Orhan Nalcioglu

Epileptogenesis provoked by prolonged experimental febrile seizures: mechanisms and biomarkers

Whether long febrile seizures (FSs) can cause epilepsy in the absence of genetic or acquired predisposing factors is unclear. Having established causality between long FSs and limbic epilepsy in an animal model, we studied here if the duration of the inciting FSs influenced the probability of developing subsequent epilepsy and the severity of the spontaneous seizures. We evaluated if interictal epileptifom activity and/or elevation of hippocampal T2 signal on magnetic resonance image (MRI) provided predictive biomarkers for epileptogenesis, and if the inflammatory mediator interleukin-1β (IL-1β), an intrinsic element of FS generation, contributed also to subsequent epileptogenesis. We found that febrile status epilepticus, lasting an average of 64 min, increased the severity and duration of subsequent spontaneous seizures compared with FSs averaging 24 min. Interictal activity in rats sustaining febrile status epilepticus was also significantly longer and more robust, and correlated with the presence of hippocampal T2 changes in individual rats. Neither T2 changes nor interictal activity predicted epileptogenesis. Hippocampal levels of IL-1β were significantly higher for >24 h after prolonged FSs. Chronically, IL-1β levels were elevated only in rats developing spontaneous limbic seizures after febrile status epilepticus, consistent with a role for this inflammatory mediator in epileptogenesis. Establishing seizure duration as an important determinant in epileptogenesis and defining the predictive roles of interictal activity, MRI, and inflammatory processes are of paramount importance to the clinical understanding of the outcome of FSs, the most common neurological insult in infants and children.

MRI evaluation of pathologically complete response and residual tumors in breast cancer after neoadjuvant chemotherapy

This study investigated the role of magnetic resonance imaging (MRI) in evaluation of pathologically complete response and residual tumors in patients who were receiving neoadjuvant chemotherapy (NAC) for both positive and negative HER‐2 breast cancer.

Development of a quantitative method for analysis of breast density based on three-dimensional breast MRI.

Breast density has been established as an independent risk factor associated with the development of breast cancer. It is known that an increase of mammographic density is associated with an increased cancer risk. Since a mammogram is a projection image, different body position, level of compression, and the x-ray intensity may lead to a large variability in the density measurement. Breast MRI provides strong soft tissue contrast between fibroglandular and fatty tissues, and three-dimensional coverage of the entire breast, thus making it suitable for density analysis. To develop the MRI-based method, the first task is to achieve consistency in segmentation of the breast region from the body. The method included an initial segmentation based on body landmarks of each individual woman, followed by fuzzy C-mean (FCM) classification to exclude air and lung tissue, B-spline curve fitting to exclude chest wall muscle, and dynamic searching to exclude skin. Then, within the segmented breast, the adaptive FCM was used for simultaneous bias field correction and fibroglandular tissue segmentation. The intraoperator and interoperator reproducibility was evaluated using 11 selected cases covering a broad spectrum of breast densities with different parenchymal patterns. The average standard deviation for breast volume and percent density measurements was in the range of 3%-4% among three trials of one operator or among three different operators. The body position dependence was also investigated by performing scans of two healthy volunteers, each at five different positions, and found the variation in the range of 3%-4%. These initial results suggest that the technique based on three-dimensional MRI can achieve reasonable consistency to be applied in longitudinal follow-up studies to detect small changes. It may also provide a reliable method for evaluating the change of breast density for risk management of women, or for evaluating the benefits/risks when considering hormonal replacement therapy or chemoprevention.

Correlation of dynamic contrast enhancement MRI parameters with microvessel density and VEGF for assessment of angiogenesis in breast cancer

To investigate the association between parameters obtained from dynamic contrast enhanced MRI (DCE‐MRI) of breast cancer using different analysis approaches, as well as their correlation with angiogenesis biomarkers (vascular endothelial growth factor and vessel density).

