Reversal of neurological deficits by opiate antagonist naloxone after cerebral ischemia in animals and humans.

Stroke induced by a carotid occlusion in gerbils was reversed by intraperitoneal (i.p.) injection of naloxone (1 mg/kg) for up to 30 min. Placebo-treated stroked gerbils died in 48 hr; 40% of gerbils implanted with 10 mg naloxone pellets survived over 2 weeks without neurologic deficit. Intravenous (i.v.) injection of naloxone produced the same transient reversal of hemiplegia in 2 patients with neurologic deficit from cerebral ischemia. These findings suggest the involvement of endorphins and opiate receptors in the pathophysiology of stroke, and suggest the possible clinical use of opiate antagonists in humans in the acute phase of stroke.

Brain choline acetyltransferase and mental function in Alzheimer disease.

OBJECTIVE: To determine whether higher brain levels of choline acetyltransferase (ChAT) are associated with improved neuropsychological function in patients with Alzheimer disease (AD). DESIGN: Case series with single-blind post hoc analysis of biopsy specimens. SETTING: Urban hospital and medical school. PATIENTS: A consecutive sample of 8 patients with AD undergoing brain biopsy and surgical implantation of intraventricular pumps for administration of potential chemotherapeutic agents. INTERVENTIONS: Brain biopsy, surgical implantation of intraventricular pumps, and, in 1 patient, ventriculoperitoneal shunt placement. MAIN OUTCOME MEASURES: All patients underwent neuropsychological testing no more than 2 weeks before surgical biopsy. Levels of ChAT were determined in fresh brain tissue from biopsy samples. RESULTS: Significant positive correlations were found between ChAT levels and 2 neuropsychological test scores, Mini-Mental State Examination and the Logical Memory subtest of the Wechsler Memory Scale. CONCLUSION: Degeneration of the cholinergic system in vivo correlates with decreasing cognitive function in patients with AD.

Cloning and characterization of CRF, a novel C1q-related factor, expressed in areas of the brain involved in motor function.

We have isolated and characterized a novel cDNA, C1q-Related Factor (CRF), that is predicted to encode a 258 amino acid polypeptide with a hydrophobic signal sequence, a collagenous region, and a globular domain at the carboxy terminus that shares homology to the C1q signature domain. Human CRF transcript is expressed at highest levels in the brain, particularly in the brainstem. In situ hybridization to mouse brain sections demonstrated that CRF transcripts are most abundant in areas of the nervous system involved in motor function, such as the Purkinje cells of the cerebellum, the accessory olivary nucleus, the pons and the red nucleus. The mouse CRF homolog is highly similar to the human gene at both the nucleotide and protein level, suggesting an important conserved role for this protein.

Time-dependent variability of infarct size and hemispheric volume in experimental focal cerebral ischemia in the rabbit.

Studies measuring the volume of infarcted tissue and survival after pharmacologic intervention in stroke are complicated by the potential effect of survival time on infarct volume. In this study, the volume of infarcted tissue as defined by 2,3,5-triphenyltetrazolium chloride staining was determined in rabbits at 28 h, 7 days, and 3 weeks after permanent middle cerebral artery occlusion. Compared to values at 28 h, infarcted tissue volume did not change at 7 days after occlusion, but decreased significantly by three weeks after occlusion (p < 0.01). Infarcted tissue volume expressed as a percent of hemispheric volume did not significantly change at either timepoint (p < 0.08). Immunocytochemical staining for glial fibrillary acidic protein (GFAP) indicated that infarct volume changes were not due to glial infiltration. Total hemispheric volume decreased by 7 days (p < 0.01) and 3 weeks (p < 0.01) after occlusion. These results suggest that changes in hemispheric volume may confound comparison of injury volumes in animals at differing times after occlusion. In experiments where drug treatments increase survival after focal cerebral ischemia, comparisons of the absolute infarct volume may not be valid if drug-treated animals survive greater than 1 week and untreated animals do not.

Treatment of stroke with opiate antagonists--effects of exogenous antagonists and dynorphin 1-13.

