Cortical expression of prolactin (PRL), growth hormone (GH) and adrenocorticotrophic hormone (ACTH) is not increased in experimental traumatic brain injury.

BACKGROUND: Cerebral cortical expression of the pituitary hormones prolactin (PRL) and growth hormone (GH) have reported in ischemic damage. Both hormones may be involved in vascular tone regulation and angiogenesis, and growth hormone is thought to be neuroprotective while prolactin stimulates astrogliosis. METHODS: We examined expression of prolactin, growth hormone and adrenocorticotrophic hormone (ACTH) using tissue microarray technology in the controlled cortical impact model of traumatic brain injury (TBI). FINDINGS: No increased expression of these hormones was seen. CONCLUSIONS: Unlike ischemia, traumatic brain injury does not result in up-regulation of the pituitary hormones PRL and GH in cerebral cortex.

Pro-inflammatory and pro-apoptotic elements of the neuroinflammatory response are activated in traumatic brain injury.

BACKGROUND: The inflammatory response may contribute to cerebral edema, increased intracranial pressure and cellular loss in traumatic brain injury (TBI). Cytokines are biomarkers of this inflammatory response and new methods allow simultaneous measurement of multiple cytokines. METHODS: We examined the IL-1beta, IL-6, IL-8 and IL-12, TNFalpha, and IL-10 in arterial and jugular blood as well as cerebrospinal fluid in patients with severe traumatic brain injury. FINDINGS: Multiple cytokines, particularly pro-inflammatory cytokines, are up-regulated following TBI. Cerebrospinal fluid and arteriovenous differences of some of the cytokines suggest production within the central nervous system. Antiinflammatory cytokines are not up-regulated. CONCLUSIONS: Cytokine up-regulation may contribute to the neuroinflammatory reaction that follows traumatic brain injury and may contribute to secondary injury.

Cerebral phaeohyphomycosis caused by ladophialophora bantiana and Fonsecaea monophora: report of three cases.

Three cases of cerebral phaeohyphomycosis are described. Two cases (Cases 1, 2) are caused by highly neurotropic fungi, Cladophialophora bantiana, and the other one (Case 3) is the first reported case in the United States, caused by the newly defined Fonsecaea monophora. (Case 1): A 65-year-old woman had been treated for a presumed diagnosis of Guillain-Barré syndrome and was found to have a ring-enhancing, fluid-filled lesion in the right frontal lobe. The lesion was aspirated twice and then resected completely. (Case 2): A 45-year-old woman with a history of severe dermatomyositis presented with subacute ischemia in the left brainstem. Approximately 2 months later, she developed acute obstructive hydrocephalus and was found to have small cystic lesions in the left ambient cistern, fourth ventricle and cerebral aqueduct, which had probably caused the previous ischemic symptoms due to emboli/ thrombi. (Case 3): A 62-year-old, post livertransplant woman developed multiple brain and bone abscesses. Cultures from these lesions grew the same fungi. Histologically, all three cases revealed multiple epithelioid and giant cell granulomata with groups of golden-brown yeast-like cells as well as chains of budding cells. In Case 3, scattered muriform cells, characteristic of chromoblastomycosis, were present. In Cases 2 and 3, the fungi were easily identified on frozen sections, which may be considered useful in determining post-operative therapy.

Microdialysate nitrate/nitrite levels following severe head injury.

Nitric oxide (NO) has important regulatory functions within the central nervous system. The purpose of this study was to measure the concentration of nitric oxide in the brain after severe traumatic brain injury. NO is oxidized in vivo to nitrate and nitrite. Measurement of these products gives an index of NO production. Laboratory studies have shown a good correlation between NO measured directly with an electrode, and indirectly by microdialysis nitrate/nitrite. Using chemiluminescence method we measured nitrate/nitrite levels in 2024 microdialysate samples obtained from 24 patients during the first five days following severe head injury. We used CMA 70 probe (AB Microdialysis, Sweden) perfused by normal saline at a rate of 2 microliters/min. The median values of nitrate/nitrite for the whole group were highest on day 1 and gradually decreased over the 5 day monitoring period (day 1-19.2 mumol/l, day 5-12.7 mumol/l). Average values were lowest in the patients that died of their injury (14.3 mumol/l), and highest in patients who recovered by 3 months after injury with a moderate or severe disability (25.8 mumol/l or 31.9 mumol/l). In addition, there was a strong interaction between the severity of neurological injury and the change in dialysate nitrate/nitrite over time. The results suggest that nitric oxide may have a role in secondary injury mechanisms, but that this role is complex and varies as the injury evolves over time.

