The most common perfusion abnormalities were reduced CBF and prolonged MTT. BACKGROUND AND PURPOSE: DCI is a serious complication following aneurysmal SAH and remains a leading cause of morbidity and mortality. Our aim was to evaluate CTP in aneurysmal SAH by using outcome measures of DCI. MATERIALS AND METHODS: This was a retrospective study of consecutive patients with SAH enrolled in a prospective institutional review board–approved clinical accuracy trial. Qualitative CTP deficits were determined by 2 neuroradiologists blinded to clinical and imaging data. Quantitative CTP was performed by using a standardized protocol with region-of-interest placement sampling of the cortex. Primary outcome measures were permanent neurologic deficits and infarction. The secondary outcome measure was DCI, defined as clinical deterioration. CTP test characteristics (95% CI) were determined for each outcome measure. Statistical significance was calculated by using the Fisher exact and Student t tests. ROC curves were generated to determine accuracy and threshold analysis. RESULTS: Ninety-six patients were included. Permanent neurologic deficits developed in 33% (32/96). CTP deficits were seen in 78% (25/32) of those who developed permanent neurologic deficits and 34% (22/64) of those without (P < .0001). CTP deficits had 78% (61%–89%) sensitivity, 66% (53%–76%) specificity, and 53% (39%–67%) positive and 86% (73%–93%) negative predictive values. Infarction occurred in 18% (17/96). CTP deficits were seen in 88% (15/17) of those who developed infarction and 41% (32/79) of those without (P = .0004). CTP deficits had an 88% (66%–97%) sensitivity, 59% (48%–70%) specificity, and 32% (20%–46%) positive and 96% (86%–99%) negative predictive values. DCI was diagnosed in 50% (48/96). CTP deficits were seen in 81% (39/48) of patients with DCI and in 17% (8/48) of those without (P < .0001). CTP deficits had 81% (68%–90%) sensitivity, 83% (70%–91%) specificity, and 83% (70%–91%) positive and 82% (69%–90%) negative predictive values. Quantitative CTP revealed significantly reduced CBF and prolonged MTT for DCI, permanent neurologic deficits, and infarction. ROC analysis showed that CBF and MTT had the highest accuracy. CONCLUSIONS: CTP may add prognostic information regarding DCI and poor outcomes in aneurysmal SAH.

Surveillance after resection of vestibular schwannoma: measurement techniques and predictors of growth.

Objectives To compare different methods of measuring tumor growth after resection of vestibular schwannoma and to identify predictors of growth. Study Design Retrospective case review. Setting Tertiary referral center, inpatient surgery with ambulatory follow-up. Patients All patients who underwent vestibular schwannoma resection by the senior author from September 1991 to April 2012 and had two or more postoperative MRI scans. Interventions Vestibular schwannoma resection. Measurement of tumor size and enhancement pattern on postoperative magnetic resonance imaging scans. Main Outcome Measures Tumor size as measured in one (linear), two (planar), and three (volumetric) dimensions using standard radiology workstation tools versus time elapsed since surgical resection. Results Eighty-eight patients were included with mean follow-up of 3.9 years. Linear measurement of tumor size was found to have modest correlation with planar and volumetric measurements. Excellent correlation was found between the planar and volumetric methods. Nodular enhancement increased risk for tumor growth (OR 6.25, p = 0.03 on planar analysis). If there was growth, tumors with nodular enhancement typically showed increase in size beginning 2 years postoperatively, whereas those with linear or no enhancement were typically stable in size through 5 years. Younger age and larger preoperative tumor size were also risk factors for growth (OR 0.9/p = 0.01 and OR 1.09/p = 0.02). Conclusion Simple planar measurement is an efficient method that correlates well with the more time-consuming volumetric method. The major risk factor for tumor growth is nodular enhancement on a baseline scan, a finding that warrants annual MRI beginning 2 years postoperatively. Younger age and larger preoperative size minimally increased risk of growth.

Appropriate Use of CT Perfusion following Aneurysmal Subarachnoid Hemorrhage: A Bayesian Analysis Approach

These investigators evaluated the test characteristics of CTP in patients with SAH for detection of delayed cerebral ischemia. Ninety-seven patients were assessed with CTP for ischemia and with DSA for vasospasm. The authors concluded that positive CTP findings identified patients who should be carefully considered for induced hypertension, hypervolemia, and hemodilution and/or intra-arterial therapy while negative CTP findings are useful in guiding a no-treatment decision. BACKGROUND AND PURPOSE: In recent years CTP has been used as a complementary diagnostic tool in the evaluation of delayed cerebral ischemia and vasospasm. Our aim was to determine the test characteristics of CTP for detecting delayed cerebral ischemia and vasospasm in SAH, and then to apply Bayesian analysis to identify subgroups for its appropriate use. MATERIALS AND METHODS: Our retrospective cohort comprised consecutive patients with SAH and CTP performed between days 6 and 8 following aneurysm rupture. Delayed cerebral ischemia was determined according to primary outcome measures of infarction and/or permanent neurologic deficits. Vasospasm was determined by using DSA. The test characteristics of CTP and its 95% CIs were calculated. Graphs of conditional probabilities were constructed by using Bayesian techniques. Local treatment thresholds (posttest probability of delayed cerebral ischemia needed to initiate induced hypertension, hypervolemia, and hemodilution or intra-arterial therapy) were determined via a survey of 6 independent neurologists. RESULTS: Ninety-seven patients with SAH were included in the study; 39% (38/97) developed delayed cerebral ischemia. Qualitative CTP deficits were seen in 49% (48/97), occurring in 84% (32/38) with delayed cerebral ischemia and 27% (16/59) without. The sensitivity, specificity, and positive and negative predictive values (95% CI) for CTP were 0.84 (0.73–0.96), 0.73 (0.62–0.84), 0.67 (0.51–0.79), and 0.88 (0.74–0.94), respectively. A subgroup of 57 patients underwent DSA; 63% (36/57) developed vasospasm. Qualitative CTP deficits were seen in 70% (40/57), occurring in 97% (35/36) with vasospasm and 23% (5/21) without. The sensitivity, specificity, and positive and negative predictive values (95% CI) for CTP were 0.97 (0.92–1.0), 0.76 (0.58–0.94), 0.88 (0.72–0.95), and 0.94 (0.69–0.99), respectively. Treatment thresholds were determined as 30% for induced hypertension, hypervolemia, and hemodilution and 70% for intra-arterial therapy. CONCLUSIONS: Positive CTP findings identify patients who should be carefully considered for induced hypertension, hypervolemia, and hemodilution and/or intra-arterial therapy while negative CTP findings are useful in guiding a no-treatment decision.

Transfection optimization for primary human CD8+ cells

Electroporation, a non-virus-mediated gene transfection method, has traditionally had poor outcomes with low gene transfection efficiency and poor cellular viability, particularly in primary human lymphocytes. Herein we have optimized the electroporation conditions for primary CD8+ cells resulting in a maximum rate of 81.3%, and a mean transfection efficiency of 59.6%. After removal of dead cells, the viability of transfected primary CD8+ cells was greater than 90%, similar to untransfected controls. Using this procedure, primary human CD8+ cells transfected with an interferon α8 plasmid produced fluids that inhibited HIV-1 replication by > 95%. This transfection protocol is useful for transfection of other primary blood cells, such as CD4+ T cells, and for studying the function of genes in primary human blood cells instead of cell lines. The transfection procedure also has potential application in gene therapy clinical trials to treat diseases utilizing transfected primary human cells.