Predicting Pathologic Response to Neoadjuvant Chemotherapy in Breast Cancer by Using MR Imaging and Quantitative 1H MR Spectroscopy

PURPOSE To compare changes in the concentration of choline-containing compounds (tCho) and in tumor size at follow-up after neoadjuvant chemotherapy (NAC) between patients who achieved pathologic complete response (pCR) and those who did not (non-pCR). MATERIALS AND METHODS This study was approved by the institutional review board and was compliant with HIPAA; each patient gave informed consent. Thirty-five patients (mean age, 48 years +/- 11 [standard deviation]; range, 29-75 years) with breast cancer were included. Treatment included doxorubicin and cyclophosphamide followed by a taxane-based regimen. Changes in tCho and tumor size in pCR versus non-pCR groups were compared by using the two-way Mann-Whitney nonparametric test. Receiver operating characteristic (ROC) analysis was performed to differentiate between them and the area under the ROC curve (AUC) was compared. RESULTS In the pCR group, the tCho level change was greater compared with change in tumor size (P = .003 at first follow-up, P = .01 at second follow-up), but they were not significantly different in the non-pCR group. Changes in tumor size and tCho level at the first follow-up study were not significantly different between the pCR and non-pCR groups but reached significance at the second follow-up. In ROC analysis, the magnetic resonance (MR) imaging and MR spectroscopic parameters had AUCs of 0.65-0.68 at first follow-up; at second follow-up, AUC for change in tumor size was 0.9, AUC for change in tCho was 0.73. CONCLUSION Patients who show greater reduction in tCho compared with changes in tumor size are more likely to achieve pCR. The change in tumor size halfway through therapy was the most accurate predictor of pCR.

In vivo quantification of optical contrast agent dynamics in rat tumors by use of diffuse optical spectroscopy with magnetic resonance imaging coregistration

We present a study of the dynamics of optical contrast agents indocyanine green (ICG) and methylene blue (MB) in an adenocarcinoma rat tumor model. Measurements are conducted with a combined frequency-domain and steady-state optical technique that facilitates rapid measurement of tissue absorption in the 650-1000-nm spectral region. Tumors were also imaged by use of contrast-enhanced magnetic resonance imaging (MRI) and coregistered with the location of the optical probe. The absolute concentrations of contrast agent, oxyhemoglobin, deoxyhemoglobin, and water are measured simultaneously each second for approximately 10 min. The differing tissue uptake kinetics of ICG and MB in these late-stage tumors arise from differences in their effective molecular weights. ICG, because of its binding to plasma proteins, behaves as a macromolecular contrast agent with a low vascular permeability. A compartmental model describing ICG dynamics is used to quantify physiologic parameters related to capillary permeability. In contrast, MB behaves as a small-molecular-weight contrast agent that leaks rapidly from the vasculature into the extravascular, extracellular space, and is sensitive to blood flow and the arterial input function.

Magnetic resonance imaging of anatomic and vascular characteristics in a canine model of human aging

Dogs exhibit both neuroanatomical and cognitive changes as a function of age that parallel those seen in aging humans. This study describes in vivo changes in neuroanatomical and cerebrovascular characteristics of the canine brain as a function of age in a group of dogs ranging from 4 to 15 years old. Dynamic contrast-enhanced magnetic resonance imaging (MRI) was used to measure the kinetics of contrast agents in the brain. Measures of vascular volume and blood-brain barrier (BBB) permeability were derived from a pharmacokinetic analysis. Cortical atrophy and ventricular enlargement were characteristic features of the aged canine brain. Vascular volume did not vary as a function of age and BBB permeability exhibited a nonsignificant increasing trend with age. However, BBB dysfunction was detected in one middle-aged dog that in addition to having unusually large ventricles, demonstrated an early onset of diffuse senile plaques at postmortem. These findings indicate that BBB dysfunction detected by magnetic resonance imaging may be useful for predicting and potentially diagnosing early pathological conditions.

The effects of random directional distributed flow in nuclear magnetic resonance imaging.