We studied the effects of acute and long-term, continuous administration of six opioid compounds--naloxone, naltrexone, diprenorphine, leucine enkephalin, dynorphin 1-13, and dynorphin 3-13--on neurologic function, survival, and infarct size in a feline model of acute focal cerebral ischemia. Acutely, naloxone, naltrexone, and diprenorphine significantly improved motor function over baseline scores; the other drugs and saline (control) had no effect. In the long-term condition, no substance administered significantly affected level of consciousness, sensory function, or pupillary reactions. Naloxone, naltrexone, and dynorphin 1-13 significantly prolonged survival (p less than 0.1); the other substances had no effect. Evaluations of cat brains postmortem showed that the infarcts involved the sensory and motor cortex, internal capsule, and caudate nucleus. Infarct size was unaltered by any treatment administered; results among groups were remarkably similar. In evaluations of opiate receptor binding characteristics, high-affinity binding of ekylketocyclozocine was significantly reduced in the right (occluded) side of the cortex. Dynorphin 1-13 given 8 h postocclusion but before sacrifice increased this binding affinity to the previous level in non-occluded cortex. The observed protective effect of dynorphin 1-13 warrants further investigation. Our results support the involvement of endogenous opioid peptides in the pathophysiology of cerebral ischemia and suggest that, administered appropriately, opiate antagonists may be useful in the treatment of focal ischemic neurologic deficits.

Penetration of dynorphin 1-13 across the blood-brain barrier.

Previous studies have demonstrated neuroprotective effects of the opioid peptide dynorphin (dyn) 1-13 in focal cerebral ischemia. The passage of dyn 1-13 across the blood-brain barrier (BBB) was studied by a modification of the Oldendorf technique in the normal rat and cat, as well as in a feline model of experimentally induced focal cerebral ischemia. In the rat, dyn 1-13 penetration of the BBB could not be detected by this technique, even in the presence of peptidase inhibitors. In contrast, dyn 1-13 did cross the BBB into the normal cat hippocampus, cortex and cerebellum. The passage of dyn 1-13 across the BBB was greater in cats with experimentally induced focal cerebral ischemia. Some of the tritium-labeled material which crossed the BBB was confirmed by high performance liquid chromatography to be dyn 1-13. These studies support the hypothesis that the therapeutic effects observed after the peripheral administration of dyn 1-13 to cats with focal cerebral ischemia can be produced by a central mechanism of action.

Naloxone reversal and morphine exacerbation of neurologic deficits secondary to focal cerebral ischemia in baboons.

The effects of an opiate agonist (morphine) and antagonist (naloxone) on neurologic function in conditions of acute and subacute focal cerebral ischemia were tested in a baboon model. Fourteen baboons (Papio papio) underwent unilateral transorbital microsurgical occlusion of the middle cerebral artery (MCA). Blood pressure, heart rate and core temperature were monitored continuously; frequent arterial blood gas measurements were made. Cardiac output, cardiac filling pressures, and regional cerebral blood cross-flow were measured in selected baboons. Naloxone administered intravenously consistently reversed hemiparesis and hemiplegia in all baboons for as long as they lived (4 h to 8 days postocclusion). Morphine administered intravenously converted hemiparesis to hemiplegia; this effect was naloxone-reversible. There were no significant changes in any parameter measured after the administration of either drug. Phenylephrine (used to elevate mean arterial pressure to 20 mm higher than the highest pressure measured after naloxone administration) and isoproterenol (used to elevate cardiac output to 1 l/min higher than the highest value measured after naloxone administration) produced no change in neurologic function. It appears that naloxone can reverse, and morphine exacerbate, focal ischemic neurologic deficits produced in baboons by MCA occlusion. The observed changes in neurologic function are not associated with or mediated by alterations in core temperature or cardiopulmonary functions.

Effects of dynorphin1-13 on opiate binding and dopamine and GABA uptake in stroked cat brain.

We previously reported that the opioid peptide dynorphin1-13 improves survival chances in stroked cats. Some evidence also suggests that changes in dopamine and gamma-aminobutyric acid (GABA) uptake may be associated with stroke. In the present study, therefore, we determined binding of the opiate [3H]ethylketocyclazocine (EKC), as well as dopamine and GABA uptake in various brain regions of control, stroked and dynorphin1-13-treated stroked cats. Cats were stroked by middle cerebral artery occlusion. In the EKC binding study, the Kd of the high-affinity site of the occluded cortex was significantly increased, relative to that of both the unoccluded side and control cortex. Dynorphin1-13 treatment reversed this effect, lowering the Kd to control level. In the dopamine uptake study, the Km was decreased and Vmax was increased significantly in unoccluded cortex, compared with that in the occluded cortex or in control cortex. Again, dynorphin1-13 reversed these effects, raising the Km and lowering the Vmax. However, the Km of occluded cortex was also increased so that it became significantly higher than that of control cortex. The Km of unoccluded subcortex in stroked cats treated with dynorphin1-13 was significantly reduced compared with control. In the GABA uptake study, there was no significant change in any parameter. The change in opioid binding observed here and its reversal by dynorphin1-13 are consistent with the notion that the peptide's beneficial effect on stroke is mediated through opiate receptors. Since opioid systems in the brain are known to have association with dopaminergic ones, the change in dopamine uptake could also be the result of an opioid effect.

