George S. Allen

Evaluating Contrast-Enhancing Brain Lesions in Patients with AIDS by Using Positron Emission Tomography

As many as 80% of patients with the acquired immunodeficiency syndrome (AIDS) are reported at autopsy to have central nervous system involvement [1], and approximately 10% develop focal brain lesions [2]. Most of these lesions are due to toxoplasmosis or primary central nervous system lymphoma, and definitive diagnosis requires brain biopsy [3, 4]. The high incidence and treatability of toxoplasmosis has led to the current recommendation that brain biopsy be reserved for those patients in whom empiric therapy for toxoplasmosis has failed or who present with lesions atypical for toxoplasmosis [5-7]. Many biopsies done under these guidelines will show primary central nervous system lymphoma [8, 9]. An imaging method that reliably differentiates between toxoplasmosis and lymphoma would allow prompt treatment of lymphoma and obviate the need for brain biopsy. Positron emission tomography can measure regional metabolic activity within tissue with a sensitivity and specificity similar to that of radioimmunoassay when used with specific labeled substrates [10]. By measuring the accumulation of fluorodeoxyglucose F-18, it can distinguish malignant brain tumors from surrounding normal tissue [11]. Experience at our institution and elsewhere [12] indicates that positron emission tomography can accurately differentiate between lymphoma and nonmalignant causes of central nervous system lesions in patients with AIDS. We did a study to determine whether evaluating contrast-enhancing central nervous system lesions in patients with AIDS by using Toxoplasma serologic testing and positron emission tomography can accurately differentiate between lymphoma and nonlymphoma diagnoses. Methods Our prospective clinical study was approved by the Vanderbilt University Committee for the Protection of Human Subjects. All patients with AIDS at Vanderbilt University Medical Center who had contrast-enhancing central nervous system lesions shown by computed tomography or magnetic resonance imaging between May 1991 and March 1993 were eligible. Patients were excluded only for failure to give informed consent. Eligible patients received a history; a physical examination; a computed tomographic or magnetic resonance imaging scan, or both; a positron emission tomographic scan; a Toxoplasma serologic test; a cerebrospinal fluid examination (if clinically indicated); a serum cryptococcal antigen test; and a CD4+ T-cell count. Autopsy consent was obtained prospectively to enable us to confirm diagnoses that remained in question. Computed tomography was done on a Siemens Somatom Plus (Siemens Medical Systems, Iselin, New Jersey) using 10-mm thick transaxial slices before and after infusion of intravenous contrast material. Magnetic resonance imaging was done on a 1.5-Tesla Siemens Magnatom SP (Siemens Gammasonics, Hoffman Estates, Illinois) using standard T1-weighted, proton density, and T2-weighted sequences before contrast and T1-weighted images after infusion of gadolinium-diethylenetriamine pentaacetic acid. Positron emission tomographic scans were obtained using a Siemens emission computed axial tomograph 933-08-16 scanner (Siemens Gammasonics) with inplane resolution of 6.5 mm and axial resolution of 8 mm. This scanner provides 15 simultaneously acquired tomographic frames over a 12.8-cm view. Images were obtained 45 minutes after the administration of 10 mCi of 2-fluorodeoxyglucose F-18 using two bed positions, 30 scans each, 4 mm apart. All patients had transmission scans for a measured attenuation correction. Counts were normalized to a homogeneous mixture of brain tissue. Lesions were considered hypometabolic if their measured activity was roughly equal to or less than the activity of white matter. Hypermetabolic lesions had at least 1.5 times the activity of white matter. (Figures 1 and 2) show the magnetic resonance and positron emission tomographic images of two patients in our study. Figure 1 is taken from patient 4, who had toxoplasmosis; Figure 2 is taken from patient 12, who had lymphoma. The magnetic resonance imaging scans are nearly identical in appearance, but the positron emission tomographic scans show hypometabolic and hypermetabolic lesions, respectively. Figure 1. Central nervous system toxoplasmosis associated with the acquired immunodeficiency syndrome. Top. Bottom. Figure 2. Lymphoma associated with the acquired immunodeficiency syndrome. Top. Bottom. Toxoplasma (IgG) serologic testing was done by immunofluorescent assay, and results were considered positive if the titer was 1:4. Autopsies were done by one of us using standard human immunodeficiency virus (HIV) precautions. After 2 weeks fixation in 10% formalin, lesions were evaluated with hematoxylin-eosin, Giemsa, Gomori methenamine silver, periodic acid-Schiff, and methyl green-pyronine stains and appropriate immunohistochemistry. Treatment The therapeutic decisions for each patient were ultimately made by