Measurement of the nitric oxide metabolites nitrate and nitrite in the human brain by microdialysis.

To examine the feasibility of measuring the nitric oxide (NO) metabolites nitrate and nitrite in microdialysate samples from the human brain, microdialysis probes were placed in normal appearing cerebral cortex of severely head injured patients in the Neurosurgical Intensive Care Unit at Ben Taub General Hospital. Nitrate/nitrite analysis was performed using NO chemiluminescence. Low micromolar levels of NO metabolites were consistently and easily detected. These levels seen are comparable to levels reported in CSF but tissue tortuosity and probe recovery considerations suggest that the absolute concentrations at the probe site are probably ten fold higher. Microdialysis with measurement of nitric oxide metabolites is technically feasible and may provide valuable insights into both normal neurochemistry and neurochemical derangements in disease.

Comparison of microdialysate arginine and glutamate levels in severely head-injured patient.

L-arginine concentrations in the brain are of interest following TBI because L-arginine is the immediate precursor of nitric oxide (NO). In addition, in vitro studies suggest that glutamate, which is a mediator of secondary injury after TBI, may stimulate release of arginine from glial cells. This study examines arginine concentrations in brain tissue using the microdialysis technique after human TBI. From 78 TBI patients, a total of 1739 microdialysate samples were collected using a CMA-70 probe perfused with normal saline at 2 microliters/min and concentrations of amino acids in microdialysate were determined. Amino acid concentrations for each patient were averaged for 8-hour periods during the first 3 days after injury, and daily for postinjury days 4 and 5. Following an initial rapid decrease in arginine, the dialysate arginine concentrations were low on days 1-3 and then increased over the days 4-5 after injury. In contrast, the microdialysate glutamate levels decreased slowly over the first 48 hours after TBI and thereafter remained low. Thirty-five episodes of jugular venous desaturation (SjvO2 < 50%) occurred during monitoring. Arginine and glutamate levels simultaneously doubled during desaturation and decreased as the clinical episode resolved. The low concentrations of arginine during the first 3 days after TBI may indicate that substrate unavailability could contribute to the decreased NO concentrations that have been observed after TBI. The simultaneous increase in glutamate and arginine during ischemic events is consistent with experimental data which has observed that glutamate induces release of arginine.

Interstitial brain adenosine and xanthine increase during jugular venous oxygen desaturations in humans after traumatic brain injury.

OBJECTIVE: Adenosine decreases the cerebral metabolic rate for oxygen and increases cerebral blood flow, and it may play an important role in cerebrometabolic and cerebrovascular responses to hypoperfusion after traumatic brain injury. Jugular venous oxygen saturation is monitored after traumatic brain injury to assess brain oxygen extraction, and desaturations may reflect secondary brain insults. We hypothesized that brain interstitial adenosine and related purine metabolites would be increased during jugular venous oxygen saturation desaturations (<50%) and determined associations between the purines, lactate, and glucose to assess the role of adenosine during secondary insults in humans. DESIGN: Study of critically ill adults with severe traumatic brain injury. SETTING: Adult neurointensive care unit. PATIENTS: We prospectively defined periods of normal saturation and desaturation in six patients after severe traumatic brain injury. INTERVENTIONS: During these periods, cerebral microdialysis samples of brain interstitial fluid were collected, and adenosine and purine metabolites were measured by high-pressure liquid chromatography. MEASUREMENTS AND MAIN RESULTS: Adenosine increased 3.1-fold and xanthine increased 2.5-fold during desaturation periods (both p <.05 vs. normal saturation period, signed rank). Adenosine, xanthine, hypoxanthine, and cyclic-adenosine monophosphate correlated with lactate over both study periods (r(2) =.32,.14,.31,.07, and.26, respectively, all p <.05, Pearson product moment correlation). CONCLUSION: The marked increases in interstitial brain adenosine that occur during jugular venous oxygen desaturations suggest that adenosine may play an important role during periods of secondary insults after traumatic brain injury. The correlation of these metabolites with lactate further suggests that adenosine is increased during periods of enhanced glycolytic metabolism.

