Martin H. Weiss

Variations on the standard transsphenoidal approach to the sellar region, with emphasis on the extended approaches and parasellar approaches: surgical experience in 105 cases.

OBJECTIVE:The traditional boundaries of the transsphenoidal approach may be expanded to include the region from the cribriform plate of the anterior cranial base to the inferior clivus in the anteroposterior plane, and laterally to expose the cavernous cranial nerves and the optic canal. We review our combined experience with these variations on the transsphenoidal approach to various lesions of the sellar and parasellar region. METHODS:From 1982 to 2003, we used the extended and parasellar transsphenoidal approaches in 105 patients presenting with a variety of lesions of the parasellar region. This study specifically reviews the breadth of pathological lesions operated and the complications associated with the approaches. RESULTS:Variations of the standard transsphenoidal approach have been used in the following series: 30 cases of pituitary adenomas extending laterally to involve the cavernous sinus, 27 craniopharyngiomas, 11 tuberculum/diaphragma sellae meningiomas, 10 sphenoid sinus mucoceles, 18 clivus chordomas, 4 cases of carcinoma of the sphenoid sinus, 2 cases of breast carcinoma metastatic to the sella, and 3 cases of monostotic fibrous dysplasia involving the clivus. There was no mortality in the series. Permanent neurological complications included one case of monocular blindness, one case of permanent diabetes insipidus, and two permanent cavernous cranial neuropathies. There were four cases of internal carotid artery hemorrhage, one of which required ligation of the cervical internal carotid artery and resulted in hemiparesis. The incidence of postoperative cerebrospinal fluid fistulae was 6% (6 of 105 cases). CONCLUSION:These modifications of the standard transsphenoidal approach are useful for lesions within the boundaries noted above, they offer excellent alternatives to transcranial approaches for these lesions, and they avoid prolonged exposure time and brain retraction. Technical details are discussed and illustrative cases presented.

Somatostatin receptor (SSTR) subtype-selective analogues differentially suppress in vitro growth hormone and prolactin in human pituitary adenomas. Novel potential therapy for functional pituitary tumors.

Previously, we have shown somatostatin receptor (SSTR) subtype-specific regulation of growth hormone (GH), thyroid-stimulating hormone, and prolactin (PRL) secretion in human fetal pituitary cultures, where GH and thyroid-stimulating hormone are mediated by both SSTR2 and SSTR5, whereas SSTR2 preferentially mediates PRL secretion. We now tested SSTR subtype-selective analogues in primary human GH- and PRL-secreting pituitary adenoma cultures. Analogue affinities determined by membrane radioligand binding in cells stably expressing human SSTR forms were either SSTR2 or SSTR5-selective. Analogues preferential either for SSTR2, including octreotide, lanreotide, and novel compounds with improved affinity for SSTR2, or new SSTR5-selective compounds suppressed GH in tumor cell cultures (up to 44% of control; P < 0.0005). However, novel analogues from both groups were 30-40% more potent than octreotide and lanreotide in suppressing GH (P < 0.05). Heterologous analogue combinations containing both SSTR2- and SSTR5-selective compounds were more potent in decreasing GH than analogues used alone (P < 0.05), or than combinations of compounds specific for the same receptor subtype (P < 0.005). In contrast, SSTR2-selective analogues did not suppress PRL release from six cultured prolactinomas studied. However, new SSTR5-selective analogues suppressed in vitro PRL secretion (30-40%; P < 0.05) in four of six prolactinomas. These results suggest that both SSTR2 and SSTR5 are involved in GH regulation in somatotroph adenoma cells, whereas SSTR5 exclusively regulates PRL secretion from prolactinoma cells. Thus, somatostatin analogues with improved selective binding affinity for these receptor subtypes may be effective in the treatment of either GH- or PRL-secreting adenomas.

PROTEIN KINASE C INHIBITORS INDUCE APOPTOSIS IN HUMAN MALIGNANT GLIOMA CELL LINES

Previous work has demonstrated the importance of the protein kinase C (PKC) system in regulating glioma growth, and has led to clinical trials utilizing PKC inhibitors as adjuncts in the therapy of patients harboring malignant gliomas. This study was performed to explore the possibility that inhibition of PKC in gliomas was triggering an apoptosis signal. Glioma cell lines were treated with PKC inhibitors staurosporine (10 nM), and tamoxifen (10 μM). DNA from cells treated with each of these drugs exhibited a ‘ladder’ pattern of oligonucleosome‐sized fragments characteristic of apoptosis, thus suggesting that in glioma cells, these drugs may be cytocidal in action.

