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The double subarachnoid hemorrhage canine model was used to test the prophylactic value of immunosuppression in the prevention of cerebral vasospasm after subarachnoid hemorrhage. Dogs treated with cyclosporine A following the regimen prescribed for organ transplant procedures in patients showed a significant reduction in the severity of angiographic constriction of cerebral arteries. While basilar artery diameter after double experimental subarachnoid hemorrhage in a series of untreated dogs (n = 34) averaged 65% of baseline diameter, arterial diameter in dogs treated prophylactically (n = 18) with 6 mg/kg/day cyclosporine A and adjunct low-dose steroid averaged 80% of baseline diameter, for a mean reduction in the severity of chronic arterial constriction of 42%. More important than the average effect, however, is the statistical observation that this mean improvement was obtained primarily by a dramatic reduction in the incidence of severe cerebral vasospasm, the situation most likely to account for morbidity and mortality after aneurysmal rupture.

1,3-Bis(2-chloroethyl)-1-nitrosourea, BCNU, a widely used anticancer agent for a variety of neoplasms, can be rapidly, conveniently, and inexpensively determined at trace levels of clinical importance, from a variety of biological media, using HPLC-UV approaches. Limits of detection for BCNU from patient and control samples have been compared for HPLC-UV, HPLC-EC, and the Griess Test. The distribution and disappearance of BCNU from blood samples can be quickly and easily determined using the methods described. Individual blood samples are completely analyzed in less than 30 mins, from the time of sampling to qualitative and quantitative results.

The dose responses of canine basilar arteries to human hemoglobin, rabbit hemoglobin, horse-heart myoglobin, and human methemoglobin and cyanomethemoglobin are compared in this paper. The in vitro arterial segments responded similarly to the hemoglobins and myoglobin when doses were based on the hemoglobin dimer rather than on the tetramer. Superoxide free radicals produced by the autoxidation of hemoglobin to methemoglobin do not seem to be involved in the mechanism of hemoglobin-induced vasocontraction as the contraction cannot be blocked by superoxide dismutase or other agents known to react with superoxide-generated products. Nonspecific uptake of hemoglobin into the smooth-muscle cells by pinocytosis is also discounted.

Based on a new subarachnoid hemorrhage model in rabbits, the electrocortical activity was evaluated over a period of one week following two successive whole blood injections in the cisterna magna. A second group was injected with artificial cerebrospinal fluid, while a third group with hemolyzed autologous blood. All the other procedures being the same, it became evident that elevated intracranial pressure (CSF injection) is not able by itself to induce true epileptiform activity; however, it releases phenomena of brainstem reflexes. During whole blood injection, the cortical activity showed a peak in true epileptogenic discharges 5 days after the first injection. Almost identical polyspikes and slow wave complexes were reproduced immediately after the injection of hemolyzed blood. The possible mechanisms involved in the appearance of these phenomena are further discussed.

The authors describe six patients with pituitary macroadenomas hypersecreting only the alpha subunit of the glycoprotein hormones. These patients had been previously diagnosed as having "non-functioning chromophobe adenomas." All of the patients had visual field abnormalities and partial hypopituitarism. The elevated serum alpha concentrations showed a variable response to stimulation by thyrotropin-releasing hormone, and could not be suppressed by thyroid hormone administration. Immunological, gel chromatographic, and immunocytochemical studies documented that only the alpha subunit was present. Following pituitary surgery and radiotherapy, serum alpha levels decreased. These patients represent a new subset of functioning pituitary tumors. Determination of alpha subunit concentration is useful in managing some patients with pituitary tumors previously thought to have non-functioning chromophobe adenomas.

We present three patients in whom Fluosol-DA 20 percent was administered in the presence of ischemic cerebral vascular disease. While transient improvement observed in two cases may have been related to Fluosol-DA administration it is premature to use these results to comment on the potential protective or therapeutic efficacy of Fluosol-DA in ischemic cerebral vascular disease. One patient progressively deteriorated neurologically during and after the infusion. Our initial impressions are limited to the observations that Fluosol-DA in doses of 20 ml/kg can be administered easily and without major effects on hemodynamic or pulmonary function. One patient had a transient leukopenia.

Twenty-four cats were divided into two groups and treated with an intravenous infusion of either fluosol DA or dextran. One-half of the animals in each group were ventilated with room air and one-half with 100% oxygen. The right middle cerebral artery was occluded for a period of 4 hours through a transorbital approach. Regional blood flow by the hydrogen clearance method was measured before and after the infusion of fluosol DA or dextran, after oxygenation in the animals on 100% oxygen, three times during the period of ischemia, and after reperfusion. Regional cerebral blood flow increased slightly with the infusion of fluosol or dextran, decreased slightly with hyperoxygenation in the animals so treated, and decreased markedly in the right hemisphere during temporary occlusion of the right middle cerebral artery in all groups. With reperfusion regional flows in the right hemisphere varied considerably, with some animals showing hyperperfusion and others essentially no flow. There was no significant difference in average regional cerebral blood flow between any of the groups. The severity of infarction in all groups was directly related to the decrease in regional cerebral blood flow in the right hemisphere during temporary occlusion. There was also a strong correlation between the regional cerebral blood flow in the right hemisphere after reperfusion and the severity of infarction. In general, the animals showing normal or increased flow after reperfusion had small infarcts and those showing no reflow had large infarcts. Mortality was high in all groups, was not significantly different between any of the groups, and was highly correlated to the size of infarction. In brief, in this study fluosol offered no advantage over dextran, and probably neither agent, in the dose used, offered any protection against cerebral ischemia.