Phase I study of adenoviral delivery of the HSV-tk gene and ganciclovir administration in patients with current malignant brain tumors.

Between December 1996 and September 1998, 13 patients with advanced recurrent malignant brain tumors (9 with glioblastoma multiforme, 1 with gliosarcoma, and 3 with anaplastic astrocytoma) were treated with a single intratumoral injection of 2 x 10(9), 2 x 10(10), 2 x 10(11), or 2 x 10(12) vector particles (VP) of a replication-defective adenoviral vector bearing the herpes simplex virus thymidine kinase gene driven by the Rous sarcoma virus promoter (Adv.RSVtk), followed by ganciclovir (GCV) treatment. The VP to infectious unit ratio was 20:1. Our primary objective was to determine the safety of this treatment. Injection of Adv.RSVtk in doses <==2 x 10(11) VP, followed by GCV, was safely tolerated. Patients treated with the highest dose, 2 x 10(12) VP, exhibited central nervous system toxicity with confusion, hyponatremia, and seizures. One patient is living and stable 29.2 months after treatment. Two patients survived >25 months before succumbing to tumor progression. Ten patients died within 10 months of treatment, 9 from tumor progression and 1 with sepsis and endocarditis. Neuropathologic examination of postmortem tissue demonstrated cavitation at the injection site, intratumoral foci of coagulative necrosis, and variable infiltration of the residual tumor with macrophages and lymphocytes.

Neuro-ophthalmologic manifestations of neuroendocrine carcinoma.

The neuro-ophthalmologic findings of parasellar neuroendocrine carcinoma are reported. Two patients with parasellar neuroendocrine carcinoma had headache, ptosis, and ophthalmoplegia. In both patients, neuroimaging revealed a parasellar mass with extension into the cavernous sinus. The tumors initially were believed to be pituitary adenomas, but histopathology confirmed neuroendocrine carcinoma. Clinicians should be aware of neuroendocrine carcinoma in the differential diagnosis of sellar/parasellar lesions causing ophthalmoplegia.

Brain nitric oxide changes after controlled cortical impact injury in rats.

Nitric oxide (NO) and the NO end products, nitrate and nitrite, were measured at the impact site after a 5-m/s, 3-mm deformation controlled cortical impact injury in rats. Immediately after the impact injury and the NO and microdialysis probes could be replaced, there was an increase from baseline in NO concentration of 83 +/- 16 (SE) nM, compared with 0.5 +/- 4 nM in the sham injured animals (P < 0.001). This marked increase in NO occurred at the time of the initial rise in blood pressure (BP) and intracranial pressure (ICP) in response to the injury. After the initial increase in BP and ICP, the BP decreased and stabilized at a value which was approximately 20 mmHg below the preinjury values, and ICP plateaued at an average value of 20 mmHg, compared with 8 mmHg in the sham-injured animals. This provided an average cerebral perfusion pressure of 40-50 mmHg, compared with 65-75 mmHg for the sham-injured animals. These values were relatively constant for the remainder of the 3-h monitoring period. The NO values also stabilized during this time period. By 1 h after the impact injury the NO concentration measured directly using the NO electrode had decreased from baseline values by an average value of 25 +/- 6 nM. NO concentration remained significantly lower than baseline values throughout the remainder of the 3-h monitoring period. The concentration of nitrate/nitrite in the dialysate fluid also decreased by an average value of 341 +/- 283 nM 20-40 min after the injury. Dialysate nitrite/nitrate concentrations remained less than the preinjury baseline values throughout the remainder of the 3-h monitoring period. Preinjury treatment with L-nitro-arginine methyl ester (L-NAME) blunted the injury-induced increase in NO and resulted in more severe immediate intracranial hypertension and more severe systemic hypotension at one hour after injury. Mortality was also 67% with L-NAME pretreatment, compared with 1% in untreated animals.

Extracellular glutamate and aspartate in head injured patients.