Suppression of post-ischemic-induced fos protein expression by an antisense oligonucleotide to c-fos mRNA leads to increased tissue damage.

Activation of c-fos, an immediate early gene, and the subsequent upregulation of Fos protein expression occur following neural injury, including focal cerebral ischemia (fci). Fos and Jun form a heterodimer known as activator protein 1, which regulates the expression of many late effector genes. To study the downstream effects of c-fos expression following ischemia, we suppressed the translation of c-fos by administering an antisense oligonucleotide (AO) to c-fos mRNA. Eighteen hours prior to fci, male, Long Evans (LE) rats received intraventricular injections of AO, mismatched AO (MS) or artificial cerebrospinal fluid (aCSF). Fci was induced by permanent right middle cerebral artery occlusion. At 24-h post-occlusion, neurological function was assessed, and the animals were sacrificed. The brains were removed and stained with triphenyltetrazolium chloride for infarct volume determination. Fos immunohistochemistry was performed in separate animals to determine the effects of treatment on Fos expression number of Fos positive cells. AO administration reduced the number of cells with fci-induced Fos expression by approximately 75%. No differences in neurological scores existed between any of the groups. AO-treated LE developed larger infarcts (40.1+/-1.0%, mean+/-S.D., p<0.001) than MS- or aCSF-treated controls (34.3+/-1.0%, 34.6+/-1.0%, respectively). These results suggest that c-fos activation and subsequent Fos protein expression exerts a neuroprotective effect, which is likely via upregulation of neurotrophins, following focal cerebral ischemia. This response, among others, may contribute to brain adaptation to injury that underlies functional recovery after stroke.

Autopsy analysis of the safety, efficacy and cartography of electrical stimulation of the central gray in humans.

Electrical brain stimulation is effective in controlling certain intractable chronic pain syndromes in humans, but the specific target site(s) for stimulation producing a maximal analgesic effect is (are) not well defined. This prospective study correlates the clinical results of chronic stimulation of the periaqueductal gray (PAG) and periventricular gray (PVG) matter in humans with the anatomic site of electrode placement as determined at autopsy, and documents the histologic reactions to electrode implantation and electrical stimulation of the area. Seven patients underwent electrode implantation to control their chronic pain; two had electrodes implanted bilaterally. All patients obtained complete analgesia with stimulation, although 3 subsequently found the stimulation to have diminished efficacy. The opiate antagonist naloxone reversed the analgesia in the 4 patients so tested. All 7 patients later died of causes unrelated to electrode implantation or stimulation. Postmortem analysis showed that, for 6 of the 9 electrodes implanted, the electrode tip was located in the ventrolateral PAG at the level of the posterior commissure; the other 3 electrodes were found in the white matter adjacent to the PAG. No evidence of gliosis or parenchymal reaction was observed along the tracts and tips of the electrodes. The results indicate that the ventrolateral PAG and PVG matter at the level of the posterior commissure is the optimal site for therapeutic electrical brain stimulation for opiate-responsive pain in humans.

Corticomotor evoked potentials in acute and chronic blunt spinal cord injury in the rat: correlation with neurological outcome and histological damage.