the attending physicians, but therapy was recommended by the protocol on the basis of the schema given in Table 1. Patients with positive Toxoplasma serologic test results and positron emission tomographic scans that showed hypometabolic lesions were assumed to have toxoplasmosis, and antitoxoplasmosis therapy was recommended. Negative serologic test results and a positron emission tomographic scan showing hypermetabolic lesions were considered indicative of lymphoma, and empiric cranial irradiation was recommended. Patients with positive serologic test results and positron emission tomographic scans that showed hypermetabolic lesions were considered to have lymphoma, and empiric cranial irradiation was recommended. Empiric antitoxoplasmosis therapy was allowed in this situation at the discretion of the attending physician. Patients with negative serologic test results and a positron emission tomographic scan showing hypometabolic lesions were considered to be candidates for brain biopsy if an alternative diagnosis was not established. Although this schema was developed to guide therapy, in some cases the actual treatment received was different from that recommended. For example, patient 9 (Table 2) had positive serologic test results and hypermetabolic lesions on a positron emission tomographic scan. The protocol would have allowed both antitoxoplasmosis therapy and radiation therapy. In fact, the patient received only radiation therapy. Similarly, patient 12 (Table 2) had hypermetabolic lesions on a positron emission tomographic scan and negative serologic test results. He received a brain biopsy even though this was not recommended by the protocol. The differences between the recommended treatment and the actual treatment received do not bias the results because confirmation of diagnoses was dependent on the actual treatment received. Table 1. Therapy Recommended for Patients with AIDS and Contrast-Enhancing Central Nervous System Mass Lesions on the Basis of Toxoplasma Serologic Testing and Positron Emission Tomographic Scanning Table 2. Major Diagnostic Findings and Diagnoses in Evaluable Patients with Contrast-Enhancing Central Nervous System Mass Lesions* Patients were followed longitudinally, and a repeated computed tomographic or magnetic resonance imaging scan, or both, was obtained after approximately 2 weeks and then at varying intervals, depending on clinical response. Clinical and radiologic findings were evaluated to determine response to therapy. Diagnoses were confirmed by clinical and radiologic improvement or resolution in response to a single type of therapy (such as antibiotics compared with radiation); by autopsy; or, in one case, by brain biopsy. Patients who had clinical and radiologic improvement in response to more than one type of therapy were only considered to have a confirmed diagnosis if it was confirmed by autopsy or brain biopsy. Results Twenty patients with focal, contrast-enhancing central nervous system lesions were enrolled in the study between May 1991 and June 1993. Two patients were not evaluable because their diagnoses could not be confirmed. Table 2 lists the confirmed diagnoses and major diagnostic findings in the 18 evaluable patients. Confirmation of Diagnoses Eight patients had toxoplasmosis; six of these diagnoses were confirmed by clinical and radiologic response to therapy and two were confirmed by autopsy. Six patients had lymphoma: One diagnosis was confirmed by clinical and radiologic response, one by stereotactic biopsy, and four by autopsy. Two patients with progressive multifocal leukoencephalopathy and one with a cerebral cryptococcoma had their diagnoses confirmed by autopsy. One patient had clinical and radiologic responses to therapy directed at both toxoplasmosis and tuberculosis; he remains alive at 9 months. Results of Serologic Testing and Positron Emission Tomographic Scanning Toxoplasma serologic testing was done in seven of the eight patients with toxoplasmosis, and all results were positive (range, 1:10 to 1:32 768). Three of the six patients with lymphoma also had positive serologic test results. Seven patients with toxoplasmosis each had a positron emission tomographic scan, and all scans showed hypometabolic lesions. In contrast, the six patients with lymphoma all had hypermetabolic lesions on positron emission tomographic scans. The difference between these two sets of results was highly significant (P < 0.001, Fisher exact test, two-tailed). Four patients had other diagnoses. Patient 17 had a cryptococcoma, negative Toxoplasma serologic test results, and hypometabolic lesions on a positron emission tomographic scan. Two patients had progressive multifocal leukoencephalopathy; the positron emission tomographic scans showed hypometabolic lesions in one and hypermetabolic lesions in the other. In patient 18, who had clinical and radiologic responses to therapy directed at both toxoplasmosis and tuberculosis, the positron emission tomographic scan showed hypometabolic lesions. Discussion Cerebral t

