Pain relief by electrical stimulation of the central gray matter in humans and its reversal by naloxone.

Relief of intractable pain was produced in six human patients by stimulation of electrodes permanently implanted in the periventricular and periaqueductal gray matter. The level of stimulation sufficient to induce pain relief seems not to alter the acute pain threshold. Indiscriminate repetitive stimulation produced tolerance to both stimulation-produced pain relief and the analgesic action of narcotic medication; this process could be reversed by abstinence from stimulation. Stimulation-produced relief of pain was reversed by naloxone in five out of six patients. These results suggest that satisfactory alleviation of persistent pain in humans may be obtained by electronic stimulation.

Stimulation of human periaqueductal gray for pain relief increases immunoreactive beta-endorphin in ventricular fluid.

Immunoreactive beta-endorphin was measured in the ventricular fluid of six patients with chronic pain. Stimulation of the periaqueductal gray matter in three patients with pain of peripheral origin resulted in significant increases (50 to 300 percent) in the concentration of ventricular immunoreactive beta-endorphin. In three other patients suffering deafferentation dysesthesia, stimulation of the posterior limb of the internal capsule did not alter the concentration of this peptide. These results provide evidence of the release of human immunoreactive beta-endorphin in vivo and suggest that naloxone-reversible pain relief achieved by stimulation of the periaqueductal gray matter may be in part mediated by the activation of beta-endorphin-rich diencephalic areas.

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.

Midbrain corectopia.

Intermittent corectopia was recently observed in a patient with bilateral, rostral midbrain infarction. Results from neuropathologic examination disclosed isolated but intact Edinger-Westphal nuclei. An explanation of midbrain corectopia centered on segmental innervation of the pupil by the Edinger-Westphal nucleus. In the presence of a paralyzed dilator muscle, select, central inhibition of sphincter tone resulted in an oval and eccentric pupil.

Treatment of intercostal neuralgia with 10 per cent ammonium sulfate.

Intercostal nerves were injected with 10 per cent annomium sulfate in 41 patients (52 total sets of injections) for management of intercostal neuralgia from radical mastectomy (six blocks), thoracotomy (20 blocks), or unknown etiology (26 blocks). Five patients failed to return for follow-up evaluation and could not be located. Sixty per cent (28/47) of the treatments produced complete or nearly complete (excellent) relief of pain. Excellent pain relief persisted for more than 20 days after 22 treatments and for more than 90 days after seven treatments. Postblock neuritis never occurred. We conclude that intercostal nerve block with 10 per cent ammonium sulfate effectively relieves intercostal neuralgia and is not associated with postblock neuritis. We therefore believe that ammonium sulfate nerve blocks should be administered for treatment of intercostal neuralgia before phenol or alcohol nerve blocks or a surgical procedure.

Proton nuclear magnetic resonance imaging of acute experimental cerebral ischemia.

To determine the efficacy of proton nuclear magnetic resonance (NMR) imaging in documenting acute ischemic infarction and to characterize the changes in these images during the first 24 hours following the ischemic insult, serial NMR imaging was performed in gerbils that had undergone unilateral carotid artery ligation. No significant changes in the signal intensity, T1 or T2 relaxation times were noted for either asymptomatic animals or the control hemisphere of symptomatic gerbils. There was a significant increase in T1 and especially T2 relaxation times and in both the relative signal intensity and Hf(v) for the ischemic hemisphere of symptomatic gerbils. These parameters appeared to increase linearly over 24 hours. The ischemic lesion first could be detected by NMR as early as 3 hours after carotid artery ligation, our earliest time point. The physiologic significance of these changes is discussed. These data suggest that NMR imaging may have significant diagnostic importance for acute cerebral ischemia and infarction in man.

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.

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.

Opiate antagonist, naloxone, strongly reduces analgesia induced by stimulation of a raphe nucleus (centralis inferior).

The analgesic effects obtained in the cat by central inferior raphe nucleus stimulation are greatly reduced by the administration of a specific opiate antagonist, naloxone. In 12 of 16 cats analgesia, tested by pinches applied on the 4 limbs or the tail, was totally abolished. Analgesia tested by considering the increase of the threshold of the jaw opening reflex was reduced to 44% of the initial value. These results emphasize the relation existing between morphine analgesia and analgesia induced by central stimulation. To try to explain the effects of naloxone, one may suppose that central stimulation releases an endogenous morphine-like substance such as enkephalin.

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.

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.