In 27 patients undergoing laminectomy, spinal cord function was monitored by epidural bipolar recordings of conducted spinal somatosensory evoked potentials (SEP's) across the laminectomy site, with calculation of spinal conduction velocity (CV). In control cases without myelopathy, the CV remained relatively constant (+/- 3%) even during prolonged operations, despite markedly changing levels of anesthesia. Acute CV changes were detected intraoperatively in three cases: these patients displayed improvement after extramedullary (Case 1) and intramedullary decompression (Case 2), and deterioration after direct unilateral dorsal column injury (Case 3). These intraoperative CV alterations correlated postoperatively with changes in the neurological examination. Although a unilateral lesion confined to the dorsal column abolished the ipsilateral SEP in Case 3, complete anterior quadrant lesions did not consistently change the CV (Case 4). This further suggests that the SEP is generated entirely by ipsilateral dorsal column activation. Accurate measurement of this dorsal column conduction velocity across the operative field provides a very sensitive means of monitoring spinal cord function during operations for neurosurgical spinal lesions.

Experimental cervical carotid aneurysms in dogs are obliterated with isobutyl-cyanoacrylate ( IBCA ) injected under direct vision into the aneurysm. Reflux of IBCA into the artery was prevented by inflating either a latex or a Silastic balloon in the carotid artery at the level of the neck of the aneurysm. This balloon was introduced through a catheter advanced into the common carotid artery by femoral catheterization. The Silastic balloon was found to be much more effective than the latex balloon in preventing spillage of IBCA into the lumen.

Seventy-six splenectomized dogs were entered in a study of the value and effects of isovolemic hemodilution. Of these, seven were not included in the analysis because of technical errors. Of the remaining 69 dogs, 35 were treated with hemodilution; 28 were subjected to a 6-hour period of temporary occlusion of the distal internal carotid artery and the proximal middle cerebral artery, and seven underwent a sham operation only, with arterial manipulation but no occlusion. The other 34 dogs were not subjected to hemodilution; 26 of these underwent temporary arterial occlusion and eight had a sham operation only. In each group the animals were about equally divided into 1) an acute protocol with regional cerebral blood flow measurements by a radioactive microsphere technique and sacrifice at the end of the acute experiment, and 2) a chronic protocol with survival for 1 week to permit daily neurological assessment and final histopathological examination but without blood flow measurements. The general experimental protocol, the hemodynamic and rheological measurements, and the changes in intracranial pressure are described in Part 1 of this report. In the animals with arterial occlusion, blood flow decreased significantly in the territory of the ischemic middle cerebral artery. This decrease was partially reversed by hemodilution in the animals so treated. When the changes in blood flow before and after hemodilution in treated animals are compared with the changes at equivalent times in animals without hemodilution, the increases in flow in the gray matter of the ischemic hemisphere brought about by hemodilution are statistically significant. The neurological condition of the animals in the chronic protocol (sacrificed 1 week after occlusion) with hemodilution, as evaluated by daily neurological assessment, was significantly better than that of the control animals. In the animals sacrificed acutely (8 hours after arterial occlusion), the volume of infarction as estimated by the tetrazolium chloride histochemical method was 7.36% of the total hemispheric volume in the control animals and 1.09% in the hemodiluted animals, showing a statistically significant difference (p less than 0.005). In the chronic animals these values were 9.84% and 1.26%, respectively (p less than 0.005), as calculated by fluorescein staining. By histopathological examination the volume of infarction in the chronic animals was calculated as 10.92% in the control animals and 1.20% in the hemodiluted animals (p less than 0.005).(ABSTRACT TRUNCATED AT 400 WORDS)

Peroxidase-containing cell bodies were found in the ipsilateral trigeminal ganglia after horseradish peroxidase was applied to the proximal segment of the middle cerebral artery in seven cats. Cell bodies containing the enzyme marker were located among clusters of cells that project via the first division. The existence of sensory pathways surrounding large cerebral arteries provides an important neuroanatomical explanation for the hemicranial distribution of headaches associated with certain strokes and migraine.

Local cerebral blood flow was measured in anaesthetized beagle dogs by the hydrogen clearance method. Dopamine was administered as a continuous intravenous infusion of varying doses. The changes in local cerebral blood flow induced by dopamine were similar at the different locations; i.e., the caudate nucleus, thalamus, frontal and parietal cortex. Blood flow responded to dopamine in the following ways: low dose (less than 2 micrograms/kg/min): blood flow decreased or remained unchanged; moderate doses (2--6 micrograms/kg/min): blood flow increased at all electrodes; high doses (7--20 micrograms/kg/min): blood flow decreased once again. The decrease in blood flow could be inhibited by the alpha-adrenergic receptor antagonist phentolamine or by the serotonin receptor antagonist methysergide. This indicates that the constrictor effect of dopamine on cerebral blood vessels is mediated via alpha-adrenergic receptors as well as via serotonin receptors. The increase in cerebral flow could be inhibited by the dopamine receptor antagonist haloperidol, indicating vascular dopamine receptors in the brain with a dilating effect. When the vasoconstrictor activity of dopamine is blocked, the single response to a dopamine infusion is a blood flow increase. This might be beneficial in the clinical situation of symptomatic vasospasm.

A medical student developed a progressive mesencephalic lesion found to be cystic in nature by computed tomographic (CT) scanning. Stereotactic aspiration of a pontomesencephalic hematoma was carried out twice, and the patient recovered. Angiography and CT scanning demonstrated a vascular lesion compatible with a venous angioma.

A fully implantable radio-telemetric differential intracranial pressure sensor is described with a zero-point calibration that can be confirmed repeatedly. Intracranial pressure (ICP) is measured with the device by the principle of applying a known external pressure to the scalp above the sensor and simultaneously detecting by radio-telemetry the zero-point of the sensor corresponding to a balance of pressures across it. The radio-telemetry is implemented by a resonant circuit in the sensor of which the resonant radiofrequency is detected outside the body. The sensor is passive, has built-in barametric compensation, negligible permeability of temperature drift, no calibration ambiguities, and fast dynamic response. The implanted sensor has been used successfully for short-term as well as long-term ICP monitoring. It has been implemented primarily for intermittent ICP measurements, but also adapted to continuous recording. Preliminary clinical experience with the system indicates that it is effective, safe, and simple to operate.

Astrocytomas, including glioblastoma multiforme, represent the most frequent and deadly primary neoplasms of the human nervous system. Despite a number of previous cytogenetic and oncogene studies primarily focusing on malignant astrocytomas, the primary mechanism of tumor initiation has remained obscure. The loss or inactivation of "tumor suppressor" genes are thought to play a fundamental role in the development of many human cancers. Thus, we have analyzed astrocytomas of various histological malignancy grades with polymorphic DNA markers to search for specific chromosomal deletions potentially pointing to loci containing tumor suppressor genes. Loss of constitutional heterozygosity indicating chromosomal loss or deletions was most frequently seen for markers on the short arm of chromosome 17 in 50% of the informative tumors (5 of 10 informative cases) and, to a lesser extent, for markers on chromosomes 1 and 10. Deletions on chromosome 17p were seen in both low-grade and high-grade malignant astrocytomas, suggesting that this chromosome may contain a tumor suppressor gene associated with the early events in tumorigenesis. The common region of deletions on the short arm of chromosome 17 is, therefore, clearly distinct from the gene causing von Recklinghausen neurofibromatosis (NF1), a tumor syndrome associated with glial tumors that maps to the long arm of chromosome 17. The search for progressively smaller deletions on chromosome 17p in astrocytomas may be the way to clone and characterize this locus, thus leading to insights into normal and abnormal growth and differentiation of glial cells.

A case of lymphocytic adenohypophysitis in a postpartum woman who became symptomatic during her 8th month of pregnancy is presented. The clinical presentation, endocrine findings, pathological findings, and operative management are discussed. Transient hypopituitarism is documented. Unlike most previously published cases, this woman had complete recovery of anterior pituitary function.

Sequential cisternal blood injections in dogs reproduce some of the morphological and physiological features seen in man after subarachnoid hemorrhage-induced vasospasm. This study reports the morphological features observed in cerebral vessels in areas exposed to subarachnoid blood. Subarachnoid hemorrhage was produced in dogs by two cisternal injections of non-heparinized autologous blood 48 hours apart. Dogs were sacrificed 48 hours after the second injection. Angiographic narrowing of the basilar artery was routinely present 48 hours after the second injection, and there was a good correlation between angiographic vasospasm and a narrowed arterial lumen at postmortem examination. All basilar arteries showed structural changes with electron microscopic examination; these included endothelial cell vacuoles, early smooth-muscle cell necrosis, intimal changes, and adventitial erythrocytes, leukocytes, and mast cells. The finding that accompanied vessel constriction most uniformly was packing of the adventitial cerebrospinal fluid spaces with erythrocytes. Angiographically visible spasm was resistant to vasodilators. These data suggest that infiltration of blood elements into the arterial wall is an important concomitant feature of morphological and angiographic vasospasm.

Diazoxide failed to safely relieve cerebral vasospasm by intracisternal injections in dogs and by intracarotid injections in monkeys despite in vitro documentation of arterial relaxation with this agent. Administration of the drug frequently produced hypotension and, in the presence of vasospasm, was associated with a high mortality rate.

We compared the results of cranial computed tomography (CT) and lumbar puncture (LP) in patients who had subarachnoid hemorrhage due to proven ruptured intracranial aneurysm. We found no correlation between the number of red blood cells in the cerebrospinal fluid collected by LP and the amount and extent of blood detected by CT.

