Activating mutations of the Gs alpha-gene in nonfunctioning pituitary tumors.

The majority of pituitary tumors are of monoclonal origin; however, the molecular basis for their formation is poorly understood. Somatic mutations in the alpha-subunit of the GTP-binding protein, Gs alpha (gsp oncogene) have been found in about one third of GH-secreting tumors. Mutations in another alpha-subunit of a GTP-binding protein, Gi2 alpha (gip mutations) have been described in other endocrine tumors. In this study, we examined 21 nonfunctioning pituitary tumors and 4 macroprolactinomas for gsp mutations and 27 nonfunctioning tumors and 4 macroprolactinomas for gip mutations. Using the polymerase chain reaction and denaturing gradient gel electrophoresis, 2 nonfunctioning pituitary tumors displayed migration abnormalities when the Gs alpha-gene was analyzed. Sequence analysis of these abnormally migrating polymerase chain reaction products revealed two previously known gsp mutations: arginine at codon 201 altered to cysteine, and glutamine at codon 227 changed to leucine. No gip mutations could be demonstrated. These findings emphasize the monoclonal origin of nonfunctioning pituitary tumors and suggest that cAMP may play a role in tumorigenesis of nonfunctioning pituitary tumors.

Relative sparing of anterior pituitary function in patients with growth hormone-secreting macroadenomas: comparison with nonfunctioning macroadenomas.

Pre- and postoperative anterior pituitary function was assessed in 26 subjects with nonfunctioning macroadenoma (NFMA) and in 15 acromegalic subjects with macroadenomas. Preoperatively, NFMA patients had a higher prevalence of secondary hypogonadism (78% vs. 40%; P < 0.05), hypothyroidism (23% vs. 0%; P = 0.06), and hypoadrenalism (43% vs. 7%; P = 0.02) compared to individuals with GH-secreting macroadenoma (GHMA). Patients with NFMA also had a higher prevalence of more severe pituitary failure compared with acromegalic patients; 56% of the patients in this group had more than one pituitary hormone axis impaired compared to only 8% in the acromegalic group. These differences could not be accounted for by tumor grade and/or stage. Transsphenoidal pituitary surgery led to a significant improvement in anterior pituitary function in the NFMA group. Nevertheless, the prevalence of pituitary deficiency postoperatively was still significantly greater in NFMA patients than in the acromegalic group (68% vs. 17%, respectively; P < 0.04). The results suggest that anterior pituitary function is better preserved in GHMA than in NFMA and that this difference is independent of tumor size. The mechanism underlying the lower rate of hypopituitarism in acromegalics with macroadenomas remains to be elucidated.

Electrocardiographic findings in brain death; description and presumed mechanism.

Electrocardiogram changes and pharmacologic responses were studied in 28 cases of brain death. Cardiac activity in this condition is possibly determined by the dynamic balance between the depressant action of hypothermia and the stimulating action of the sympathetic nervous system (without any vagal or central influence). The electrocardiographic alterations are the results of this dual influence, and are probably characteristic of this condition. In the initial stage of brain death the ECG shows J waves in the terminal part of the QRS, prolongation of the QT interval and the ST-T changes; in the advanced stages, progressive showing of the heart rate and the depolarization and repolarization processes are observed (manifested by gradual accentuation of the findings mentioned above); in the terminal stage dynamic electrocardiographic changes (among them, progressive depression of sinus activity, atrial fibrillation, atrioventricular and intraventricular conduction disturbances and severe ST-T changes) appear. It is possible that additional factors, like metabolic changes and possible myocardial damage in some instances, may have some influence on the electrocardiographic pattern. Final conclusions cannot be drawn from these preliminary observations. The atropine test was found to be an efficient and simple diagnostic aid in cases of brain death.

Saphenous nerve entrapment simulating vascular disorder.

Saphenous nerve entrapment may cause a painful syndrome simulating vascular disorder of the leg. The anatomical relationship of the saphenous nerve is described to explain the pathogenesis of the syndrome. The clinical features, diagnosis, and results of treatment of 32 patients are reported. The differential diagnosis of the syndrome is discussed. It is concluded that entrapment of the saphenous nerve should be considered when other known syndromes are unable to explain the symptomatology.