NMR imaging of acute experimental cerebral ischemia: time course and pharmacologic manipulations.

Nuclear magnetic resonance (NMR) imaging was used to evaluate the intracerebral changes over time in gerbils after unilateral carotid artery ligation. Each animal was imaged during one of three stated periods 3-28 hr after surgery and again after administration of dexamethasone, morphine, or naloxone, agents reported to affect the clinical outcome of ischemic cerebral lesions. Asymptomatic animals exhibited no differences between the occluded and control hemispheres in relative signal intensity or in T1 or T2 relaxation times, but symptomatic animals demonstrated significant differences in these parameters between hemispheres. The ischemic lesion was detected at the earliest imaging time, 3 hr after surgery. A linear increase was observed in the relative interhemispheric signal intensity in three of four intensity images and in T1 and T2 relaxation times over the 24 hr experiment. No effect was noted on any image parameter as a result of pharmacologic manipulations. The results suggest that NMR may be of significant diagnostic importance for acute cerebral ischemia and infarction in man.

Brain stem auditory evoked response and brain stem compression.

For the study of brain stem auditory evoked response (BAER) changes due to acutely expanding mass lesions, posterior fossa balloon catheters were inflated slowly in anesthetized cats while supratentorial and infratentorial intracranial pressure and vital signs were monitored. Reliable changes in BAER occurred before the Cushing response and were reversible by balloon deflation. Because BAER changes precede the agonal changes of the Cushing response, serial BAER recording in patients with known or suspected posterior fossa masses may be useful in the management of these lesions.

Brachytherapy of recurrent tumors of the skull base and spine with iodine-125 sources.

Thirteen patients with recurrent, previously irradiated tumors of the skull base or spine were reirradiated with 125I sources implanted interstitially using microsurgical or stereotactic techniques. Patients harbored difficult, end-stage recurrences of chordoma, meningioma, malignant meningioma, fibrosarcoma, invasive pituitary adenoma, and malignant schwannoma. In two other patients with malignant meningioma, the dose of external radiation was augmented by implanting 125I sources during the initial operation for excision of the lesion or at a separate surgical procedure after conventional teletherapy. Microsurgical implantation of 125I sources into basal tumors was limited by the difficulties inherent in operating in this region; it is not possible to visualize the entire tumor that requires implantation. Three of five chordomas stabilized or regressed; these patients probably benefited from the procedure. Two patients with recurrent malignant meningiomas had long term remission after interstitial brachytherapy. Interstitial 125I brachytherapy for recurrent tumors at the base of skull or adjacent to the spine can be more successful only if more aggressive surgical exposures of these regions are attempted. Implantation of sources for a "boost" dose, either microsurgically during the initial surgical resection of the lesion before conventional teletherapy or stereotactically after conventional teletherapy, may be a valuable adjunct to external irradiation for the control of potentially devastating tumors (such as chordomas and malignant meningiomas) before they recur with the severe consequences seen in the patients reported here.

Subcortical electrical stimulation for control of intractable pain in humans. Report of 122 cases (1970-1984).

Chronic electrical stimulation of the subcortical area of the brain by implanted electrodes provides satisfactory control of a number of intractable pain syndromes that are refractory to medication. This series of 122 patients who underwent electrode implantation for the control of severe chronic pain was evaluated over a follow-up period of 2 to 14 years. Of the 65 patients with pain of peripheral origin, who were treated with stimulation of the periaqueductal gray region (PAG), 50 obtained successful pain control. Of 76 patients with a deafferentation pain syndrome, 44 obtained control of the dysesthesia with stimulation of the subcortical somatosensory region. Nineteen patients with both leg and back pain received electrodes in the PAG and the somatosensory regions; whereas back pain was relieved by PAG stimulation, dysesthetic leg pain was controlled more effectively by somatosensory region stimulation. The electrical stimulation technique appears to provide long-term pain control safely, with few side effects or complications.

Direct surgical treatment of giant intracranial aneurysms.

The author has operated on 40 patients with giant intracranial aneurysms, using various surgical approaches. Giant aneurysms predominated in females (3:1) and were most common in the age group 30 to 60 years. Patients presented with subarachnoid hemorrhage (17), visual disturbance (18), chronic headache (14), transient or progressive hemispheric deficit (6), seizure (2), dementia (2), and cerebrospinal fluid rhinorrhea (1). Giant aneurysms were located at the carotid artery (25), the basovertebral artery (8), the anterior communicating artery (5), and the middle cerebral artery (2). