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We reviewed our experience with 21 patients who had Cushing's disease due to ACTH-secreting macroadenomas to clarify the natural history of this disease. All patients had typical clinical and biochemical features of ACTH-dependent hypercortisolism. Their mean maximal tumor diameter was 1.6 +/- 0.1 cm, and the range was 1.0-2.7 cm. Six patients had cavernous sinus invasion, three had invasion of the floor of their sella, and nine had suprasellar extension. The observed remission rate was significantly lower in macroadenoma patients than in microadenoma patients (67% vs. 91%; chi 2 = 5.7; P < 0.02). Cavernous sinus invasion (odds ratio, 35; 95% confidence interval, 2.6-475; P < 0.008) and presence of a maximum tumor diameter 2.0 cm or more (odds ratio, 12.9; 95% confidence interval, 1.4-124; P < 0.02) emerged as the only predictors of residual disease after surgery. The observed recurrence rate was significantly higher in macroadenoma patients than in microadenoma patients (36% vs. 12%; chi 2 = 4.2; P < 0.05). Macroadenoma patients tended to suffer from recurrences earlier than did microadenoma patients (16 vs. 49 months). Stepwise multiple logistic regression did not identify any predictors of disease recurrence in macroadenoma patients. Eight macroadenoma patients underwent a total of nine repeat surgical procedures, but none of these resulted in clinical remissions. Only four of seven (57%) patients followed for a sufficient period of time achieved normal urinary free cortisol levels after conventional radiotherapy. Three (75%) of these four patients had re-recurrent hypercortisolism after brief periods of eucortisolism. Pharmacological agents and adrenalectomy were effective in the management of hypercortisolism in patients with residual and recurrent disease. Our results indicate that ACTH-secreting macroadenomas are more refractory to conventional treatments than are ACTH-secreting microadenomas.

Mutant, guanosine triphosphatase-deficient, alpha-subunits of the G protein, Gs, gsp ocogene have been discovered in 40% of GH-secreting pituitary adenomas. Therefore, we hypothesized that a novel G protein class, G alpha q, involved in pituitary signal transduction, might be involved in pituitary tumorigenesis. Recombinant mutations of G alpha q result in constitutive activation of phospholipase C and have transforming activity. Therefore, we screened tumor samples from 37 pituitary adenomas for the presence of activating mutations of the G alpha q gene. Importantly, our sample contains 8 FSH and LH adenomas. In the pituitary gland, FSH and LH are linked to the GnRH-G alpha q signaling cascade, making these tumors a logical choice for screening for G alpha q mutations. Complementary DNA (cDNA) was synthesized by RT-PCR with G alpha q specific primers to exclude pseudogene transcripts. Fragments of G alpha q cDNA-encompassing residues (Arg183, Gln209) were screened by single-strand conformation polymorphism and then sequenced in both directions. No mutations were detected. We conclude that mutations in these regions of the G alpha q cDNA occur infrequently, if at all, in human pituitary adenomas. Alternative mechanisms underlying pituitary tumorigenesis should be explored.

Specific factors involved in the pathogenesis of tumors that stimulate clonal human pituitary adenoma cell proliferation remain unknown. An important question regarding the pathogenesis of human pituitary tumors is whether they synthesize autocrine regulatory factors that regulate both hormone biosynthesis and neoplastic growth. Activin and inhibin are both comprised of inhibin subunits and have diverse regulatory roles as growth and differentiation factors in normal and neoplastic tissue. Activin stimulates FSH beta messenger ribonucleic acid (mRNA) biosynthesis and FSH secretion, and these effects are down-regulated in normal gonadotrophs by the endogenous glycoprotein follistatin. In addition to its effects on gonadotrophs, activin modulates hormone secretion by somatotroph and corticotroph cell lines. It is not known whether human neoplastic pituitary tissue synthesizes inhibin subunits or follistatin or whether their expression is cell type specific. We investigated whether alpha-, beta A-, and beta B-inhibin subunit and follistatin mRNAs could be detected in 27 human pituitary adenomas [clinically nonfunctioning (n = 11), somatotroph (n = 5), corticotroph (n = 5), and lactotroph (n = 6)] using reverse transcriptase-polymerase chain reaction techniques. Twenty-six of the tumors contained mRNAs encoding one or more inhibin subunits. beta B-Inhibin mRNA was the most prevalent (81% of tumors), followed by beta A-inhibin (59% of tumors) and alpha-inhibin (52% of tumors). Endogenous alpha-, beta A-, and beta B-inhibin subunit mRNA synthesis was also examined in normal human pituitary and testicular complementary DNA libraries, and all subunit mRNAs were detected. In contrast to the widespread expression of inhibin subunits in pituitary tumors, follistatin mRNA was detected in a subset of nonfunctioning tumors (54%) as well as in control normal human pituitary and testicular complementary DNA libraries. Tumor-specific follistatin biosynthesis was not observed in other pituitary tumor subtypes. These data are the first to demonstrate that 1) endogenous inhibin subunits are synthesized in human pituitary adenomas of all known secretory phenotypes as well as normal pituitary tissue; and 2) follistatin gene expression in pituitary adenomas is specific to clinically nonfunctioning or gonadotropin subunit-producing tumors. The characterization of inhibin subunit and follistatin biosynthesis by human pituitary tumors will be important in investigating their potential roles in regulating both tumor phenotype and cell proliferation.