Organization of layers II-III connections in human visual cortex revealed by in vitro injections of biocytin.

In the search for cortical mechanisms subserving psychological phenomena, a better understanding of human cortical circuitry is crucial. In this report we describe aspects of intrinsic connectivity of supragranular layers in human visual cortex, revealed by extracellular injections of the anterograde tracer biocytin in vitro. Human cortical slices were obtained from visual association cortex in the posterior-medial portion of the dorsal bank of the occipital lobe, removed during neurosurgical tumor ablations. Small iontophoretic injections of biocytin into layers II-III revealed intense Golgi-like staining of axonal projections emanating from the injection sites. Vertically descending axons are grouped in bundles 20 microns in diameter which are spaced 15 microns apart. Some of these axons enter the white matter and send long oblique and horizontal collaterals. The main horizontal spread of the axons could be observed in layers II-III and V. The bulk of projections extends to a distance of 1.5 mm in layers II-III and 1.1 mm in layer V. Few individual axons could be observed at greater distances. In contrast, layer IV is almost devoid of horizontal connections, forming a clear gap between supra- and infragranular layers. Axon collaterals in the infragranular layers project mostly in a descending oblique direction with long horizontal collaterals in lower layer VI.

Cortical spreading depression recorded from the human brain using a multiparametric monitoring system.

The number of parameters (i.e., EEG or ICP-intracranial pressure) routinely monitored under clinical situations is limited. The brain function analyzer described in this paper enables simultaneous, continuous on-line monitoring of cerebral blood flow (CBF) and volume (CBV), intramitochondrial NADH redox state, extracellular K+ concentrations, DC potential, electrocorticography and ICP from the cerebral cortex. Brain function of 14 patients with severe head injury (GCS < or = 8), who were hospitalized in the neurosurgical or general intensive care unit was monitored using this analyzer. Leao cortical spreading depression (SD) has been reported in many experimental animals but not in the human cerebral cortex. In one of the patients monitored, spreading depression was observed. This is the first time that spontaneous repetitive cortical SD cycles have been recorded from the cerebral cortex of a patient suffering from severe head injury. Typical SD cycles appeared 4-5 h after the beginning of monitoring this patient. During the first 3-4 cycles the responses of this patient were very similar to the responses to SD recorded in normoxic experimental animals. Electrocorticography was depressed whereas extracellular K+ levels increased. The metabolic response to spreading depression was characterized by oxidation of intramitochondrial NADH concomitant to a large increase in CBF. During brain death, an ischemic depolarization, characterized by decrease in CBF and an irreversible increase in extracellular K+, was recorded.

Nasal visual field loss with intracranial lesions of the optic nerve pathways.

Five patients developed nasal visual field defects as a result of involvement of the intracranial portion of the optic nerves. The cause in each patient, respectively, was as follows: (1) dolichoectatic carotid arteries, (2) optochiasmatic arachnoiditis, (3) meningioma of the olfactory groove, (4) pituitary apoplexy, and (5) pituitary chromophobe adenoma. The common factor in these cases was probably impaired circulation in the prechiasmal arterial anastomotic network. The nasal visual field loss present in these cases was characterized by a pattern similar to that seen in glaucoma but with impairment of visual acuity. The superior nasal visual field was usually normal and the lower temporal visual field often defective.

New trend in neuroscience: low-power laser effect on peripheral and central nervous system (basic science, preclinical and clinical studies).

