Walter A. Hall

Pituitary magnetic resonance imaging in normal human volunteers: occult adenomas in the general population.

Magnetic resonance imaging (MRI) at 1.5 tesla, combined with the use of the paramagnetic contrast agent, gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA), enhances the capacity to visualize the pituitary gland and to screen patients for pituitary adenomas. However, in autopsy series of unselected humans, the prevalence of silent pituitary adenomas was estimated to be 3% to 27% [1-5]. If there is a substantial prevalence of occult pituitary adenomas detected by MRI in the general population, the usefulness of MRI as a screening test or as a method to confirm the pituitary cause of endocrinopathy is compromised. To determine the prevalence of focal pituitary lesions compatible with the diagnosis of a pituitary adenoma in humans with normal endocrine function, we did MRI scans of the pituitary gland before and after administration of Gd-DTPA in 100 volunteers. Methods Seventy women and 30 men, 18 to 60 years old, were recruited from the general population and the normal-volunteers office of the National Institutes of Health. The volunteers had normal physical examinations and were selected by age and sex to correspond to the distribution of patients with symptomatic pituitary adenomas [6, 7]. Fifty-eight of the women (83%) were between 20 and 45 years old, and 27 of the men (90%) were between 30 and 60 years old. Random basal values of serum prolactin and -subunit, plasma growth hormone, thyroid-stimulating hormone, thyroxine, triiodothyronine, free thyroxine, and thyroxine-binding globulin were measured. Young women selected for the study had normal menstrual cycles. Persons with previous or current endocrine disturbances were excluded. The protocol was approved by the Investigational Review Board of the National Institute of Neurological Disorders and Stroke, and all participants gave informed consent. Magnetic Resonance Imaging All scans were obtained with a 1.5-T scanner (Sigma, General Electric; Milwaukee, Wisconsin). T1-weighted coronal and sagittal images of the pituitary fossa were obtained with a repetition time (TR) of 600 ms and an echo time (TE) of 15 ms (TR/TE = 600/15). In the coronal plane, interleaved sections 3 mm in thickness without intersection gap were obtained with two repetitions and a 16-cm field of view. The acquisition matrix was 256 192. Gadolinium-DTPA (0.1 mmol/kg body weight) was administered intravenously over 2 minutes, and the T1-weighted coronal images were repeated immediately (Figure 1). Figure 1. Pituitary magnetic resonance scan of a normal volunteer. Left. Right. Evaluation of Pituitary Glands Magnetic resonance scans were interpreted independently by three experienced reviewers. The scans of the normal volunteers were randomly mixed with scans of 57 patients with surgically confirmed Cushing disease. The reviewers were aware that the scans of the patients had been intermingled with those of the volunteers. Identifying information for patients and volunteers was masked. Reviewers evaluated the pituitary gland before and after the administration of Gd-DTPA by appraising gland and sellar size, stalk deviation, gland convexity, and position and size of focal pituitary abnormalities. Measurements were made with hand-held calipers. The readers also provided a summary interpretation of each MRI scan. The diagnosis of a pituitary abnormality, including the presence of an adenoma, was accepted only when the same area of the gland was independently interpreted as similarly abnormal by at least two of the three reviewers. Results Pituitary Gland Magnetic Resonance Scans in Normal Volunteers Pituitary Size and Shape The mean gland height in the 100 volunteers was 6.9 0.1 mm. It was greater in women (7.1 1.3 mm; mean SD) than in men (6.6 1.2 mm; P = 0.008). On coronal scans, the superior surface of the gland was convex upward in 33 persons (29 women). Upward convexity of the superior surface of the gland was limited to one side in 21 persons (12 right, 10 left) and occurred centrally in 11. The posterior pituitary gland was identified as a small focus of high-signal intensity in the posterior sella by at least two reviewers in 92 persons (by three reviewers in 77). One participant was considered to have an enlarged sella. Fifty-nine volunteers were interpreted by all three reviewers as having a normal pituitary gland. In 3, cerebrospinal fluid filled the superior portion of the sella (partially empty sella). Focal Pituitary Abnormalities Before Gd-DTPA was administered, 22 sites of focal abnormal signal intensity in the pituitary were detected by at least one reviewer in 21 volunteers (Table 1). All three reviewers considered the same site as an adenoma (by the presence of an area of low-signal intensity) in 1 person. Seven (6 women, 1 man) had focal areas of decreased signal, which were interpreted by at least two of the three reviewers as adenomas. Fourteen sites in 13 persons were considered abnormal by a single reviewer. Table 1. Pituitary Magnetic Resonance Imaging in 100 Normal Women and Men After Gd-DPTA