Isolated hypersecretion of the alpha subunit of the glycoprotein hormones occurred in two men with previously diagnosed "nonfunctioning chromophobe adenomas." The alpha hypersecretion was unresponsive to hypothalamic releasing hormone, thyroid hormone, and sex-steroid hormones. After trans-sphenoidal surgery and conventional pituitary irradiation, alpha secretion was decreased. Increased quantities of immunologically active and biologically inactive luteinizing hormone (LH) material were detected in serum and in tumor homogenate. Immunologic and gel-chromatographic studies determined that only the alpha subunit was present and that it was cross-reacting in the LH immunoassay. These studies suggest that the alpha subunit may be a useful marker of pituitary tumors, particularly in patients without clinical evidence of hormonal hypersecretion.

Anatomical and clinical observations suggest that supratentorial vascular structures contain afferent projections from the trigeminal ganglia. To characterize this innervation, horseradish peroxidase (HRP) and HRP conjugated to wheat germ agglutinin were applied to the pial and dural arteries and sinuses of 33 cats. HRP was restricted to the site of interest by applying it dissolved in a viscous polymer, polyvinyl alcohol (PVA), to achieve slow release and minimize diffusion. The ganglia of cranial nerves V, VII, IX, and X and the superior cervical ganglia (SCGs) were examined bilaterally for the presence of retrogradely transported protein. Horseradish peroxidase applied to the proximal middle cerebral artery was located in cell bodies occupying the portion of the ipsilateral trigeminal ganglion corresponding to the ophthalmic division and throughout both SCGs. When the tracer was applied to the right anterior or posterior superior sagittal sinus, HRP-positive cells were present as above, predominantly in the ipsilateral trigeminal ganglia corresponding to the ophthalmic division and throughout both SCG. When applied to the right middle meningeal artery, HRP was observed within neurons of ipsilateral SCG and in the ophthalmic division of trigeminal ganglia; a few enzyme-containing cells were present in ipsilateral regions corresponding to the second and third divisions. These observations support the concept that supratentorial vascular structures receive afferent nervous projections from trigeminal neurons.

Sudden headache, visual loss, and mental change developed in three patients with unsuspected pituitary tumours. In each case stereotaxic transnasal cannulation of the intrasellar mass demonstrated a liquid haematoma under moderate pressure which could be easily aspirated. Restoration of vision and relief from neurological disturbances was prompt. Radiation therapy was then administered to prevent recurrence.

A group of 112 consecutive patients who initially had no neurological deficits after subarachnoid hemorrhage (SAH) was followed intensively for at least 1 year. Ninety-four were in neurological Grade I or II (Hunt and Hess classification) on arrival. A hundred patients underwent late surgery but, despite excellent surgical results, major morbidity and mortality rates were observed related to preoperative complications. In the preoperative period, 14 (13%) rebled, 41 (37%) had symptomatic cerebral vasospasm, and 24 (21%) had hydrocephalus that required treatment. Of the 100 surgical patients, 73 were in Grade I or II, 26 in Grade III, and one in Grade IV. Six patients had intraoperative neurological complications, and two had delayed postoperative cerebral infarction. Six patients died during hospitalization, but only one as a result of operation. Six others died during the year following discharge of causes unrelated to the operation. The ultimate functional outcome at 1 year of these initially good-risk patients was poor. Only 46% were fully recovered, and 25% reported emotional or psychological disturbances that interfered with their daily lives. Forty-four percent could return to their previous jobs or a comparable position, and 20% obtained lesser employment. Management mortality at 1 year was 11%, and morbidity related to persistent neurological deficits (mainly strokes from vasospasm) was 20%. Thus, management mortality and morbidity at 1 year was 31%, and the number of patients returning to useful life was disappointing. The authors support the suggestion by previous workers that an analysis of at least the 6-month and perhaps the 1-year outcome (especially management mortality for all patients) provides the most important parameter for judging outcome and comparing different management protocols for SAH.

A modification of the crossed leg raising test has been helpful in identifying patients with intervertebral disc disorders. Simultaneous flexion of the neck and elevation of the contralateral leg produced pain in the ipsilateral (presenting) sciatic notch in five patients with either free fragments or herniated disc found at operation. All patients were symptom-free postoperatively.