The Efficacy of Linear Accelerator Radiosurgery in the Management of Patients with Cushing’s Disease

We identified 35 patients who had undergone stereotactic radiosurgery (SRS) for their biochemically proven Cushing’s disease in order to assess the efficacy of SRS with regard to control of hypercortisolism, improvement of clinical features and prevention of tumor progression, and subsequent incidence of hypopituitarism. Seventeen (49%) patients achieved control of their cortisol levels following SRS; the mean time to normalization was 7.5 months (range: 1–33). Four (19%) patients experienced recurrent hypercortisolism at a mean time of 35.5 months following therapy (range: 17–64). Control of tumor progression was achieved in 91% patients. Fourteen (40%) patients demonstrated a new pituitary deficiency following SRS. Our results suggest that cortisol levels are normalized more efficiently and with a lower recurrence rate with SRS than with conventional fractionated external beam radiotherapy (EBT). We have confirmed the near 100% tumor control rate reported with SRS. The percentage of patients developing pituitary insufficiency following SRS is less than that of patients having undergone EBT; however, deficits occurred up to 10 years posttreatment. We advocate the use of SRS as the primary therapeutic modality in those patients who are poor surgical candidates, or as the adjunct treatment to microsurgery in eliminating residual tumor cells or disease that is not easily amenable to resection.

Lovastatin is a potent inhibitor of meningioma cell proliferation: evidence for inhibition of a mitogen associated protein kinase.

Lovastatin inhibits 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase the rate limiting enzyme for synthesis of mevalonic acid, a precursor for cholesterol, farnesyl and geranylgeranyl pyrophosphate isoprenoids. Recent studies suggest it also has growth inhibitory properties. Posttranslational farnesyl or geranylgeranylation of low molecular weight GTP-binding proteins such as RAS and RHO are thought to be an essential step in activation of phosphorylation cascades such as the RAS–RAF-1–MEK-1–MAPK/ERK pathway which stimulate cell proliferation. In this study, we evaluated lovastatin effects on meningioma cell proliferation and activation of the MEK-1–MAPK/ERK pathway.The effect of lovastatin on cell proliferation was assessed in eight human meningioma cell cultures stimulated by platelet derived growth factor (PDGF)-BB, cerebrospinal fluid (CSF), and fetal bovine serum (FBS). Concomitant lovastatin effects on phosphorylation/activation of mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) kinase (MEK-1) and MAPK/ERK were assessed by Western blot. Whether lovastatin acts via a mevalonate-dependent mechanism was also evaluated.Coadministration of lovastatin completely blocked PDGF-BB, CSF, and FBS stimulation of [3H]-thymidine incorporation and cell proliferation. Lovastatin inhibited PDGF-BBs stimulatory effect in a dose dependent manner. Concomitant with its growth inhibitory effects, lovastatin reduced phosphorylation/activation of MEK-1/2 in five meningiomas and MAPK/ERK in seven. Coadministration of mevalonate with lovastatin partially restored PDGFs mitogenic effect.Lovastatin is a potent inhibitor of meningioma cell proliferation which may act in part by reducing activation of MEK-1–MAPK/ERK pathway. Additional studies are warranted to assess whether lovastatin and similar HMG-CoA reductase inhibitors represent a new adjunctive chemotherapy for recurrent meningiomas.