was administered, 41 different sites of abnormal signal intensity in the pituitary gland were detected in 34 volunteers. Ten of them (7 women, 3 men) had focal areas of decreased signal intensity that were interpreted as pituitary adenomas by at least two reviewers. All three reviewers considered the same site as an adenoma in 2 persons. Six of the 7 women were 25 to 45 years old (1 was 48 years old) and the men were 22, 35, and 53 years old. The lesions were 3 3 mm to 6 6 mm in diameter (coronal plane). Thirty-two sites in 23 participants were considered abnormal by a single reviewer. The scan of only 1 volunteer interpreted as having an adenoma had stalk deviation. An upward convex shape of the superior surface of the pituitary gland occurred in 8 of the 10 volunteers considered to have an adenoma. However, in only five of these studies was the elevation on the side of the lesion. Endocrine Screening Tests The endocrine studies done were normal in the 10 persons with an abnormal MRI scan. In the 90 volunteers whose MRI scans were interpreted as normal, 3 (1 woman, 41 years old; 2 men, 37 and 48 years old) had evidence of mild primary hypothyroidism. Three women (33, 34, and 44 years old) had elevated growth hormone levels (>10 g/L; single random sample). Pituitary Gland Magnetic Resonance Scans in Patients with Cushing Disease Cushing disease was confirmed by adrenocorticotropin staining of an adenoma or by remission of hypercortisolism after selective adenomectomy or hemihypophysectomy. Five macroadenomas and 45 microadenomas were identified at surgery in the 57 patients with Cushing disease. In the 50 patients with adenomas identified at surgery, 56% (all patients with macroadenomas and 51% of 45 patients with microadenomas) had areas of focal low-signal intensity after administration of Gd-DTPA that were diagnosed by at least two reviewers as adenomas. However, in 4 of the 23 patients with microadenomas and a focal pituitary MRI abnormality, the position of the adenoma in the gland was incorrect as read on the MRI scan. In two patients, the MRI scan indicated a lateral tumor, but the tumor was found in the midline at surgery. In the third patient the reverse occurred, and in the fourth the tumor was found on the opposite side of the gland. Thus, 26 of 45 (58%) of the 45 microadenomas that were large enough to be found and selectively excised at surgery were not detected by MRI. The size of the tumors that were not detected (6 2 mm) did not differ significantly from the size of those that were (5 2 mm). Discussion The configuration of the pituitary gland is influenced by age and sex, the location of the carotid arteries, the shape of the pituitary fossa, transmission of cerebrospinal fluid pulsation into the sella turcica permitted by an incompetent diaphragma sella, and the presence of an intrasellar mass [8-12]. The results of our study of the size and shape of the normal pituitary gland confirm the findings of other studies using computed tomography (CT) or MRI scanning without Gd-DPTA enhancement [11, 12]. A convex contour of the superior surface of the pituitary gland was once considered to be unusual or abnormal [3, 11, 12]. (However), recent studies using CT or MRI scanning found that convex superior contours occur in as many as 35% to 44% of women of childbearing age [9, 12, 13]. An upward convex shape of the superior surface of the pituitary gland occurred in 34% of our 70 women. Deviation of the pituitary stalk also has been suggested as an indirect sign of the presence and site of an adenoma. However, rates of stalk deviation as high as 46% have been reported in normal persons [14]. Stalk deviation occurred in 13% of our volunteers. The 4% incidence of an empty sella in our volunteers agrees with the 3% to 4% prevalence reported by others using CT [3, 12] and MRI [13]. Autopsy series estimate the prevalence of asymptomatic pituitary adenomas to be 1.5% to 27% [1-6]. Microscopic examination of the pituitary gland at autopsy is much more sensitive than contrast-enhanced MRI scanning for detecting adenomas, and immunohistochemical techniques allow direct hormonal assessment of the tissue. However, the prevalence of asymptomatic adenomas in a young adult cohort is unknown because autopsy series do not accurately reflect this population. Young women, the group in which symptomatic pituitary tumors occur most frequently, are under-represented in autopsy studies. Previous imaging techniques, such as plain roentgenography, polytomography, and pneumoencephalography, were unreliable for detecting pituitary microadenomas [1]. Shortly after its introduction, CT scanning became the diagnostic procedure of choice for examining the pituitary gland because it was noninvasive, offered improved resolution, and, for the first time, permitted direct visualization of the pituitary gland. By high-resolution, contrast-enhanced CT scanning, Wolpert and colleagues [12] identified p

Safety and efficacy of a multicenter study using intraarterial chemotherapy in conjunction with osmotic opening of the blood-brain barrier for the treatment of patients with malignant brain tumors.