The present review summarizes findings in our continuing study of the use of low-power laser irradiation (LPLI) in the treatment of severely injured peripheral (PNS) and central nervous systems (CNS). The radiation method was proposed by Rochkind and has been modified over the last 13 years. LPLI in specific wavelengths and energy density maintains the electrophysiological activity of severely injured peripheral nerve in rats, preventing scar formation (at injury site) as well as degenerative changes in the corresponding motor neurons of the spinal cord, thus accelerating regeneration of the injured nerve. Laser irradiation applied to the spinal cord of dogs following severe spinal cord injury and implantation of a segment of the peripheral nerve into the injured area diminished glial scar formation, induced axonal sprouting in the injured area and restoration of locomotor function. The use of laser irradiation in mammalian CNS transplantation shows that laser therapy prevents extensive glial scar formation (a limiting factor in CNS regeneration) between a neural transplant and the host brain or spinal cord. Abundant capillaries developed in the laser-irradiated transplants, and was of crucial importance in their survival. Intraoperative clinical use of laser therapy following surgical treatment of the tethered spinal cord (resulting from myelomeningocele, lipomyelomeningocele, thickened filum terminale or fibrous scar) increases functional activity of the irradiated spinal cord. In a previous experimental work, we showed that direct laser treatment on nerve tissue promotes restoration of the electrophysiological activity of the severely injured peripheral nerve, prevents degenerative changes in neurons of the spinal cord and induces proliferation of astrocytes and oligodendrocytes. This suggested a higher metabolism in neurons and improved ability for myelin production under the influence of laser treatment. The tethering of the spinal cord causes mechanical damage to neuronal cell membranes leading to metabolic disturbances in the neurons. For this reason, we believe that using LPLI may improve neuronal metabolism, prevent neuronal degeneration and promote improved spinal cord function and repair. The possible mechanism of LPLI is investigated. Using electron paramagnetic resonance in cell culture models, we found that at low radiation doses, singlet oxygen is produced by energy transfer from porphyrin (not cytochrome as commonly assumed) which is known to be present in the cell. At low concentration, singlet oxygen can modulate biochemical processes taking place in the cell and trigger accelerated cell division. On the other hand, at high concentration, singlet oxygen damages the cell.(ABSTRACT TRUNCATED AT 400 WORDS)

Hydrocephalus and headaches in Paget's disease of the skull: complete relief by ventriculo-atrial shunt.

A 76 year old patient with a long history of headaches was found to have Paget's disease and communicating hydrocephalus. There were (otherwise) no neurological or musculo-skeletal manifestations of Paget's disease, but moderate impairment of intellectual function was present. Treatment with disphosphonates did not bring any significant improvement, but three days following a ventriculo-atrial shunting procedure, the patient became headache-free for the first time in several years. In the literature, patients with hydrocephalus have been shown to respond quite unevenly to atrio-ventricular shunting, but in most instances the descriptions concerned advanced cases with well-established symptoms of dementia, ataxia and incontinence. Our case is reported to stress the importance of early diagnosis and management of hydrocephalus in Paget's disease for the prevention of widespread neurological dysfunction.

Microsurgical anatomy of the pituitary gland and the sellar region. 1. The pituitary gland.

The microsurgical anatomy of the pituitary gland was studied on dissections of 250 cadaver sphenoidal blocks and on detailed operative reports of 266 patients who underwent transsphenoidal hypophysectomy (185 breast cancer patients and 81 patients with diabetic retinopathy). Whereas the various measurements (width, length, height, weight) and the structures of the two lobes of the pituitary gland were studied in cadavers, texture, consistency, color, and attachment to surrounding structures were best observed during surgical procedures. These latter aspects of the pituitary gland were correlated with the age, sex, and hormonal status of the patients. Variations in the shape, size, and appearance of the pituitary gland are frequent. Knowledge of such variations is important for a precise microsurgical approach to the sellar region.

Microsurgical anatomy of the pituitary gland and the sellar region. 2. The bony structures.

Measurements of the sella turcica (depth, length, width, volume, thickness of the floor, intraclinoid distance, length of tuberculum sellae) were made in cadaver sphenoid blocks, skulls, and in patients undergoing transsphenoidal surgery. Variations in the sphenoidal septae, sinuses and bulging of surrounding structures (carotid arteries and optic nerves) were studied. Results were compared with observations made during surgery and with data reported in the literature. Anatomic variations of the sella turcica and sphenoid sinus may complicate surgical intervention in the region of the sella turcica. However, these variations were never, in our experience, the cause for interruption of transsphenoidal surgery.

Geniculate neuralgia and audio-vestibular disturbances due to compression of the intermediate and eighth nerves by the postero-inferior cerebellar artery.