The results of transsphenoidal adenomectomy for growth hormone (GH)-secreting pituitary adenomas in acromegaly performed over a 17-year period were analyzed retrospectively to determine which preoperative factors significantly influenced the long-term surgical outcome. These variables were then used to develop a logistic regression model to determine the probability of surgical failure. The series consisted of 103 patients. Long-term follow-up study (mean duration 102 +/- 64 months) was performed to derive outcome analysis and determinants of failure. Surgical control was defined as a long-term postoperative serum basal GH level of less than 5 micrograms/liter, a long-term postoperative serum somatomedin C (SM-C) level of less than 2.2 U/ml, and a favorable clinical response. Eighteen (17.5%) patients did not meet these criteria. The overall control rate by the GH criteria was 81.3% and by the SM-C criteria 76.2%. By multivariate logistic regression analysis, tumor stage was the strongest predictor of outcome (p < 0.05). The preoperative GH level, tumor grade, and preoperative SM-C level were significant univariate predictors (p < 0.05). There were statistically significant differences in mean preoperative GH and SM-C levels (p < 0.05, t-test) and tumor stage (p < 0.05, chi-squared test) between patients whose acromegaly was controlled by surgery and those whose acromegaly was not. Furthermore, estimates were derived of the probability of surgical failure based on preoperative GH level, preoperative SM-C level, and tumor grade and stage. The authors believe these findings will enhance clinical decision-making for neurosurgeons considering transsphenoidal microsurgery in patients with acromegaly.

Sellar magnetic resonance imaging studies obtained with half doses of gadopentetate dimeglumine (0.05 mmol/kg) were prospectively interpreted and retrospectively rated in 26 patients who subsequently underwent transsphenoidal sellar surgery for suspected pituitary adenoma. Studies included a sagittal scout view followed by a non-contrast-material-enhanced, an immediate postcontrast, and a delayed postcontrast T1-weighted image (obtained at 1.0 or 1.5 T). Ten of 11 confirmed microadenomas were identified prospectively; all were identifiable in retrospect. Macroadenomas (12 cases) were well demonstrated. The high signal intensity of the posterior pituitary and of intrasellar hemorrhage was obscured on postcontrast studies. Delayed images proved unnecessary. This prospective evaluation suggests that a half-dose study is comparable to retrospective studies in which full-dose techniques were used for detection of micro- and macroadenomas. Imaging times are reasonably short, and cost of contrast material is potentially reduced. Confirmation with larger studies is required, and careful endocrinologic and clinical follow-up of nonsurgical patients is necessary.

The diagnosis and management of lumbar disc disease has undergone significant changes in recent years. This is especially true for diagnostic imaging studies (MRI and CT). Currently, CT/myelography or unenhanced MRI may be used to confirm the diagnosis and the level of involvement of lumbar disc disease. The indications for lumbar disc surgery include patients with neurologic deficits and/or those in whom intractable pain does not respond to conservative measures. Conventional disc surgery and/or microdiscectomy are both good operative procedures for lumbar disc disease, and each yields excellent results when criteria for diagnosis and surgery are strictly followed.