The aim of this study was to determine the safety and efficacy of intraarterial chemotherapy with osmotic opening of the blood‐brain barrier (BBB) for the treatment of malignant brain tumors when administered across multiple centers.

A Generic Framework for Non-rigid Registration Based on Non-uniform Multi-level Free-Form Deformations

This work presents a framework for non-rigid registration which extends and generalizes a previously developed technique by Rueckert et al. [1]. We combine multi-resolution optimization with free-form deformations (FFDs) based on multi-level B-splines to simulate a non-uniform control point distribution. We have applied this to a number of different medical registration tasks to demonstrate its wide applicability, including interventional MRI brain tissue deformation compensation, breathing motion compensation in liver MRI, intra-modality inter-modality registration of pre-operative brain MRI to CT electrode implant data, and inter-subject registration of brain MRI. Our results demonstrate that the new algorithm can successfully register images with an improved performance, while achieving a significant reduction in run-time.

Chemotherapy Delivery Issues in Central Nervous System Malignancy: A Reality Check

PURPOSE This review assesses the current state of knowledge regarding preclinical and clinical pharmacology for brain tumor chemotherapy and evaluates relevant brain tumor pharmacology studies before October 2006. RESULTS Chemotherapeutic regimens in brain tumor therapy have often emerged from empirical clinical studies with retrospective pharmacologic explanations, rather than prospective trials of rational chemotherapeutic approaches. Brain tumors are largely composed of CNS metastases of systemic cancers. Primary brain tumors, such as glioblastoma multiforme or primary CNS lymphomas, are less common. Few of these tumors have well-defined optimal treatment. Brain tumors are protected from systemic chemotherapy by the blood-brain barrier (BBB) and by intrinsic properties of the tumors. Pharmacologic studies of delivery of conventional chemotherapeutics and novel therapeutics showing actual tumor concentrations and biologic effect are lacking. CONCLUSION In this article, we review drug delivery across the BBB, as well as blood-tumor and -cerebrospinal fluid (CSF) barriers, and mechanisms to increase drug delivery to CNS and CSF tumors. Because of the difficulty in treating CNS tumors, innovative treatments and alternative delivery techniques involving brain/cord capillaries, choroid plexus, and CSF are needed.

Safety, efficacy, and functionality of high-field strength interventional magnetic resonance imaging for neurosurgery

OBJECTIVE Interventional magnetic resonance imaging (MRI) allows neurosurgeons to interactively perform surgery using MRI guidance. High-field strength (1.5-T) imaging permits exceptional observation of intracranial and spinal pathological features. The development of this technology and its application to a variety of neurosurgical procedures are described. METHODS We report on the first 101 cases that were treated in the interventional MRI unit (between January 1997 and September 1998). These cases included 39 brain biopsies, 30 tumor resections, 9 functional neurosurgical cases, 8 cyst drainages, 5 laminectomies, and 10 miscellaneous cases. Patients ranged in age from 14 months to 84 years (median, 43 yr); 61 patients were male and 40 were female. Intraoperative functional techniques that were used to influence surgical decision-making included magnetic resonance spectroscopy, functional MRI, magnetic resonance angiography and venography, chemical shift imaging, and diffusion-weighted imaging. All surgery was performed using MRI-compatible instruments within the 5-gauss line and conventional instruments outside that line. RESULTS All 39 brain biopsies yielded diagnostic tissue. Of the 30 tumor resections, 24 (80%) were considered radiographically complete. The incidence of serious complications was low and was comparable to that associated with conventional operating rooms. One patient developed a Propionibacterium acnes brain abscess 6 weeks after surgery and another patient experienced Staphylococcus aureus scalp cellulitis after a brain biopsy, yielding an infection rate of less than 2%. No clinically significant hemorrhage was observed in immediate postoperative imaging scans, although one patient developed a delayed hematoma after a thalamotomy. One patient experienced a stroke after resection of a hippocampal tumor. No untoward events were associated with MRI-compatible instrumentation or intraoperative patient monitoring. CONCLUSION High-field (1.5-T) interventional MRI is a safe and effective technology for assisting neurosurgeons in achieving the goals of surgery. Preliminary results suggest that the functional capabilities of this technology can yield data that can significantly influence intraoperative neurosurgical decision-making. The rates of serious complications, such as infection, associated with this new technology were low.