A compression of the intermediate, cochlear and vestibular parts of the VIII nerve by a redundant loop of the posterior inferior cerebellar artery (PICA) was found at autopsy in a patient who suffered during 21 years of geniculate neuralgia associated with tinnitus, hypoacousia and occasional dizziness. The relationship of arterial cross compression to geniculate neuralgia and audio-vestibular disturbance is discussed.

Bilateral trigeminal neuralgia.

A 56-year-old woman previously treated by a retrogasserian neurectomy for a right tic douloureux was rendered free of pain, but complete anaesthesia of the right half of her face remained. Seven years later, she developed a typical left trigeminal neuralgia. Contralateral rhizotomy was refused because of the patient's concern about having bilateral facial anaesthesia. Through a suboccipital craniectomy, the trigeminal nerve was decompressed from a thickened arachnoid membrane and a large bridging vein near the root entry zone. After eighteen months, the patient was free of pain with intact facial sensations on the left side. Therapeutic considerations in cases of bilateral trigeminal neuralgia are discussed.

Real-time multiparametric monitoring of the injured human cerebral cortex--a new approach.

Intracranial pressure (ICP) is currently the main parameter monitored following severe head injury or during the post operative period in neurosurgical patients. The normal cerebral cortex depends upon a continuous supply of O2, and direct coupling exists between adequate cerebral blood flow (O2 supply) and ion homeostasis as well as electrical activities. We have developed a new "Brain Function Analyzer-BFA" which enabled monitoring of the following parameters continuously in real time from the surface of the cortex: ICP; tissue blood flow & volume; intramitochondrial NADH redox state; DC steady potential; electrocorticography; tissue temperature. The probes were assembled in a Brain Function Multiprobe (BFM) which was connected to the brain via the burr hole procedure used for ICP monitoring. Measurements were performed in 18 comatose patients after severe head injury (GCS < or = 8) who were monitored in the ICU for 48-72 hours. The basic concept of the multiparametric monitoring approach was proven to be practical in neurosurgical patients. Clear correlations were recorded between hemodynamic, metabolic, ionic and electrical activities under various treatments administered to the patients or after pathological events. Responses similar to cortical spreading depression and ischemic depolarization were recorded from a severely head injured patient.

The evaluation of brain CBF and mitochondrial function by a fiber optic tissue spectroscope in neurosurgical patients.

The brain of neurosurgical patients are exposed to various manipulations in the ICU or during surgery. Under such conditions brain O2 balance may become negative and as a result brain vitality and function will deteriorate. In order to evaluate brain vitality in real time it is important to measure more than one parameter. The multiparametric monitoring system used in our previous study to monitor comatose patients (Mayevsky et al., Brain Res. 740: 268-274, 1996) was changed into a "simplified" tissue spectroscope for real time monitoring of brain O2 balance. Mitochondrial function was evaluated by monitoring the NADH redox state by surface fluorometry. Microcirculatory blood flow was assessed by laser Doppler flowmetry. The combined optical probe was located on the surface of the brain during various neurosurgical procedures and the responses were recorded and presented in real time to the surgeon. A total of 32 patients were monitored during various procedures. The results could be summarized as follows: 1. Hypercapnia led to 3 different types of responses. In two patients the 'stealing' like event was recorded. In the other 7 patients the responses to high CO2 was not detectable. In the last group of 6 patients a clear CBF elevation was recorded with variable response of mitochondrial NADH. 2. Our monitoring device was able to evaluate the efficacy of the STA-MCA anastomosis during aneurysm surgery. 3. A significant correlation was recorded between CBF and NADH redox state during changes in blood pressure, papaverine injection, spontaneous drop in blood supply to the brain or during releasing of high ICP levels. We conclude that in order to evaluate the metabolic state of the brain during neurosurgical procedures it is necessary to monitor both CBF and mitochondrial NADH by using the tissue spectroscope.

Brain viability and function analyzer: multiparametric real-time monitoring in neurosurgical patients.