Registration of multimodal volume head images via attached markers

We investigate the accuracy of registering arbitrarily oriented, multimodal, volume images of the human head, both to other images and to physical space, by aligning a configuration of three or more fiducial points that are the centers of attached markers. To compute the centers we use an extension of an adaptive thresholding algorithm due to Kittler. Because the markers are indistinguishable it is necessary to establish their correspondence between images. We have evaluated geometric matching algorithms for this purpose. The inherent errors in fiducial localization arising with digital images limits the accuracy with which anatomical targets can be registered. To accommodate this error we apply a least-squares registration algorithm to the fiducials. To evaluate the resulting target registration accuracy we have conducted experiments on images of internally implanted markers in a cadaver and images of externally attached markers in volunteers. We have also produced computer simulations of volume images of a hemispherical model of the head, randomly picking corresponding fiducial points and targets in the images, introducing uniformly distributed error into the fiducial locations, registering the images, and measuring target registration accuracy at the 95% confidence level. Our results indicate that submillimetric accuracy is feasible for high resolution images with four markers.

Registration of head volume images using implantable fiducial markers

In this paper, we describe an extrinsic point-based, interactive image-guided neurosurgical system designed at Vanderbilt University as part of a collaborative effort among the departments of neurological surgery, computer science, and biomedical engineering. Multimodal image-to- image and image-to-physical registration is accomplished using implantable markers. Physical space tracking is accomplished with optical triangulation. We investigate the theoretical accuracy of point-based registration using numerical simulations, the experimental accuracy of our system using data obtained with a phantom, and the clinical accuracy of our system using data acquired in a prospective clinical trial by six neurosurgeons at four medical centers from 158 patients undergoing craniotomies to resect cerebral lesions. We can determine the position of our markers with an error of approximately 0.4 mm in x-ray computed tomography (CT) and magnetic resonance (MR) images and 0.3 mm in physical space. The theoretical registration error using four such markers distributed around the head in a configuration that is clinically practical is approximately 0.5 - 0.6 mm. The mean CT-physical registration error for the phantom experiments is 0.5 mm and for the clinical data obtained with rigid head fixation during scanning is 0.7 mm. The mean CT-MR registration error for the clinical data obtained without rigid head fixation during scanning is 1.4 mm, which is the highest mean error that we observed. These theoretical and experimental findings indicate that this system is an accurate navigational aid that can provide real-time feedback to the surgeon about anatomical structures encountered in the surgical field.

Role of calcium antagonists in cerebral arterial spasm

Spasm of the large cerebral arteries at the base of the brain causes delayed ischemic neurologic deficits in approximately 30% of patients after a subarachnoid hemorrhage from an intracranial aneurysm. In vitro chamber studies have shown that both dog and human large cerebral artery segments contract to a variety of vasoactive agents, and the dog and human segments are remarkedly similar in their responses. The source of calcium necessary to initiate contraction was found to be extracellular for large cerebral arteries. In contrast, systemic arteries such as the femoral artery use a bound intracellular pool of calcium for contraction. The calcium antagonists nifedipine and nimodipine were found to selectively inhibit the contractions of large cerebral arteries but not the femoral artery. In vivo experiments demonstrated that both nifedipine and nimodipine, given sublingually, would prevent and reverse cerebral arterial spasm in the dog after a subarachnoid hemorrhage. Nimodipine was found to be more potent, both in the chamber and in the live dog experiments. Nimodipine significantly decreased the occurrence of severe neurologic deficits from spasm alone in a multi-institutional, prospective, double-blind, randomized, placebo-controlled trial.

The utility of external beam radiation and intracystic 32P radiation in the treatment of craniopharyngiomas.