Investigation of intraoperative brain deformation using a 1.5-T interventional MR system: preliminary results

All image-guided neurosurgical systems that the authors are aware of assume that the head and its contents behave as a rigid body. It is important to measure intraoperative brain deformation (brain shift) to provide some indication of the application accuracy of image-guided surgical systems, and also to provide data to develop and validate nonrigid registration algorithms to correct for such deformation. The authors are collecting data from patients undergoing neurosurgery in a high-field (1.5 T) interventional magnetic resonance (MR) scanner. High-contrast and high-resolution gradient-echo MR image volumes are collected immediately prior to surgery, during surgery, and at the end of surgery, with the patient intubated and lying on the operating table in the operative position. Here, the authors report initial results from six patients: one freehand biopsy, one stereotactic functional procedure, and four resections. The authors investigate intraoperative brain deformation by examining threshold boundary overlays and difference images and by measuring ventricular volume. They also present preliminary results obtained using a nonrigid registration algorithm to quantify deformation. They found that some cases had much greater deformation than others, and also that, regardless of the procedure, there was very little deformation of the midline, the tentorium, the hemisphere contralateral to the procedure, and ipsilateral structures except those that are within 1 cm of the lesion or are gravitationally above the surgical site.

Postoperative Central Nervous System Infection: Incidence and Associated Factors in 2111 Neurosurgical Procedures

BACKGROUND Postoperative central nervous system infection (PCNSI) in patients undergoing neurosurgical procedures represents a serious problem that requires immediate attention. PCNSI most commonly manifests as meningitis, subdural empyema, and/or brain abscess. Recent studies (which have included a minimum of 1000 operations) have reported that the incidence of PCNSI after neurosurgical procedures is 5%-7%, and many physicians believe that the true incidence is even higher. To address this issue, we examined the incidence of PCNSI in a sizeable patient population. METHODS The medical records and postoperative courses for patients involved in 2111 neurosurgical procedures at our institution during 1991-2005 were reviewed retrospectively to determine the incidence of PCNSI, the identity of offending organisms, and the factors associated with infection. RESULTS The median age of patients at the time of surgery was 45 years. Of the 1587 cranial operations, 14 (0.8%) were complicated by PCNSI, whereas none of the 32 peripheral nerve operations resulted in PCNSI. The remaining 492 operative cases involved spinal surgery, of which 2 (0.4%) were complicated by PCNSI. The overall incidence of PCNSI was 0.8% (occurring after 16 of 2111 operations); the incidence of bacterial meningitis was 0.3% (occurring after 4 of 1587 operations), and the incidence of brain abscess was 0.2% (occurring after 3 of 1587 operations). The most common offending organism was Staphylococcus aureus (8 cases; 50% of infections), followed by Propionibacterium acnes (4 cases; 25% of infections). Cerebrospinal fluid leakage, diabetes mellitus, and male sex were not associated with PCNSI (P>.05). CONCLUSIONS In one of the largest neurosurgical studies to have investigated PCNSI, the incidence of infection after neurosurgical procedures was <1%--more than 6 times lower than that reported in recent series of comparable numerical size. Cerebrospinal fluid leak, diabetes mellitus, and male sex were not associated with an increased incidence of PCNSI. The results from this study indicate that the true incidence of PCNSI after neurosurgical procedures may be greatly overestimated in the literature and that, in surgical procedures associated with a high risk of infection, prophylaxis for S. aureus and/or P. acnes infection should be of primary concern.

Stereotactic radiosurgery for recurrent malignant gliomas.

PURPOSE To evaluate the role of stereotactic radiosurgery in the management of recurrent malignant gliomas. PATIENTS AND METHODS We treated 35 patients with large (median treatment volume, 28 cm3) recurrent tumors that had failed to respond to conventional treatment. Twenty-six patients (74%) had glioblastomas multiforme (GBM) and nine (26%) had anaplastic astrocytomas (AA). RESULTS The mean time from diagnosis to radiosurgery was 10 months (range, 1 to 36), from radiosurgery to death, 8.0 months (range, 1 to 23). Twenty-one GBM (81%) and six AA (67%) patients have died. The actuarial survival time for all patients was 21 months from diagnosis and 8 months from radiosurgery. Twenty-two of 26 patients (85%) died of local or marginal failure, three (12%) of noncontiguous failure, and one (4%) of CSF dissemination. Age (P = .0405) was associated with improved survival on multivariate analysis, and age (P = .0110) and Karnofsky performance status (KPS) (P = .0285) on univariate analysis. Histology, treatment volume, and treatment dose were not significant variables by univariate analysis. Seven patients required surgical resection for increasing mass effect a mean of 4.0 months after radiosurgery, for an actuarial reoperation rate of 31%. Surgery did not significantly influence survival. At surgery, four patients had recurrent tumor, two had radiation necrosis, and one had both tumor and necrosis. The actuarial necrosis rate was 14% and the pathologic findings could have been predicted by the integrated logistic formula for developing symptomatic brain injury. CONCLUSION Stereotactic radiosurgery appears to prolong survival for recurrent malignant gliomas and has a lower reoperative rate for symptomatic necrosis than does brachytherapy. Patterns of failure are similar for both of these techniques.