A total of 76 splenectomized dogs were entered in a study of the value and effects of isovolemic hemodilution. Of these, seven were not included in the analysis because of technical errors. Of the remaining 69 dogs, 35 were treated with hemodilution; 28 were subjected to a 6-hour period of temporary occlusion of the distal internal carotid artery and the proximal middle cerebral artery, and seven underwent a sham operation only, with arterial manipulation but no occlusion. The other 34 dogs were not subjected to hemodilution; 26 of these underwent temporary arterial occlusion and eight had a sham operation only. In each group the animals were about equally divided into 1) an acute protocol with regional cerebral blood flow measurements by a radioactive microsphere technique and sacrifice at the end of the acute experiment, and 2) a chronic protocol with survival for 1 week to permit daily neurological assessment and final histopathological examination but without blood flow measurements. Isovolemic hemodilution was performed about 1 hour after the arterial occlusion or sham operation and was accomplished by phlebotomy and infusions of low molecular weight dextran to bring the hematocrit to a level of 30% to 32%. This treatment resulted in a very significant reduction in viscosity and fibrinogen levels. The decrease in hematocrit lasted throughout the week in the animals in the chronic protocol. The decrease in viscosity correlated almost linearly with the decrease in hematocrit. There was a slight decrease in systemic arterial pressure with hemodilution but there were no significant changes in central venous pressure or in pulmonary arterial or wedge pressure. There was a slight decrease in cardiac index in both the hemodilution and control groups, which may have been due to the effects of barbiturate anesthesia. There was a slight increase in the measured blood volume in both groups, which was probably artifactual and related to the method of calculation. Intracranial pressure increased significantly with time in all animals subjected to arterial occlusion, but this increase was less severe in the hemodilution group. There was no significant change in intracranial pressure in sham-operated animals, whether hemodiluted or not. The results of cerebral blood flow measurements, assessment of neurological conditions, and measurement of infarct size are given in Part 2 of this report.

Irrigation of the subarachnoid space after aneurysmal subarachnoid hemorrhage (SAH) has been reported to alleviate subsequent arterial vasospasm. The authors have investigated the effect of lavage of the cerebrospinal fluid (CSF) space in the two-hemorrhage canine model of vasospasm. Twelve dogs had basilar cistern lavage with 120 cc of artificial CSF 24 hours after each of two SAH's, and 12 control dogs had two sequential SAH's without intervening lavage of clot. The amount of clot on the ventral brain stem was evaluated at sacrifice and was graded from 0 (no clot) to 4 (maximum clot) to assess the adequacy of clot removal. Dogs that had undergone lavage had a median grade of 1 (range Grade 0 to 2); control dogs had a median grade of 2 (range Grade 1 to 3.5, p less than 0.001. Wilcoxon rank sum test), indicating significant reduction of gross clot by lavage. The neurological findings were graded from 0 to 5, based on meningismus, ataxia, paresis, and cranial nerve deficits. No significant differences in neurological grade were found on any day between the two groups. Satisfactory angiograms were obtained before and 7 days after hemorrhage and were controlled for blood pressure and blood gases; these showed significant spasm in both groups. There was a mean reduction (+/- standard deviation) of 21.6% +/- 16.2% in basilar artery diameter in control dogs, compared to a 28.8% +/- 15.1% reduction in dogs with lavage (difference not significant, t-test). There was a strong, but insignificant, trend toward reduction of endothelial desquamation in the basilar and middle cerebral arteries in dogs with lavage compared to control animals (p = 0.06). Corrugation and tearing of the elastica, thickened intima, intimal fibroplasia, vacuolization of the endothelial or smooth-muscle cells, and presence of blood cells in the adventitia occurred similarly in both groups. It appears that cisternal lavage 24 hours after hemorrhage in this model has no effect on the angiographic, neurological, or most morphological sequelae of SAH, in spite of evidence for removal of clot as seen at sacrifice. Any postulated interaction of clot and vessel resulting in chronic vasospasm must occur before this time. Evaluation of the effect of much earlier lavage (for instance, 1 hour after hemorrhage) may elucidate the point at which vasospasm is instigated after SAH, and help in determining what factors cause vasospasm.

Experimental subarachnoid hemorrhage (SAH) was induced in adult rabbits by three repeated cisterna magna injections of autologous nonheparinized blood. One week after the last blood injection the animals were sacrificed and examined for morphological change. No vasculopathy was noted in the basilar arteries and no periarterial thrombus was seen around the majority of these arteries. Gross and microscopic changes were observed in both the ventricles and choroid plexus. Ventricular changes included dilation of the lateral ventricles, destruction of ciliated ependymal cells, and deposition of small amounts of blood throughout the ventricular system. These ventricular changes are similar to the pathological sequelae of SAH in patients. Choroid plexus changes included electron-dense cytoplasmic inclusions and dilation of the lateral and subcellular spaces. The ventricular surface and the choroid plexus are both affected by the intracisternal injection of blood. The hydrocephalus that follows SAH may be potentiated by ependymal disruption and loss of ciliated activity in the ventricles. Changes in choroid plexus function may also occur.