Transcallosal, interfornicial approaches for lesions affecting the third ventricle: surgical considerations and consequences

A group of 11 patients with a variety of lesions affecting the 3rd ventricle have been treated using a direct transcallosal interfornicial approach to the region. In 3 patients, no attendant hydrocephalus was present. In an effort to minimize potential cortical injury related to the approach, we studied the venous anatomy in the region of the coronal suture. Based on this study, appropriate flap placement and interhemispheric entry points were defined. Although no lasting, clinically apparent morbidity was observed in any of the 11 cases, we performed more sophisticated studies of the interhemispheric transfer of somesthetic and perceptual motor tasks, as well as psychometric testing related to parameters of intelligence and memory, 3 to 8 months postoperatively in 6 cases. The results and clinical material indicate that this surgical technique is a safe, feasible alternative in the management of a wide spectrum of pathological lesions within this region. A transcallosal, interfornicial approach offers excellent visualization of the entire 3rd ventricle without the dependence on hydrocephalus or an extensive extra-axial mass to enhance the exposure. With proper planning and technique, it may be accomplished with a minimum of physiological consequence.

Cerebrovascular Accumulation and Increased Blood‐Brain Barrier Permeability to Circulating Alzheimer's Amyloid β Peptide in Aged Squirrel Monkey with Cerebral Amyloid Angiopathy

Abstract: Senescent squirrel monkey is a valuable model to study pathogenesis of cerebrovascular amyloid angiopathy (CAA). Cerebrovascular sequestration and blood‐brain barrier (BBB) permeability to 125I‐amyloid β(1‐40) synthetic peptide (sAβ1‐40) were studied in adult versus aged squirrel monkey 1 h after a single intravenous injection. In aged monkey, the half‐time of elimination of sAβ1‐40, te1/2, was prolonged by 0.6 h, the systemic clearance, ClSS, was reduced from 1.8 to 1.1 ml/min/kg, and the mean residence time of intact peptide in the circulation was increased by 1 h (45%). In adult monkey, cerebrovascular sequestration of intact sAβ1‐40 was significant, and the BBB permeability was 18.6‐fold higher than for inulin. In aged monkey, the sequestration of intact sAβ1‐40 by cortical and leptomeningeal microvessels and the BBB permeability were increased by 5.9, 1.8‐, and 2.1‐fold, respectively, in the presence of an unchanged barrier to inulin. In brain parenchyma of aged animals, 76.1% of circulating sAβ1‐40 remained intact versus 45.7% in adult. We conclude that multiple age‐related systemic effects, i.e., reduced body elimination and systemic clearance of sAβ1‐40, and reduced peripheral metabolism, may act in concert with BBB mechanisms, i.e., increased transendothelial transport and microvascular accumulation of blood‐borne sAβ1‐40, and reduced brain metabolism to enhance the development of CAA.

Tissue Plasminogen Activator (tPA) Deficiency Exacerbates Cerebrovascular Fibrin Deposition and Brain Injury in a Murine Stroke Model Studies in tPA-Deficient Mice and Wild-Type Mice on a Matched Genetic Background

Although the serine protease, tissue plasminogen activator (tPA), is approved by the US Food and Drug Administration for therapy to combat focal cerebral infarction, the basic concept of thrombolytic tPA therapy for stroke was challenged by recent studies that used genetically manipulated tPA-deficient (tPA-/-) mice, which suggested that tPA mediates ischemic neuronal damage. However, those studies were potentially flawed because the genotypes of tPA-/- and wild-type control mice were not entirely clear, and ischemic neuronal injury was evaluated in isolation of tPA effects on brain thrombosis. Using mice with appropriate genetic backgrounds and a middle cerebral artery occlusion stroke model with nonsiliconized thread, which does lead to microvascular thrombus formation, in the present study we determined the risk for cerebrovascular thrombosis and neuronal injury in tPA-/- and genetically matched tPA+/+ mice subjected to transient focal ischemia. Cerebrovascular fibrin deposition and the infarction volume were increased by 8.2- and 6. 7-fold in tPA-/- versus tPA+/+ mice, respectively, and these variables were correlated with reduced cerebral blood flow up to 58% (P<0.05) and impaired motor neurological score by 70% (P<0.05). Our findings indicate that tPA deficiency exacerbates ischemia-induced cerebrovascular thrombosis and that endogenous tPA protects the brain from an ischemic insult, presumably through its thrombolytic action. In addition, our study emphasizes the importance of appropriate genetic controls in murine stroke research.