Eleven patients who experienced significant loss of vision after transsphenoidal surgery are reported on. The mechanisms involved in these visual complications include direct injury or devascularization of the optic apparatus, fracture of the orbit, postoperative hematoma, cerebral vasospasm, and prolapse of the optic chiasm into an empty sella. Factors that may increase the risk of visual complications include the presence of a pituitary macroadenoma, previous visual impairment, a "bottleneck" or dumbbell-shaped tumor, previous surgery and/or radiation therapy, and, possibly, use of a lumbar subarachnoid catheter during operation. A practical approach to the management and avoidance of these complications is presented.

From 1977 to 1988, 56 patients with a preoperative diagnosis of Cushing's disease were treated by transsphenoidal microsurgical exploration of the pituitary gland. In 42 patients, a discrete tumor was found and a selective adenomectomy was performed. Total hypophysectomy was performed in nine patients. In an attempt to preserve pituitary function, a technique of subtotal hypophysectomy was utilized in the remaining five patients. Regular and adequate follow-up results were obtained in 53 patients. A sustained remission was obtained in 45 of these 53 patients for a remission rate of 84.9%. Eight patients were classified as therapeutic failures. The causes for failure included: 1) invasive tumor; 2) hyperplasia mistaken for an adenoma; 3) a presumed ectopic source of adrenocorticotropic hormone; 4) misdiagnosis; 5) atypical tumor; and 6) recurrence of disease after remission. In cases of therapeutic failure, the original diagnosis of Cushing's disease must be reevaluated and treatment continued until sustained remission is achieved. Necessary measures to help avoid surgical failures and an approach for further diagnostic and therapeutic maneuvers in these cases are discussed.

Supratentorial epithelial cysts are rare entities that have evoked controversy regarding their pathogenesis. Recent ultrastructural studies have failed to resolve this controversy. We present a case report and an ultrastructural study of such a cyst. The cyst wall was lined by columnar epithelial cells with prominent cilia and microvilli at their apical surface. They were joined by well-developed junctional complexes and contained abundant intracytoplasmic, electron-dense, granular material, some of which was membrane-bound. These ultrastructural findings suggest that epithelial cysts are derived from elements of the embryological tela choroidea.

A case of Arnold-Chiari malformation Type I presented with the isolated finding of downbeat nystagmus. The mechanism of downbeat nystagmus is discussed along with its subjective manifestation referred to as oscillopsia. In addition, the value of metrizamide cisternography in diagnosing the Arnold-Chiari malformation is illustrated.

Transsphenoidal hypophysectomy was performed in 13 patients with advanced malignant melanoma. Although three minor responses were observed, there were no complete or partial responses. All three patients with bone pain had a decrease in discomfort lasting 1-2 months. All five patients with minor responses or stable disease had postoperative decreases in the excretion of the dihydroxyphenylalanine (DOPA) metabolite 3-O-methyldopamine; all but one patient with clinical progression had postoperative increases in excretion. Average survival of those whose postoperative excretion fell (143 +/- days; range, 60-217+) was significantly longer (P less than 0.004) than that of those whose postsurgical values rose (30 days; range, 15-58).

A flexible ventriculofiberscope was used to diagnose intraventricular pathological conditions in eight adult hydrocephalic patients. In each case the entire procedure was recorded on videotape for documentation, review, and teaching. Four representative cases are presented to illustrate the use and value of this technique.

Eighteen patients with cerebral vasospasm following subarachnoid hemorrhage were treated with 21 trials of intravenous aminophylline and isoproterenol. After angiographic demonstration of spasm, all patients were started on a continuous intravenous infusion of aminophylline 125 mg/hr and isoproterenol 125 micrograms/hr, preferably for a period of at least five days before the medications were tapered. Of the 21 treatment trials, there were 11 definite beneficial responses and ten failures. This study emphasizes the importance of instituting this therapy as rapidly as possible following the confirmation of symptomatic cerebral vasospasm. In addition, if a response occurs it will be noted within 24 hours of institution of the medications. If no response is noted following this time period, the medications should be discontinued. The major complications of this therapy include hypotension, tachycardia and arrythmias. These complications may necessitate diminishing the dosage of the medications. However, if a response has been obtained, every effort should be made to avoid discontinuing therapy prematurely since cerebral vasospasm may recur. The use of isoproterenol and aminophylline is based on their demonstrated ability to increase cyclic adenosine monophosphate (cyclic AMP) levels in vascular smooth muscle, thus producing relaxation of vasospasm.