AbstractBackground. The management of craniopharyngiomas has historically been controversial in terms of the extent of initial surgical resection and the use of additional treatments. Various options include radical excision versus a more conservative surgical approach followed by external beam radiation; most recently, intracystic 32P radiation has been used in selected patients. Methods. We reviewed our experience with 25 patients with craniopharyngiomas treated between 1984 and 1999 to assess the effectiveness of external beam radiation and intracystic 32P radiation therapy in preventing progression and recurrence of local disease. Results. All patients underwent surgery as a component of initial therapy for their histologically-proven craniopharyngiomas. Fifteen patients additionally received external beam radiation. Forty-five percent of patients who underwent incomplete resections followed by external beam radiation required additional therapy. In contrast, 80% of patients who had incomplete resections without post-operative external beam radiation required further treatment. Seven patients had intracystic 32P colloid injections. Neither of the two patients receiving 32P intracystic radiation as part of their initial therapy needed further treatment. Only one of the five patients receiving 32P intracavitary radiation for disease progression following initial therapy required further intervention. Of the remaining four patients, three enjoyed responses to treatment and one had stable disease. Conclusions. Our observations support the use of external beam radiation for prevention of tumor progression in adults unable to receive a complete surgical resection. Our results additionally suggest that intracystic 32P radiation results in control of cystic components of craniopharyngiomas in the majority of cases.

Immunohistochemical Localization of Carboxypeptidases D, E, and Z in Pituitary Adenomas and Normal Human Pituitary

Carboxypeptidases may play important role(s) in prohormone processing in normal and neoplastic adenohypophyseal cells of the pituitary. We have recently demonstrated carboxypeptidase E (CPE) and carboxypeptidase Z (CPZ) in the majority of adenohypophyseal cells with carboxypeptidase D (CPD) immunoreactivity largely confined to adrenocorticotrophs. This study evaluated the expression patterns of CPE, CPD, and CPZ immunoreactivity in 48 pituitary adenomas. Our immunohistochemistry demonstrated extensive intracytoplasmic immunoreactivity for CPE, CPD, and CPZ in adrenocorticotrophic hormone (ACTH)-producing adrenocorticotroph cells, prolactin-producing lactotroph cells, and growth hormone (GH)-producing somatotroph cell adenomas, all of which require carboxypeptide processing of prohormones to produce active endocrine hormones. In contrast to the restricted expression in the normal adenohypophysis, CPD appeared to be widespread in the majority of adenomas, suggesting that CPD levels are increased in adenomas. In luteinizing hormone/follicle-stimulating hormone (LH/FSH)-producing gonadotroph adenomas, which do not require carboxypeptidases to produce gonadotropins, only CPZ immunostaining was demonstrated. In null-cell adenomas, CPE immunoreactivity was detected in the majority of tumors, but CPD and CPZ were identified only in a minority of cases. CPE in these cells may process other peptides critical for pituitary cell function, such as chromogranin A or B. These findings suggest that CPs participate in the functioning of pituitary adenomas.

Perioperative Management for Transplant of Autologous Adrenal Medulla to the Brain for Parkinsonism

N 2 O, perfusion de sufentanil et vecuronium avec de faibles concentrations disoflurane procurent une anesthesie suffisante

Technique for the three-dimensional localization of implanted fiducial markers

Registration of image space and physical space lies at the heart of any interactive, image- guided neurosurgery system. We have developed a localization technique that enables permanently implanted fiducial markers to be used for the registration of these spaces. Permanently implanted markers are desirable for surgical follow-up, monitoring of therapy efficacy, fractionated stereotactic radiosurgery and improved patient comfort over stereotactic frames. Bone-implanted extrinsic fiducial markers represent a potential long-term mechanism for registration. The major challenge to using implanted markers is the localization of the markers in physical space after implantation. We have developed and tested an A-mode ultrasound technique for determining the location of small cylindrical markers (3.7 mm in diameter, 3 mm in height). Accuracy tests were conducted on a phantom of a patients head. The accuracy of the system was characterized by comparing the location of a marker analogue with an optically tracked pointer and with the ultrasound localization. Analyzing the phantom in several orientations revealed a mean system accuracy of 0.5 mm with a +/- 0.1 mm 95% confidence interval. These initial tests indicate that transcutaneous localization of implanted fiducial markers is possible with a high degree of accuracy. The results of these experiments will help in determining a final marker design.