Capillary flow or microscopic random directional coherent flow as a model of perfusion is investigated both theoretically and experimentally. In the model, we assumed that molecular motion within a finite resolvable volume element (voxel) is a superposition of flow of randomly oriented small capillaries. In such a case, the observed signal from the capillary flow within a voxel will be attenuated in signal amplitude without any change in phase. Although this attenuation effect is similar to the diffusion phenomenon, it differs basically in the following aspects: since the motion in each capillary segment is coherent, phase cancellation occurs at even echoes due to spin rephasing, while the diffusion phenomenon is a purely random Brownian motion of the thermally agitated molecules, changing both in direction and speed during the measurement period. Because of the random character of diffusion, even-echo rephasing cannot be observed. Thus capillary flow or perfusionlike microscopic flow can be measured based on the above distinct flow characteristics, i.e., signal restoration at even echoes versus signal amplitude attenuation at odd echoes. By applying a suitable mathematical algorithm, information on the capillary flow alone can be extracted from the two separate distinct measurements, i.e., one with a single echo and the other with a double echo. Both a theoretical calculation of the capillary flow, as well as the experimental results with a human volunteer by a 0.6-T nuclear magnetic resonance imager, are presented.

The Immune Response to Herpes Simplex Virus Type 1 Infection in Susceptible Mice Is a Major Cause of Central Nervous System Pathology Resulting in Fatal Encephalitis

ABSTRACT This study was undertaken to investigate possible immune mechanisms in fatal herpes simplex virus type 1 (HSV-1) encephalitis (HSE) after HSV-1 corneal inoculation. Susceptible 129S6 (129) but not resistant C57BL/6 (B6) mice developed intense focal inflammatory brain stem lesions of primarily F4/80+ macrophages and Gr-1+ neutrophils detectable by magnetic resonance imaging as early as day 6 postinfection (p.i.). Depletion of macrophages and neutrophils significantly enhanced the survival of infected 129 mice. Immunodeficient B6 (IL-7R−/− Kitw41/w41) mice lacking adaptive cells (B6-E mice) and transplanted with 129 bone marrow showed significantly accelerated fatal HSE compared to B6-E mice transplanted with B6 marrow or control nontransplanted B6-E mice. In contrast, there was no difference in ocular viral shedding in B6-E mice transplanted with 129 or B6 bone marrow. Acyclovir treatment of 129 mice beginning on day 4 p.i. (24 h after HSV-1 first reaches the brain stem) reduced nervous system viral titers to undetectable levels but did not alter brain stem inflammation or mortality. We conclude that fatal HSE in 129 mice results from widespread damage in the brain stem caused by destructive inflammatory responses initiated early in infection by massive infiltration of innate cells.

Serial MRI after experimental febrile seizures: Altered T2 signal without neuronal death

Whereas most febrile seizures (FSs) carry a benign outcome, a subpopulation of individuals with prolonged FSs are at risk for later temporal lobe epilepsy. Signal changes on magnetic resonance imaging (MRI) may provide early markers for changes in neuronal integrity that may promote epileptogenesis in such individuals. Here, we used serial MRIs, obtained before and at several time points after experimental prolonged FSs, to determine the prevalence and distribution of signal changes on T2‐weighted images and to investigate the pathological substrates leading to these changes. Seventy‐five percent of immature rats with experimental prolonged FSs had abnormal T2 signal enhancement at 24 hours, and 87.5% at 8 days after the seizures. The altered T2 values involved the dorsal hippocampus (75%), the piriform cortex (87.5%), and the amygdala (25%). However, these changes were not accompanied by evidence of neuronal injury or death in these regions, as assessed using the Fluoro‐Jade method. Thus, experimental prolonged FSs lead to relatively frequent abnormal MRI signal in “temporal lobe” structures. Although these changes do not signify cell death, they may denote pathological cellular processes that promote epileptogenesis. Ann Neurol 2004