Stephen S. Gebarski

Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing's syndrome

Patients with chronic hypercortisolemia due to Cushings syndrome (CS) exhibit cognitive dysfunction. Because glucocorticoid excess is associated with hippocampal damage in animals, and the hippocampus participates in learning and memory, we explored the relationships between hippocampal formation (HF) volume, memory dysfunction, and cortisol levels in 12 patients with CS. After magnetic resonance imaging, HF volume was determined using digital sum of track ball traces of dentate gyrus, hippocampus proper and subiculum, correcting for total intracranial volume. For 27% of the patients, HF volume fell outside the 95% confidence intervals for normal subject volume given in the literature. In addition, there were significant and specific correlations between HF volume and scores for verbal paired associate learning, verbal recall, and verbal recall corrected for full-scale IQ (r = 0.57 to 0.70, p < 0.05). HF volume was negatively correlated with plasma cortisol levels (r = -0.73, p < 0.05). These studies suggest an association between reduced HF volume, memory dysfunction, and elevated cortisol in patients with CS.

Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing’s disease

BACKGROUND Decreased hippocampal volume is observed in patients with Cushings syndrome and other conditions associated with elevated cortisol levels, stress, or both. Reversibility of hippocampal neuronal atrophy resulting from stress occurs in animals. Our study investigated the potential for reversibility of human hippocampal atrophy. METHODS The study included 22 patients with Cushings disease. Magnetic resonance brain imaging was performed prior to transsphenoidal microadenomectomy and again after treatment. RESULTS Following treatment, hippocampal formation volume (HFV) increased by up to 10%. The mean percent change (3.2 +/- 2.5) was significantly greater (p < .04) than that of the comparison structure, caudate head volume (1.5 +/- 3.4). Increase in HFV was significantly associated with magnitude of decrease in urinary free cortisol (r = -.61, p < .01). This relationship strengthened after adjustments for age, duration of disease, and months elapsed since surgery (r = -.70, p < .001). There was no significant correlation between caudate head volume change and magnitude of cortisol decrease. CONCLUSIONS Changes in human HFV associated with sustained hypercortisolemia are reversible, at least in part, once cortisol levels decrease. While many brain regions are likely affected by hypercortisolemia, the human hippocampus exhibits increased sensitivity to cortisol, affecting both volume loss and recovery.

Survival and Failure Patterns of High-Grade Gliomas After Three-Dimensional Conformal Radiotherapy

PURPOSE The goal of three-dimensional (3-D) conformal radiation is to increase the dose delivered to tumor while minimizing dose to surrounding normal brain. Previously it has been shown that even escalated doses of 70 to 80 Gy have failure patterns that are predominantly local. This article describes the failure patterns and survival seen with high-grade gliomas given 90 Gy using a 3-D conformal intensity-modulated radiation technique. PATIENTS AND METHODS From April 1996 to April 1999, 34 patients with supratentorial high-grade gliomas were treated to 90 Gy. For those that recurred, failure patterns were defined in terms of percentage of recurrent tumor located within the high-dose region. Recurrences with more than 95% of their volume within the high-dose region were considered central; those with 80% to 95%, 20% to 80%, and less than 20% were considered in-field, marginal, and distant, respectively. RESULTS The median age was 55 years, and median follow-up was 11.7 months. At time of analysis, 23 (67.6%) of 34 patients had developed radiographic evidence of recurrence. The patterns of failure were 18 (78%) of 23 central, three (13%) of 23 in-field, two (9%) of 23 marginal, and zero (0%) of 23 distant. The median survival was 11.7 months, with 1-year survival of 47.1% and 2-year survival of 12.9%. No significant treatment toxicities were observed. CONCLUSION Despite dose escalation to 90 Gy, the predominant failure pattern in high-grade gliomas remains local. This suggests that close margins used in highly conformal treatments do not increase the risk of marginal or distant recurrences. Our results indicate that intensification of local radiotherapy with dose escalation is feasible and deserves further evaluation for high-grade gliomas.

Parotid gland sparing in patients undergoing bilateral head and neck irradiation: Techniques and early results.

PURPOSE To minimize xerostomia in patients receiving bilateral head and neck irradiation (RT) by using conformal RT planning to spare a significant volume of one parotid gland from radiation. METHODS AND MATERIALS The study involved 15 patients with head and neck tumors in whom bilateral neck radiation was indicated. The major salivary glands and the targets (tumor, surgical bed, metastases to lymph nodes, and the locations of lymph nodes at risk for metastases) were outlined on axial computed tomography images. Beams-eye view (BEV) displays were used to construct conformal beams that delivered the prescribed doses to the targets while sparing from direct radiation most of one parotid gland. The gland that was planned to be spared resided in the neck side that was judged in each patient to be at a lesser risk of metastatic disease. Major salivary gland flow rates and the responses to a subjective xerostomia questionnaire were assessed before, during, and after radiation. RESULTS Radiation planning for patients with central oropharyngeal tumors required the generation of multiple axial nonopposed beams. The resulting isodoses encompassed the targets, including the retropharyngeal nodes and the jugular nodes up to the base of skull bilaterally, while limiting the dose to the oral cavity, spinal cord, and one parotid gland. For patients with lateralized tumors, the ipsilateral neck side was treated up to the base of the skull; in the contralateral neck side, the treatment included the subdigastric nodes but excluded the jugular nodes at the base of the skull and most of the parotid gland. This was accomplished by a moderate gantry angle that was chosen using the BEV displays. Three months following the completion of radiation, the spared parotid glands retained on average 50% of their unstimulated and stimulated flows. In contrast, no saliva flow was measured from the unspared glands in any of the patients. Subjective xerostomia was absent, mild, or not different from that reported before radiation in 10 of 15 patients (67%). CONCLUSION Partial parotid gland sparing is feasible by using three-dimensional planning in patients undergoing bilateral head and neck radiation. Approximately 50% of the saliva flow from the spared glands may be retained, and most patients thus treated have no or mild xerostomia in the early period after the completion of radiation. Whether tumor control and late complications are comparable to standard radiation will be assessed as more experience is gained.