Longitudinal evaluation of patients with untreated prolactin-secreting pituitary adenomas

A group of 43 patients with galactorrhea, hyperprolactinemia, and radiographic evidence of pituitary adenomas were followed from 3 to 20 years. Initial polytomography and computerized tomographic (CT) scans revealed no evidence of extrasellar extension. Serum levels of prolactin (PRL) were measured at 6 month intervals, and visual fields were assessed annually. Polytomograms and CT scans were repeated every 9 to 36 months. During the period of follow-up, CT scans (but not polytomograms) indicated tumor enlargement in two patients, both of whom underwent selective transsphenoidal removal of the tumor. Polytomograms and CT scans did not show any change in the other 41 patients, and three of them have resumed normal menses, are no longer lactating, and have normal PRL levels. The initial results of this ongoing study indicate that most patients with small pituitary adenomas can be followed with annual CT scans with or without medical therapy, and that surgical treatment should be reserved for those patients with large tumors, those with visual-field loss, and those who show signs of enlargement of the tumor.

Long-Term Administration of Mifepristone (RU486): Clinical Tolerance During Extended Treatment of Meningioma

Background: Mifepristone (RU486) is an oral antiprogestational and, to a lesser extent, antiglucocorticoid agent commonly used for short-term (single-day) therapy. However, treatment of neoplasms or chronic conditions will require long-term administration. Meningioma is a benign central nervous system tumor that is often progesterone-but not estrogen-receptor positive, making long-term antiprogestational therapy a logical treatment strategy. Methods: Patients with unresectable meningioma were treated with oral mifepristone 200 mg/day. This dose was selected to provide significant antiprogestational but not antiglucocorticoid activity. Patients also received oral dexamethasone 1 mg/day for the first 14 days. Serial follow-up allowed evaluation for tolerability and side effects of long-term therapy as well as observation for efficacy (tumor shrinkage or improvement in visual fields). Results: Twenty-eight patients received daily oral mifepristone for a total of 1,626 patient-months of treatment. The median duration of therapy was 35 months (range 2–157 months). Repeated oral administration was well tolerated with mild fatigue (22 patients), hot flashes (13 patients), and gynecomastia/breast tenderness (6 patients) being the most common side effects. However, endometrial hyperplasia or polyps were documented in 3 patients and one patient developed peritoneal adenocarcinoma after 9 years of therapy. Minor responses (improved automated visual field examination or improved CT or MRI scan) were noted in 8 patients, 7 of whom were male or premenopausal female. Conclusions: Long-term administration of mifepristone is feasible and clinically well tolerated, with generally mild toxicity. However, endometrial hyperplasia was noted in several patients. In view of the association between long-term treatment with tamoxifen (another agent that can induce an unopposed estrogen effect) and endometrial cancer, this observation will require further investigation and screening. Minor regression of meningioma that can result in significant clinical benefit is suggested in the male and premenopausal female subgroups of patients.

Acidophil stem cell adenoma of the human pituitary: Clinicopathologic analysis of 15 cases

In material of 347 surgically removed pituitary adenomas, 15 tumors (4.3%) were diagnosed as acidophil stem cell adenomas. These are immature neoplasms, assumed to derive from the common progenitor of growth hormone and prolactin cells, and usually containing both hormones by the immunoperoxidase technique. Clinically, they are regularly associated with hyperprolactinemia. Some patients may exhibit physical stigmata of acromegaly without biochemical evidence of the disease (“fugitive acromegaly”). The entity is also characterized by (1) relatively short clinical history; (2) large (grade III‐IV), locally invasive adenoma, and (3) relatively low hormonal activity. By electron microscopy, these tumors are unicellular with immature cytoplasm, exhibiting some features of adenomatous growth hormone and prolactin cells and frequently mitochondrial abnormalities as well. They are more aggressive than the well‐differentiated adenomas of the “acidophil” cell line—a fact to be considered in postoperative management.

High dose glucocorticoids in the management of severe head injury.

Eighty-eight patients with a Glasgow coma score of 8 or less 6 hours after nonpenetrating head trauma were given either high dose methylprednisolone sodium succinate (30 mg/kg q6h X2, then 250 mg q6h X6, then tapering over 8 days), low dose methylprednisolone (1.5 mg/kg q6h X2, then 25 mg q6h X6, then tapering over 8 days), or placebo. Standard care including the removal of traumatic hematomas, assisted ventilation, and intracranial pressure monitoring and control was carried out. Follow-up assessments were performed on all surviving patients at 6 months and were graded according to the Glascow outcome scale. No statistically significant difference in outcome was seen between the low dose group and the placebo group. The high dose group experienced a mortality of 39% as compared to a 52% mortality in the low dose and placebo groups (P less than 0.05). Mortality differences were most marked in patients less than 40 years old, with the high dose group experiencing a mortality of 6% as compared to a 43% mortality for the low dose and placebo groups (P less than 0.05). For patients under 50 years old, the incidence of recovery of speech was 62% compared to 36% in the low dose and placebo groups (P less than 0.5). The increased survival in those treated with high dose corticoids, however, was associated with an increase in the poorer outcome categories.