Alteration in heart rate and respiratory rate and depth occurred in association with intracranial pressure (ICP) waves in 27 patients with head injuries. Usually the ICP wave was preceded by a transient increase in end-alveolar CO2 levels. Thereafter, the ICP gradually increased and was accompanied by simultaneous decreases in heart rate and respiratory rate and depth. Immediately before the termination of the ICP wave, there was an abrupt increase in heart rate and respiratory rate and depth. After the ICP fell to base line level, heart rate and respiratory returned to control values. It is suggested that the transient alterations in the CO2 level at the beginning and during the ICP wave probably initiate these abnormal waves. While the heart rate changes are striking, their role in the formation and termination of ICP pressure waves is uncertain.

A retrospective study was undertaken in 113 patients with surgically proven pituitary adenomas to correlate the frequency, type, and location of computed tomographic (CT) abnormalities with surgical findings. There were 63 prolactin-secreting, 19 growth-hormone-secreting, 12 adrenocorticotropic-hormone-secreting, two thyroid-stimulating-hormone-secreting, and 17 nonfunctioning adenomas. The 51 functioning and nonfunctioning macroadenomas had similar CT appearances. Only 34 secretory adenomas presented as discrete, focal, hypodense lesions; the rest were isodense with the adjacent pituitary gland. Secretory adenomas were clinically apparent earlier, and accordingly the abnormalities seen on CT were less developed. The location of the normal pituitary gland could not be determined by attenuation characteristics; only by infundibulum displacement or opposite to a discrete, focal, hypodense lesion could the gland location be predicted reliably. Adenomas with hemorrhage, infarction, and cyst formation were indistinguishable from those without these findings. CT was helpful in identifying the mass effect of macroadenomas; however, in microadenomas of all types CT abnormalities were uncommon. Thus, the diagnostic evaluation of the patient suspected of harboring a pituitary adenoma, particularly a microadenoma, must remain a joint effort based on clinical, radiographic, and endocrinologic data.

Intracranial pressure monitoring facilitates the management of patients with severe craniocerebral trauma. The advantages of monitoring from the intraventricular space are outweighed by the increased incidence of infections with this technique. A system using an implanted Rickham reservoir attached to an intraventricular catheter with exchangeable external connections has been used successfully for monitoring intracranial pressure in 34 of 35 consecutive head-injured patients, with one minor infection.

The authors report a rare case of a cerebellar ganglioglioma. A review of 12 previously reported cases and our case suggest that surgical removal of this neoplasm carries a good prognosis.

Sixty patients with metastatic breast cancer had transsphenoidal hypophysectomy at Emory University Hospital. Median survival for the entire group was ten months. Survival was increased (longer than 14 months) in good responders as compared to nonresponders (three months). Pain was significantly relieved in the majority of those patients who had severe pain. Operative complications were minimal. The technic of transsphenoidal hypophysectomy offers a substantial chance of objective and subjective palliation with minimal morbidity in advanced breast cancer.

An anatomical-angiographic classification for carotid-cavernous sinus fistulas is introduced and a series of 14 patients with spontaneous carotid-cavernous sinus fistulas is reviewed to illustrate the usefulness of such a classification for patient evaluation and treatment. Fistulas are divided into four types: Type A are direct high-flow shunts between the internal carotid artery and the cavernous sinus; Type B are dural shunts between meningeal branches of the internal carotid artery and the cavernous sinus; Type C are dural shunts between meningeal branches of the external carotid artery and the cavernous sinus; and Type D are dural shunts between meningeal branches of both the internal and external carotid arteries and the cavernous sinus. The anatomy, clinical manifestations, angiographic evaluation, indications for therapy, and therapeutic options for spontaneous carotid-cavernous sinus fistulas are discussed.

Anterior pituitary lobe function was measured pre- and postoperatively in 40 patients with pituitary tumors who were managed surgically by the trans-sphenoidal approach. Of 23 patients with normal anterior lobe function preoperatively, 21 (91%) were normal postoperatively. Of 17 preoperatively impaired patients, 7 (40%) regained normal function, 3 (18%) improved, 4 (24%) remained the same, and 3 (18%) were further impaired by the surgery. In this small series, the likelihood of recovery of pituitary function varied inversely with the degree of preoperative impairment and the size of the tumor, suggesting that more aggressive surgical management of small, minimally symptomatic pituitary tumors is justified.