We have developed the Brain Viability (BVA) and Brain Function (BFA) Analyzers for monitoring the following parameters from the human cerebral cortex cerebral blood flow: (CBF), NADH redox state, Electro corticography (ECoG), brain temperature, extracellular K+, DC potential and intracranial pressure (ICP). The BVA monitors the first 4 parameters only. The Brain viability probe (BVP) and Brain function multiprobe (BFM) were used during 11 operations and in 18 ICU patients, respectively. Preliminary results from the OR showed that 5 patients exhibited a typical increase in CBF in response to changes in end-tidal CO2 without a significant change in the NADH redox state. In 4 other patients no changes in CBF and NADH were observed. Two patients exhibited a "steeling response", i.e., a decrease in CBF and an increase in NADH. In 18 comatose patients monitored in the ICU, the ICP, CBF and ECoG were measured correctly in most patients, whereas NADH and K+ were more problematic. One patient exhibited a typical response, may be due to repeated cortical spreading depression cycles and an ischemic depolarization event. Continuous realtime multiparametric monitoring in neurosurgical patients is feasible and practical in the OR and the ICU. The information provided could be used as a diagnostic tool to guide the procedures or treatment given to the patients.

Diagnosis and management of posttraumatic oculorrhea.

Posttraumatic cranio-orbital cerebrospinal fluid (CSF) fistula is very rare. Diagnosis of these fistulas may be difficult, and it is possible that this complication of craniofacial injury is underdiagnosed. Early recognition and adequate treatment is of paramount importance to prevent hazardous complications. The authors report the case of a 20-year-old woman in whom a CSF leak developed through the medial canthus area of her eye after she sustained a mild sports-related injury. Clinical examination and chemical analysis of the fluid led to the correct diagnosis, and the leak was stopped with conservative treatment. It is proposed that a CSF leak through the eye be termed "oculorrhea" as compared with otorrhea and rhinorrhea. The mechanism of the fistula in this patient is discussed, as is the pertinent radiologically demonstrated anatomy and the mechanism of injury. Management and controversies are also discussed.

[Multiple intracranial aneurysms associated with primary hyperaldosteronism]. / Anévrysmes intracrâniens multiples associés à un hyperaldostéronisme primaire.

Multiple intracranial aneurysms have been reported in association with polycystic disease of the kidney, brain tumor, pituitary adenoma and coarctation of the aorta. We report the association of multiple aneurysms with primary hyperaldosteronism due to bilateral adrenal hyperplasia in an 18 year old left-handed man who presented with subarachnoid hemorrhage and arterial hypertension. We report the excellent outcome of this patient in spite of a difficult and surgical management. Ligation of all three intracranial aneurysms was performed after an extra-intracranial arterial bypass was done as a protective measure.

[Late post-traumatic syringomyelia. Discussion apropos an atypical case]. / Syringomyélie post-traumatique tardive? Discussion à propos d'un cas atypique.

Late post-traumatic syringomyelia is uncommon, the clinical signs appearing several years after severe trauma to the cervical spinal cord. It is due to progressive cavitation in the spinal cord. In the case reported here progress was atypical because there were no immediate neurological signs and the symptoms of syringomyelia developed only 3 weeks after injury. Several possibilities are open to discussion. Was the trauma responsible for the syringomyelia? Did it cause an aggravation of a pre-existing hydromyelia or were both lesions purely coincidental? A silicon tube draining the cavity in the cord to the subarachnoid space resulted in a real improvement in the neurological condition.

[Experimental microsurgery on submillimetric vessels: technic and results (author's transl)]. / Microchirurgie vasculaire expérimentale submillimétrique: technique et résultats.

This experimental work presents the results of 180 submillimetric microvascular interventions performed on the carotid arteries and jugular veins of 130 white rats weighting 100-150 g each. End to end (54 cases), end to side (76 cases) anastomosis, repair of arteriotomies by microsutures (30 cases) or patch graft (20 cases) were performed on submillimetric vessels (0.5 to 0.8 mm). Rats were used as acute preparation (70 cases) for the development of technical skill but in 100 cases they were kept alive between 1 to 3 weeks and then operated again. The patency rate, confirmed by arteriographies in 32 cases, was about 92%. At the end of training all the microvascular surgical procedures, even the most sophisticated, were patent at 100 %. The discussion emphasizes some points of technic concerning the choice of micro-instruments, sutures and clips and the realisation of submillimetric micro-anastomosis.