Approximately 25% of patients with pituitary adenomas have no clinical or biochemical evidence for excess hormone secretion and are classified as having null cell or nonfunctioning adenomas. To characterize the cell type of these tumors, we analyzed pituitary hormone gene expression in clinically nonfunctioning pituitary adenomas using specific oligonucleotide probes for the messenger (m)RNAs encoding growth hormone, prolactin, ACTH, and the glycoprotein hormone subunits, alpha, luteinizing hormone (LH)beta, follicle-stimulating hormone (FSH)beta, and thyroid-stimulating hormone (TSH)beta. Expression of one or more of the anterior pituitary hormone genes was found in 12/14 (86%) of the patients with clinically classified nonfunctioning adenomas. Expression of one or more of the glycoprotein hormone genes (alpha, LH beta, FSH beta, TSH beta) was identified most commonly (79%) with expression of multiple beta-subunit genes in many cases. Expression of alpha-subunit mRNA was found in each of the adenomas from patients expressing one of the beta-subunit mRNAs and in three patients with no detectable beta-subunit mRNA. Although FSH beta and LH beta mRNAs were found with similar frequencies in nonfunctioning adenomas, expression of FSH beta mRNA was generally much more abundant. TSH beta mRNA was detected in only one adenoma. The levels of glycoprotein hormone subunit mRNAs were variable in different adenomas, but the lengths of the mRNAs and transcriptional start sites for the alpha- and beta-subunit genes were the same in the pituitary adenomas and in normal pituitary. Growth hormone and prolactin gene expression were not observed in the nonfunctioning adenomas, but ACTH mRNA was found in a single case. Immunohistochemistry of the adenomas confirmed production of one or more pituitary hormones in 13/14 (93%) nonfunctioning tumors, with a distribution of hormone production similar to that of the hormone mRNAs. These data indicate that pituitary adenomas originating from cells producing glycoprotein hormones are common, but are difficult to recognize clinically because of the absence of characteristic endocrine syndromes and defective hormone biosynthesis and secretion.

Study Objective: To determine whether men with hypogonadism are at risk for hyperlipidemia., Design: Case-control study., Setting: Neuroendocrine clinical center of a referral-based university medical center., Patients: Consecutive sample of 18 men with testosterone deficiency who had prolactin-secreting pituitary adenomas, 15 men with acquired secondary hypogonadism and normal prolactin levels, and 33 normal male controls., Measurements and Main Results: We found a significant elevation in fasting cholesterol (6.23 +/- 0.28 mmol/L [mean +/- SE] compared with 5.17 +/- 0.13 mmol/L [241 +/- 11 mg/dL compared with 200 +/- 5 mg/dL], P less than 0.01), low density lipoprotein (LDL) cholesterol (4.11 +/- 0.23 mmol/L compared with 3.34 +/- 0.13 mmol/L [159 +/- 9 mg/dL compared with 129 +/- 5 mg/dL], P less than 0.05), and triglycerides (1.85 +/- 0.26 mmol/L compared with 1.11 +/- 0.07 mmol/L [164 +/- 23 mg/dL compared with 98 +/- 6 mg/dL], P less than 0.001) in men with hyperprolactinemia compared with controls. In the normoprolactinemic hypogonadal men, cholesterol (6.28 +/- 0.34 mmol/L [243 +/- 13 mg/dL], P less than 0.01), LDL cholesterol (4.34 +/- 0.34 mmol/L [168 +/- 13 mg/dL], P less than 0.01), and triglycerides (1.61 +/- 0.18 mmol/L [143 +/- 16 mg/dL], P less than 0.05) were also significantly higher than in the controls, and were the same as in the hyperprolactinemic men. High density lipoprotein (HDL) cholesterol did not differ among the three groups., Conclusions: Hypogonadism in men, with or without hyperprolactinemia, may be associated with elevation of fasting serum cholesterol, LDL cholesterol, and triglycerides compared with normal men. These data suggest that serum lipid levels should be evaluated in hypogonadal men. The presence of lipid abnormalities may affect the decision to treat testosterone deficiency in these patients.

Two hundred fifty-five consecutive transsphenoidal procedures for pituitary adenomas were reviewed to evaluate complications and their management. There were no operative deaths. Cerebrospinal fluid (CSF) rhinorrhea was the most common complication, occurring in 2.7% of cases; diabetes insipidus was next, lasting less than 1 year in 1.6% of patients and over a year in 0.4%. Sinusitis occurred in 1.2% of patients, and delayed epistaxis occurred in 0.8%. Postoperative hematomas, meningitis, hydrocephalus, and deep venous thrombosis each occurred in 0.4% of cases. These results are discussed in the context of previous reports, including an international survey of pituitary surgeons. Although transsphenoidal surgery has a low morbidity and mortality, it is nevertheless associated with potentially serious difficulties that should be expeditiously recognized and managed.