Measurements of cerebral spinal fluid pressure, arterial pressure, and internal carotid artery blood flow were obtained in a series of patients during a Valsalva maneuver. During straining (phase II), an 11% reduction in mean arterial pressure was associated with a 21% decrease in internal carotid flow from control values; and following release (phase IV), the 19% increase in mean arterial pressure produced a 22% increase in internal carotid artery flow. Perfusion pressure computed as the mean arterial pressure minus cerebral spinal fluid pressure and internal carotid artery blood flow were used to calculate an index of cerebral vascular resistance. The data indicate that a modest but significant decrease in vascular resistance occurred during phases II and III followed by return to control levels during phase IV. These changes in vascular resistance were not rapid enough or of sufficient magnitude to maintain constant cerebral perfusion during the Valsalva maneuver.

The pars nervosa of the neurohypophysis from 12 patients undergoing hypophysectomy for palliative treatment of advanced carcinoma was studied electron microscopically. Special attention was given to the cellular elements, the pituicytes. Five different classes of pituicytes, with various transitional forms, were elucidated based on their ultrastructural characteristics: (1) The most common type, referred to as "major pituicytes", is reminiscent of astrocytes. (2) "Dark pituicytes" are thought to represent different functional stages of the "major pituicytes". (3) "Ependymal pituicytes" are believed to provide ultrastructural evidence that human pituicytes are phylogenetically derived from ependymal cells. (4) "Oncocytic pituicytes" were observed in all cases and are of unknown significane. (5) The ultrastructural features of "granular pituicytes" suggest the existence of an active uptake and catabolism of extracellular material by pituicytes, probably through "ultraphagocytosis" or "endocytosis". These five classes of pituicytes are considered to represent different functional forms of one cell line that originates phylogenetically from the ependyma.

Three cases of an entirely suprasellar symptomatic Rathke's cleft cyst, two of which were associated with normal sella turcicas, are reported. In all cases, the cysts caused compression of the optic chiasm, and two produced hypothalamic dysfunction. The diagnosis of these entirely suprasellar masses was enhanced by metrizamide cisternography. Two cases were treated by frontal craniotomy and one was treated transsphenoidally, with good results in all cases. The radiology, pathology, and surgical treatment of these unusual cases is presented. An embryological pathogenesis for the occurrence of an entirely suprasellar Rathke's cleft cyst is discussed.

Nine cases of pituitary tumors composed of mixed tissue elements of adenohypophysial adenoma and Rathke's cleft cyst are reported. All cases were associated with hyperprolactinemia and were managed by transsphenoidal adenomectomy with good results. The clinical and pathological features are presented, and embryological pathogenesis for the occurrence of this unique association is discussed in connection with the high incidence of immunoreactive S-100 protein cells identified in tumor tissues. Patients with this kind of pituitary tumor can be managed in the same fashion as patients with other types of pituitary adenoma.

A neuroradiological technique for demonstrating the empty sella syndrome using a low dose of intrathecally injected Amipaque (metrizamide) combined with computerized tomography scanning is described. Two case reports illustrating the potential value of the technique are presented. We have performed 55 cisternograms and have demonstrated the empty sella syndrome in six patients. The procedure is easier to perform and the morbidity is less than in pneumoencephalography.

Current neurodiagnostic and endocrine evaluation for pituitary tumors, empty sella syndrome, and parasellar lesions includes new techniques. Multidirectional polytomography of the sella turcica in detecting very small pituitary adenomas is important. Also, the role of computerized axial tomography (CT scanning) in defining size and extent of sellar and parasellar lesions is increasing. There has been a decline in the use of cerebral angiography and pneumoencephalography, especially the latter, in the diagnostic workup of these patients since the introduction of CT scanning.

The authors describe a case of a granuloma of histiocytosis X localized in the pituitary gland. The patient presented with diabetes insipidus and hyperprolactinemia. The diagnosis was established by surgical removal of the pituitary lesion through a transsphenoidal approach. The clinical and pathological aspects of the case are discussed.