Single dose versus fractionated stereotactic radiotherapy for recurrent high-grade gliomas

PURPOSE To evaluate the efficacy of stereotactic radiotherapy (SRT) in patients with recurrent high-grade gliomas by comparing two different treatment regimens, single dose or fractionated radiotherapy. METHODS AND MATERIALS Between April 1991 and January 1998, 71 patients with recurrent high-grade gliomas were treated with SRT. Forty-six patients (65%) were treated with single dose radiosurgery (SRS) and 25 patients (35 %) with fractionated stereotactic radiotherapy (FSRT). For the SRS group, the median radiosurgical dose of 17 Gy was delivered to the median of 50% isodose surface (IDS) encompassing the target. For the FSRT group, the median dose of 37.5 Gy in 15 fractions was delivered to the median of 85% IDS. RESULTS Actuarial median survival time was 11 months for the SRS group and 12 months for the FSRT group (p = 0.3, log-rank test). Variables predicting longer survival were younger age (p = 0.006), lower grade (p = 0.0006), higher Karnofsky Performance Scale (KPS) (p = 0.0005), and smaller tumor volume (p = 0.02). Patients in the SRS group had more favorable prognostic factors, with median age of 48 years, KPS of 70, and tumor volume of 10 ml versus median age of 53 years, KPS of 60, and tumor volume of 25 ml in the FSRT group. Late complications developed in 14 patients in the SRS group and 2 patients in the FSRT group (p<0.05). CONCLUSION Given that FSRT patients had comparable survival to SRS patients, despite having poorer pretreatment prognostic factors and a lower risk of late complications, FSRT may be a better option for patients with larger tumors or tumors in eloquent structures. Since this is a nonrandomized study, further investigation is needed to confirm this and to determine an optimal dose/fractionation scheme.

Safety, Tolerability, and Tumor Response of IL4-Pseudomonas Exotoxin (NBI-3001) in Patients with Recurrent Malignant Glioma

SummaryPurpose: This was an open-label, dose-escalation trial of intratumoral administration of IL-4Pseudomonas exotoxin (NBI-3001) in patients with recurrent malignant glioma. Patients and methods: A total of 31 patients with histologically verified supratentorial grades 3 and 4 astrocytoma were studied. Of these, 25 patients were diagnosed with glioblastoma multiforme (GBM) while six were diagnosed with anaplastic astrocytoma. Patients were over 18 years of age and had Karnofsky performance scores ≥60. Patients were assigned to one of four dose groups in a dose-escalation fashion: 6 µg/ml × 40 ml, 9 µg/ml × 40 ml, 15 µg/ml × 40 ml, or 9 µg/ml × 100 ml of NBI-3001 administered via convection-enhanced delivery intratumorally using stereotactically placed catheters. Patients were followed with serial MRI scans and clinical assessments every four weeks for the first 16 weeks and then every eight weeks until week 26. Results: No drug-related systemic toxicity, as evident by lack of hematological or serum chemical changes, was apparent in any patients; treatment-related adverse effects were limited to the central nervous system. No deaths were attributable to treatment. Drug-related grade 3 or 4 toxicity was seen in 39% of patients in all dose groups and 22% of patients at the maximum tolerated dose of 6 µg/ml × 40 ml. The overall median survival was 8.2 months with a median survival of 5.8 months for the GBM patients. Six-month survival was 52% and 48%, respectively. Gadolinium-enhanced magnetic resonance imaging of the brain showed areas of decreased signal intensity within the tumor consistent with tumor necrosis following treatment in many patients. Conclusions: NBI-3001 appears to have an acceptable safety and toxicity profile when administered intratumorally in patients with recurrent malignant glioma.