Eighty-six patients in coma from a severe head injury underwent monitoring of extracellular concentrations of glutamate and aspartate by a microdialysis technique during the first few days after injury. The median value for glutamate was 7.4 microM (interquartile range 3.6-18.8 microM). The median value for aspartate was 2.4 microM (interquartile range 1.1-5.0 microM). Average values for the dialysate concentrations of glutamate and aspartate, were closely related to outcome (p < .001 and p = .002, respectively). Patients who died of their head injury had significantly higher dialysate glutamate and aspartate concentrations compared to patients who recovered to a Glasgow Outcome Score of good recovery or moderate disability. Dialysate glutamate and aspartate levels were also significantly related to type of injury (p = .008 and p = .004, respectively). The highest values were found in patients with gunshot wounds, followed by patients with evacuated and unevacuated mass lesions. Patients with diffuse injuries had the lowest values of glutamate and aspartate. These results suggest that excitatory amino acids may play a role in the evolution of injury to the brain after trauma.

Cerebral hemodynamic effects of phenylephrine and L-arginine after cortical impact injury.

OBJECTIVE: To determine the effects of a pressor agent (phenylephrine and L-arginine) on the abnormal cerebral hemodynamics and on neurologic outcome after a severe cortical impact injury in rats. DESIGN: Prospective, randomized study. SETTING: University laboratory. SUBJECTS: Male Long-Evans rats, weighing 300 to 400 g, fasted overnight. INTERVENTIONS: The animals were anesthetized with isoflurane, and a severe cortical impact injury (velocity, 5 m/sec; deformation, 3 mm) was produced in the right parietal cortex. Five minutes after impact injury, one of the following three treatments were infused: 1 mL saline intravenously for 10 mins, 300 mg/kg L-arginine in 1 mL saline intravenously for 10 mins, or 0.3 microg/kg/min phenylephrine intravenously for 3 hrs. Mean arterial pressure, intracranial pressure (ICP), cerebral perfusion pressure (CPP), and laser Doppler flow (LDF) at the impact site and in the contralateral parietal cortex were monitored for 3 hrs after the impact injury. Histologic examination of the brain was performed at 2 wks after injury in a separate group of L-arginine- and saline-treated animals. MEASUREMENTS AND MAIN RESULTS: The immediate response to the impact injury was an increase in ICP, and a decrease in mean arterial pressure, CPP, and LDF. In the saline-treated animals, LDF decreased to <25% of the baseline values at the impact site and stayed at that level for the entire 3-hr monitoring period. On the contralateral side, LDF decreased initially and recovered gradually to approximately 50% of the preimpact baseline value. Infusion of both phenylephrine and L-arginine increased LDF back to near-baseline levels. However, phenylephrine increased ICP significantly, whereas ICP with L-arginine did not change. L-arginine treatment reduced the contusion volume from a median value of 5.28 mm3 to 0.63 mm3. CONCLUSIONS: Phenylephrine increased cerebral blood flow (CBF) by increasing CPP. L-arginine, however, increased CBF without changing CPP. The improvement in CBF was accompanied by a decrease in neurologic injury. Although the pressor agents are used currently to increase CBF after traumatic brain injury, other strategies may also increase CBF without the potential adverse effects of induced hypertension.

Microscopic appearance of iatrogenic foreign bodies in neurosurgery.

Increased frequency of reoperation in neurosurgery has made the microscopic examination of tissue from previously operated sites more common. Various synthetic materials are in common use in neurosurgery, and these can cause clinical complications as well as presenting a diagnostic dilemma for the pathologist. The microscopic appearance of synthetic materials used by neurosurgeons to aid hemostasis, prevent aneurysm rupture, serve as dural prosthesis and suture wounds is reviewed. The importance of the polarizing microscope in differentiating synthetic materials is emphasized.

Validation of a controlled cortical impact model of head injury in mice.

A controlled cortical impact model of head injury was validated with mice. Mice were randomly assigned to moderate head injury, mild head injury, and sham injury groups. Beam balancing, open field activity, slant board inclination, grasp strength, and motor coordination were assessed prior to the injury and on days 1-5 postinjury. Morris water maze performance was evaluated on days 11-15 postinjury. Moderately head-injured mice took a significantly longer time to complete the motor coordination task and to find the hidden platform on the Morris water maze and had significantly fewer successful trials on both tasks than the mildly head-injured and sham-injured mice. Mildly head-injured and sham-injured mice performed similarly on both tasks. Contusion volume at the site of impact varied with severity of injury. Moderately head-injured mice had significantly larger contusions than mice with a mild head injury, and these mice in turn had significantly larger contusions than the sham-injured mice. Both moderately and mildly head injured mice had significantly fewer surviving cells in CA1 than the sham-injured mice but did not differ from each other in this regard. Although there was a group effect, only the mildly head-injured mice had significantly fewer surviving cells in CA3.