Somatosensory evoked potentials (SSEPs) and corticomotor evoked potentials (CMEPs) were utilized to study acute and chronic blunt spinal cord trauma. Rats, anesthetized with ketamine hydrochloride, were subjected to parasagittal craniectomies and midthoracic laminectomies. SSEPs were cortically recorded and CMEPs were transcortically produced using epidural ball and disc electrodes. SSEPs were elicited and CMEPs were recorded via hindlimb percutaneous needle electrodes. After control records, animals were subjected to a 50-g/cm impact to the dorsal cord surface using a modified weight drop technique. Evaluation of neurological injury was performed by SSEP and CMEP analysis and was compared with neurological assessments obtained before injury and 1 hour, 1 week, 3 weeks, and 6 weeks after injury. Neurohistopathological verification of each spinal cord lesion was performed at 6 weeks after injury. Animals subjected to a 50-g/cm cord impact showed no change in SSEP wave forms, but all components of the CMEP were greatly attenuated with this injury. Acutely, either very weak movement or no movement to noxious stimulation was present without vocalization. There was a spectrum of clinical recovery that correlated closely with the return and normalization of the amplitude of the CMEP in 100% of the animals tested. The eventual degree of clinical and CMEP improvement correlated well with the degree of histological damage present. The results of this study suggest that the CMEP is a reliable indicator of the initial degree of loss of neurological motor function in acute blunt spinal cord injury in the rat, as well as an accurate measure of the degree and extent of recovery. The rat model as outlined here is a simple and inexpensive system for evaluation both clinically and electrophysiologically of the degree of motor recovery from spinal cord injury. This model should prove useful in the evaluation of promising pharmacological agents for potential use in the treatment of acute spinal cord injury.

Corticomotor and somatosensory evoked potential evaluation of acute spinal cord injury in the rat.

Somatosensory evoked potentials (SSEPs) and corticomotor evoked potentials (CMEPs) were utilized to study acute blunt spinal cord trauma. Rats, anesthetized with ketamine hydrochloride, were subjected to a parasagittal craniotomy and a midthoracic laminectomy. SSEPs were cortically recorded and CMEPs were transcortically produced using epidural ball and disc electrodes. SSEPs were elicited and CMEPs were recorded via hindlimb percutaneous needle electrodes. After control records were made, animals were subjected to a 25-, 50-, or 75-g/cm impact to the dorsal cord surface via a modified weight drop procedure. Evaluation of neurological injury was made by SSEP and CMEP analysis as well as by physical testing with noxious stimulation applied to the hindlimb. Neurohistopathological verification of each spinal cord lesion was performed. No significant change in SSEP configuration was identified in animals subjected to a 25-g/cm cord impact; however, a small decrement in CMEP amplitude was consistently observed. Although vocalization to noxious stimulation was present, flexion activity was less than normal. Animals subjected to a 50-g/cm cord impact also showed no change in SSEP wave forms. All components of the CMEP were greatly attenuated with this injury. Either very weak movement or no movement to noxious stimulation was present without vocalization. After a 75-g/cm cord impact, both SSEPs and CMEPs were abolished. There was no movement or vocalization in response to noxious stimulation. Serial sections of the spinal cords revealed incremental destruction with increasing severity of injury. These results support the hypothesis that CMEPs are a more sensitive indicator of residual spinal cord function after injury than are SSEPs.

Fatal subarachnoid hemorrhage from the rupture of a totally intracavernous carotid artery aneurysm: case report.

Intracavernous carotid artery aneurysms usually cause symptoms because of gradual expansion without rupture. Most such aneurysms that do rupture lead to a carotid-cavernous fistula. Very few cases of rupture leading to subarachnoid hemorrhage have been reported. We report a case in which rupture of an entirely intracavernous carotid artery aneurysm led to death from a massive subarachnoid hemorrhage.

Isolated C-2 osteomyelitis of hematogenous origin: case report and literature review.

A case of hematogenous Staphylococcus aureus osteomyelitis isolated to the 2nd cervical vertebra is presented. To our knowledge, this is the second case to be reported of hematogenous infection involving only the body and odontoid process of the axis. The first report was published prior to the advent of computed tomography, bone scans, and halo orthosis. The pathophysiology of blood-borne atlantoaxial infection is described, as well as methods of diagnostic evaluation and therapeutic recommendations. The use of computed tomography to define the extent of the lesion is illustrated.

Vancomycin penetration of a brain abscess: case report and review of the literature.

A 56-year-old man developed an abscess within a right parietal cystic anaplastic astrocytoma 3 days after removal of iodine-125 sources placed 9 days earlier for interstitial radiation therapy. After treatment with cephalosporin antibiotics proved unsuccessful, the patient was treated with intravenous vancomycin and intermittent percutaneous drainage of the abscess. Vancomycin levels obtained from the brain abscess fluid, both before and during later operative removal of the abscess, were 15 and 18 micrograms/ml, respectively; the serum vancomycin level was 21 micrograms/ml. This is the first report of the excellent penetration of vancomycin into brain abscess fluid.