Improvement in learning associated with increase in hippocampal formation volume

BACKGROUND Patients with spontaneous Cushings syndrome are exposed to elevated levels of endogenous cortisol for months to years. We previously reported that hippocampal formation volume (HFV) increased in such patients after treatment lowered cortisol to normal concentrations. In the present study, we examined whether the structural increase was associated with improvement in cognition. METHODS Twenty-four patients with Cushings disease were studied before treatment and following treatment. Magnetic resonance imaging was used to measure HFV and caudate head volume. Neuropsychologic tests of verbal cognition, learning, and memory were also administered. RESULTS Patients showed variability in improvement on neuropsychologic test performance. After partialing out age, education, duration of illness, and time since surgical treatment, greater improvement in word list learning, as measured by the Selective Reminding Test was associated with greater increase in HFV (r =.59, p <.02). There were no significant associations between improvement in paragraph or paired-word learning or memory tasks and increase in HFV. Improvement in other verbal tasks not strongly dependent on the hippocampus were not significantly associated with increase in HFV. CONCLUSIONS After cortisol levels decline to normal concentrations, structural volumetric increase in HFV is accompanied by functional improvement in learning of unrelated words.

Diffusion MRI: A new strategy for assessment of cancer therapeutic efficacy

The use of anatomical imaging in clinical oncology practice traditionally relies on comparison of patient scans acquired before and following completion of therapeutic intervention. Therapeutic success is typically determined from inspection of gross anatomical images to assess changes in tumor size. Imaging could provide significant additional insight into therapeutic impact if a specific parameter or combination of parameters could be identified which reflect tissue changes at the cellular or physiologic level. This would provide an early indicator or treatment response/outcome in an individual patient before completion of therapy. Moreover, response of a tumor to therapeutic intervention may be heterogeneous. The use of imaging could assist in delineating therapeutic-induced spatial heterogeneity within a tumor mass by providing information related to specific regions that are resistant or responsive to treatment. Largely untapped potential resides in exploratory methods such as diffusion MRI, which is a nonvolumetric intravoxel measure of tumor response based upon water molecular mobility. Alterations in water mobility reflect changes in tissue structure at the cellular level. While the clinical utility of diffusion MRI for oncologic practice is still under active investigation, this overview on the use of diffusion MRI for the evaluation of brain tumors will serve to introduce how this approach may be applied in the future for the management of patients with solid tumors.

Integration of magnetic resonance imaging into radiation therapy treatment planning: i. technical considerations

This paper presents the results of a feasibility study specifically addressing the technical and operational difficulties in making quantitative use of Magnetic Resonance Imaging (MRI) in radiation therapy treatment planning (RTTP). Selected radiotherapy patients have been studied with both CT and MRI as part of the treatment planning process. Both sets of images, along with mechanically-obtained external contour and simulator film data, are entered into the treatment planning system. All of the capabilities of the fully three dimensional planning system U-MPlan are available to both the CT and MRI images, in which any image can be used as the backdrop for interactive beam positioning, beam portal simulation, and dose distribution displays for external beam and brachytherapy applications in both 2- and 3-dimensionally-oriented displays. The study has shown that to use MRI data for RTTP, one must (a) use careful patient positioning and marking, (b) transfer information from CT to MRI and vice versa, (c) determine the geometrical consistency between the CT and MR data sets, (d) investigate the unwarping of distorted MR images, and (e) have the ability to use non-axial images for determination of beam treatment technique, dose calculations, and plan evaluation.

Familial Large Vestibular Aqueduct Syndrome

The large vestibular aqueduct syndrome (LVAS) is a distinct clinical entity characterized by stepwise progressive sensorineural hearing loss associated with isolated enlargement of the vestibular aqueduct.

Pentobarbital vs chloral hydrate for sedation of children undergoing MRI: efficacy and recovery characteristics.

Background : Chloral hydrate (CH) sedation for magnetic resonance imaging (MRI) is associated with significant failure rates, adverse events and delayed recovery. Pentobarbital (PB), reportedly produces successful sedation in 98% of children undergoing diagnostic imaging. This study compared the efficacy, adverse events and recovery characteristics of CH vs PB in children undergoing MRI.

Patterns of cognitive change over time and relationship to age following successful treatment of Cushing's disease

Chronically elevated levels of cortisol have been associated with changes in cognitive functioning and brain morphology. Using Cushings disease as a model to assess the effects of high levels of cortisol on cognitive functioning, 27 patients with Cushings disease were examined at baseline and three successive follow-up periods up to 18 months after successful surgical treatment. At all follow-up periods, patients were administered cognitive tests as well as measures of plasma and urinary free cortisol. Structural MRIs and a depression measure were taken at baseline and one-year follow-up. Results showed that there is a specific pattern of significant cognitive and morphological improvement following successful treatment. Verbal fluency and recall showed recovery, although brief attention did not. Age of participants was a significant factor as to when recovery of function occurred; younger patients regained and sustained their improvement in cognitive functioning more quickly than older participants. Improvement in verbal recall also was associated with a decrease in cortisol levels as well as an increase in hippocampal formation volume one year after treatment. Overall, these findings suggest that at least some of the deleterious effects of prolonged hypercortisolemia on cognitive functioning are potentially reversible, up to at least 18 months post treatment.