Extracellular lactate and glucose alterations in the brain after head injury measured by microdialysis.

OBJECTIVE: To study cerebral glucose and lactate metabolism in head-injured patients using microdialysis. DESIGN: Prospective, nonrandomized, clinical study. SETTING: Neurosurgical intensive care unit in a university-affiliated county hospital. PATIENTS: One hundred twenty-six head-injured patients. INTERVENTIONS: Cerebral cortical neurochemical monitoring using microdialysis coupled with systemic hemodynamic and oxygenation monitoring, measurement of cerebral perfusion pressure and intracranial pressure, and measurement of global cerebral oxygenation using jugular venous oxygen saturation in all 126 patients. In selected cases, cerebral blood flow was also measured using cortical thermodilution probes in 33 patients, and regional cerebral oxygenation was measured using PO2 probes in 65 patients. MEASUREMENTS AND MAIN RESULTS: Elevated extracellular lactate, reduced glucose, and an elevated lactate/glucose ratio were observed with cerebral hypoxia and ischemia. Elevated lactate and an increased lactate/glucose ratio strongly correlated with death. Other more subtle alterations of lactate and glucose were seen early after injury that may reflect compensatory alterations in cerebral metabolism. CONCLUSIONS: Clinical neurochemical monitoring of glucose and lactate levels in the extracellular space of the cerebral cortex is technically feasible and provides insight into the bioenergetic status of the brain. Increased lactate and decreased glucose, indicating accelerated glycolysis, commonly occurred with cerebral ischemia or hypoxia, and increased anaerobic glycolysis in this setting is associated with a poor outcome.

Simultaneous measurement of cortical potassium, calcium, and magnesium levels measured in head injured patients using microdialysis with ion chromatography.

Potassium, calcium and magnesium were measured in 3717 microdialysate samples in 43 patients with head injury experiencing refractory increased ICP, episodes of jugular venous oxygen desaturation and brain death. Cation analysis was performed with 'ion chromatography'. Potassium levels remained stable until severe physiological deterioration occurred, whereupon they increased 100-400%, usually associated with release of amino-acids including glutamate, aspartate, and taurine into the extracellular space. The magnesium and calcium levels remained unchanged, regardless of the severity of physiological deterioration.

The role of semantic context and memory in the acquisition of novel nouns.

Three studies assessed the ability of 2-year-olds to use semantic context to infer the meanings of novel nouns and to retain those meanings a day later. In the first experiment, 24 2-year-olds heard novel nouns in sentences that contained semantically constraining verbs (e.g., "Mommy feeds the ferret"). They chose from a set of four novel object pictures to indicate the referent. Children learned a majority of the novel words. However, they occasionally failed to choose the correct object even when they understood the verb. Experiment 2 examined whether this was due to an inability to identify some of the pictures of novel objects. Experiment 3 tested 24 2-year-olds' memory for the newly learned nouns following a 24 hr delay and found significant retention. Results are discussed in terms of learning mechanisms that facilitate vocabulary acquisition in young children.

Homonymous hemianopsia due to a dural cavernous hemangioma.

The clinical and radiographic features of extra-axial cavernous hemangiomas are described, and a case of homonymous visual field loss due to a dural-based occipital cavernous hemangioma is reported. A patient presented with a homonymous hemianopsia due to an enhancing tentorial mass lesion. The preoperative clinical and magnetic resonance imaging features were suggestive of meningioma. The patient underwent gross total resection of the lesion and the final pathologic examination was consistent with cavernous hemangioma. There was complete resolution of the visual field defect after surgery. Extra-axial cavernous hemangiomas differ from intra-axial cavernous hemangiomas in their clinical and radiographic features. The former lesions may mimic meningioma and should be considered in the differential diagnosis of a dural-based mass. Early recognition of the lesion is important because surgical removal of cavernous hemangiomas may be associated with a higher morbidity and mortality rate than meningiomas.