Pituitary tumors secreting intact glycoprotein hormones (LH, FSH, and TSH) and/or alpha-subunit are being increasingly recognized. Because chronic administration of GnRH analogs decreases gonadotropin secretion in normal subjects, we investigated gonadotropin and alpha-subunit responses to chronic GnRH analog administration in five men with glycoprotein hormone-secreting pituitary tumors. Two patients (patients A and B) received the GnRH agonist analog (D-Trp6-Pro9-NEt-LHRH) for 4 weeks as a daily sc dose (8 micrograms/kg.day). In both, secretion of LH and/or alpha-subunit increased markedly. Subsequently, three patients received a higher analog dose (32 micrograms/kg.day) for a longer duration (8 weeks). One patient with a LH- and FSH-secreting tumor (patient C) had a highly significant (P less than 0.001) fall in serum LH and FSH concentrations; however, alpha-subunit secretion increased. During a subsequent study, when this patient received a lower dose (8 micrograms/kg.day) for 8 weeks, gonadotropin suppression also occurred. In two additional patients who received this dose (32 micrograms/kg.day), it had a persistent agonist effect on FSH beta (patient D) and alpha-subunit secretion (patient E). A marked increase in alpha-subunit secretion occurred in all five patients, regardless of whether basal serum alpha-subunit concentrations were elevated. These patients received the GnRH analog at doses 2-8 times greater than those that suppress gonadotropin secretion in normal men. Serum LH and FSH concentrations decreased in only one patient with a gonadotropin-secreting adenoma. The serum LH and FSH responses to acute GnRH stimulation did not predict the gonadotropin responses to chronic GnRH analog administration. Thus, gonadotropin and alpha-subunit production by most pituitary adenomas is augmented during chronic GnRH analog administration, consistent with defective GnRH desensitization in the adenomatous tissue. Despite the heterogeneous gonadotropin responses to the GnRH analog in these patients, serum alpha-subunit levels increased in all patients, indicating dissociation in the secretion of intact gonadotropins and alpha-subunit.

A prospective, randomized clinical trial in 95 patients undergoing neurosurgical operative procedures was performed to investigate the efficacy of external pneumatic compression (EPC) of the calves as compared with results in a control group that received no specific form of prophylaxis for prevention of deep vein thrombosis (DVT). The diagnosis of DVT was established by the I125 fibrinogen scan and radiographic contrast phlebography. The data indicate that EPC provides significant protection against the development of DVT in comparison with results in the control group (p less than 0.005). There were no known pulmonary emboli in any of the EPC-treated patients. There were no complications of EPC.

A survey of neurosurgeons and neurologists assessed physician practices in the declaration of brain death. Ninety-four per cent of the respondents thought that the diagnosis of brain death was legitimate; most thought that it was justified by a failure of somatic survival after brain death. Fifty-four per cent of the respondents had made the diagnosis themselves 1 to 5 times a year. The criteria used to make the diagnosis varied significantly among the respondents. Most required the absence of a pupillary reflex (88%), the absence of a corneal reflex (85%), a lack of ventilatory effort with disconnection of the ventilator (84%), and the absence of eye movements with head turning (80%). Fewer required an absent cough reflex (61%) or gag reflex (69%), dilated pupils (59%), a body temperature under 90 degrees F (56%), or a blood barbiturate level of zero (43%). Over 65% required an isoelectric electroencephalogram; 29% required only one, and 36% required two electroencephalograms 24 hours apart. Twenty-six per cent required absent deep tendon reflexes. The time required for the declaration varied from 6 to 24 hours. There was wide variation in the response to a hypothetical situation in which the family of a patient fulfilling brain death criteria did not want death to be declared. Seventy-eight per cent of the respondents would continue ventilatory support, although about a third of these would declare the patient dead while doing so. Only 6% would stop the ventilator despite the family's wishes. These results substantiate a wide variation in the actions of neurologists and neurosurgeons in brain death declaration. This has important implications for decisions about death in neurology and neurosurgery.

alpha-Subunit and gonadotropin responses to a LHRH infusion (0.2 micrograms/min) for 4 h were studied in eight hyperprolactinemic amenorrheic women, ages 23-40, and in five normal women in the early follicular phase of the menstrual cycle. Basal alpha-subunit and LH concentrations were comparable to normal women; however, basal FSH concentrations were significantly (P less than 0.05) lower. Peak serum alpha, LH, and FSH concentrations during the LHRH infusion were significantly higher than controls (P less than 0.01, P less than 0.05, and P less than 0.01, respectively). Gel chromatography of serum confirmed the presence of both free alpha-subunit and intact LH which had normal biological activity. Six of the women were restudied in the early follicular phase of the cycle after return of normal ovulatory function and normalization of serum PRL concentrations. During bromocriptine therapy, peak serum alpha, LH, and FSH concentrations decreased significantly (P less than 0.02, P less than 0.05, and P less than 0.001, respectively) and were comparable to control subjects. The changes in serum alpha and gonadotropin responses to the LHRH infusion during bromocriptine therapy occurred independently of the serum estradiol concentrations. Abnormalities in the regulation of alpha-subunit and gonadotropin secretion are present in hyperprolactinemia. These abnormalities reverse with bromocriptine therapy and may occur independently of changes in gonadal steroids.

Local cerebral blood flow was measured with the hydrogen clearance technique during intravenous infusion of nitroprusside in monkeys. Concentrations of the drug required to reduce the mean arterial blood pressure by less than 40% resulted in no significant change or only a slight increase in regional cerebral blood flow. Larger doses, however, produced a loss of cerebral autoregulation, thereby inducing a drop in cerebral blood flow. Intracranial pressure rose proportionately to the nitroprusside dose during the infusion.