Transsphenoidal treatment of non-neoplastic intrasellar cysts. A report of 38 cases.

Thirty-eight patients underwent transsphenoidal microsurgical treatment of non-neoplastic intrasellar cysts: 36 had cyst drainage and biopsy of the cyst wall, and in two the cyst was totally removed. Surgical morbidity was 8%. The mean follow-up time was 46.3 months; 100% patient follow-up evaluation was achieved. Sixteen female patients (mean age 24.6 years) had pars intermedia cysts: 88% had menstrual irregularities, 63% had galactorrhea, 31% had headache, and 56% had hyperprolactinemia. Within these groups, menstrual cycles returned in 86%, galactorrhea ceased in 90%, headaches resolved in 80%, and serum prolactin levels were restored to normal in 66%. Eight females and three males had Rathke's cleft cysts (mean age 34.0 years): of these 11 patients, 91% had headaches and 18% had hyperprolactinemia; of the eight females, 63% had amenorrhea and 63% had galactorrhea. Within these groups, serum prolactin levels normalized in 50%, and 80% noted reduced headache. Of the females, 80% had return of menses and 50% noted cessation of galactorrhea. Six males and two females had arachnoid cysts (mean age 42.2 years): 50% had headaches; 50% were asymptomatic. Preoperatively, 50% of these patients had hypothyroidism and 25% had adrenal hypofunction. Postoperatively, 75% of patients with headache noted improvement, and 33% of patients with abnormal thyroid function had normal function. Adrenal function did not improve. Three patients had an intrasellar cysticercosis cyst, epidermoid cyst, and postoperative cyst, respectively. All had evidence of partial hypopituitarism; none improved postoperatively. The results indicate that different types of pituitary cysts produce different clinical syndromes, and suggest that simple transsphenoidal drainage and partial removal of the cyst wall can provide safe and effective therapy.

Surgical management of craniopharyngiomas. A review of 74 cases.

A series of 74 patients with craniopharyngiomas were treated during a 15-year period. Of the 74 patients, 40 were males and 34 were females, with a mean age of 27 years (range 3 to 65 years). Twenty-eight patients (38%) were less than 18 years of age. Remission was defined as clinical improvement with stable ophthalmological and neurological status, radiological evidence of a decrease in tumor size, and either a continued decrease or a stable tumor size on follow-up radiological evaluations. A fair result was considered remission with new neurological deficits related to surgical intervention. All other results were considered a failure. The mean follow-up period in this study was 4 years, with 100% of the patients monitored. In children, the most common presentation was that of growth failure (93%). In adults, sexual dysfunction was the most common presentation, with 88% of males presenting with impotence or marked decrease in sexual drive, and 82% of females presenting with primary or secondary amenorrhea, often associated with galactorrhea. Considering the pediatric and adult populations together, the most common presenting symptom was visual dysfunction, with 71% of patients presenting in this manner. Fifty percent of patients presented with severe headache. The most frequent preoperative finding was a visual field defect, with 72% of patients so affected; 42% of patients had preoperative hypothyroidism and 24% had hypoadrenalism. Diabetes insipidus was present preoperatively in 23%. Hydrocephalus was uncommon, being present in only 15%. A subfrontal craniotomy was used in 47% of patients, a transsphenoidal approach in 39%, a subtemporal approach in 11%, a transcallosal approach in 5%, and a suboccipital craniectomy in 2%. Multiple procedures were required in 15% of patients in order to provide significant relief of compressive symptomatology. The results of therapy indicate that total tumor removal was deemed to have been achieved in only seven patients, six of whom have had no recurrence. However, 91% of patients are in remission, one had a fair result, and two died as a direct result of surgical intervention. One patient died from uncontrolled disease, and three patients died from unrelated causes. The results of this study indicate that radical subtotal removal followed by radiotherapy is an acceptable treatment for craniopharyngioma.

Transsphenoidal surgery of intrasellar germinomas. Report of two cases.

Two patients with diabetes insipidus, hypopituitarism, and an enlarged sella turcica underwent a transsphenoidal operation for the treatment of intrasellar germinomas. Successful transsphenoidal treatment of such neoplasms has not been reported previously. The cases indicate that the diagnostic possibility of intrasellar germinoma should be considered in young patients with combined diabetes insipidus and hypopituitarism, even when the sella is markedly expanded.