The unexpected finding of an extension of a neurogenic tumor from the thorax through the spinal foramen into the neural canal complicates its removal. Serious neurological complications may result from a two-stage approach, whether done first through the thorax or neural canal. Vertebral tomography or computed tomographic scanning reveals enlargement of a spinal foramen in advance of operation. Myelography confirms the probable presence of an intraspinal component. Four patients have been operated on using an approach designed to allow wide posterolateral thoracotomy and concomitant laminectomy for single-stage removal of the entire tumor. In 3 patients the diagnosis was schwannoma and in 1, neurofibroma. All had good results.

An overview of the possible factors that might contribute to the development of cerebral vasospasm is presented, with particular emphasis on the possibility that spasm arises from a malfunction of the regulatory or contractile processes in smooth muscle cells. This possibility is emphasized because the evidence for cellular damage and the delayed occurrence of vasospasm are suggestive of pathological alteration. Data regarding the development of spasm in vivo has been reviewed and, to the extent possible, correlated with in vitro studies of cerebrovascular smooth muscle contractility. Short-term in vitro studies of normal cerebral arteries may be of little relevance to the prolonged and severe cerebral vasoconstriction that occurs only after a delay of several days from the initial insult.

Pituitary tumors in which no excess hormone secretion can be identified clinically have been considered as nonfunctioning or null-cell adenomas. Immunocytochemical data presented here suggest that many of these tumors contain subunits of the glycoprotein hormones. Of 160 patients referred for pituitary surgery, 37 (23%) had no evidence of excess hormone secretion on preoperative endocrine evaluation. Immunocytochemical staining of these tumors was carried out using antibodies specific for prolactin, growth hormone, adrenocorticotropic hormone, the beta subunits of luteinizing hormone (beta-LH), follicle-stimulating hormone (beta-FSH), and thyroid-stimulating hormone (beta-TSH), and the alpha subunit. One or more of these pituitary hormones were detected in 73% of cases. The alpha and beta subunits were detected most frequently, being found in 68% of cases; 27% had staining for one or more beta subunits and 37.9% had staining for both alpha and beta subunits. The incidence was: beta-FSH in 58%, beta-LH in 47%, beta-TSH in 33%, and the alpha subunit in 42%. Staining for multiple glycoprotein hormones was common (52%), and mixed glycoprotein hormones and prolactin cell types were found in 16% of cases. These data suggest that most apparently nonfunctioning pituitary tumors contain immunoreactive hormones and the majority of these are subunits of the glycoprotein hormones. Since the glycoprotein hormone beta subunits must combine with the alpha subunit to produce biologically active hormones, the production of the subunits alone may not have endocrine manifestations.

We evaluated the ability of transsphenoidal surgery to produce visual improvement, endocrine remission, and complete tumor removal in 113 patients with pituitary adenomas extending beyond the sella turcica. Eighty-one percent of patients with preoperative visual field defects had postoperative improvement, 19% had no change, and none deteriorated significantly. Seventy-nine percent of patients with diminished preoperative visual acuity had postoperative improvement; none deteriorated. Endocrine remission of functioning tumors was achieved in 43% of patients and complete resection by computed tomography scanning was also obtained in 43%. There were no deaths in this series and the major complication was cerebrospinal fluid leak, which occurred in 3% of patients. Comparison with transfrontal surgery suggests that these results are as good as those with transfrontal procedures and that the incidence of serious side effects is considerably lower. Transsphenoidal surgery is safe and effective in the surgical management of large pituitary adenomas.

Clinical trials for abatement of intractable pelvic cancer pain were conducted in two patients, each electing surgical implantation of one of two indwelling catheter systems for administration of morphine into the spinal epidural space. Both systems, one consisting of a partially indwelling Broviac catheter, and the other, completely indwelling, consisting of a morphine reservoir connected to a shunt pump and on-off Hakim valve assembly, permitted the patients to return home where they could self-administer epidural morphine. Each patient reported that 2 mg of epidural morphine provided 8 to 12 hours of pain relief at a level of superior to their previous narcotic medication. On a regimen of 2 mg of epidural morphine administered twice daily, both patients experienced analgesia for 6 months, unaccompanied by alterations in sensory, motor, or cognitive functioning, and with a little drug tolerance reaction.

Profound vascular damage secondary to high-flow extracranial states has been well characterized. However, changes in cerebral vasculature secondary to high-flow states have not been studied. To determine changes related to high-flow states in cerebral vessels, a rabbit model was developed in which torrential flow was created in the vertebrals, carotids, basilar, and vessels of the circle of Willis by means of a carotid-jugular shunt after ligation of the proximal carotid. The clinical, angiographic, and histologic changes noted in the animal model include: abrupt clinical deterioration after a variable interval with some animals developing ptosis, afferent vessel dilatation and the development of prominent anastomotic channels, variable cerebral vessel histopathology--related to duration and relative proximity to the shunt--affecting all three vessel layers, plump, irregular, and clumped endothelium, denuded with adherent platelets, irregular, duplicated, and thinned internal elastic membrane, frayed with invasion of the intima by mesenchymal cells, vacuolization and necrosis of the media muscle, and invasion of adventitia by foreign cells and small blood vessels. The high-flow angiopathy seen in this model may help explain vascular changes associated with high-flow cerebral vascular lesions, as well as other types of vascular damage.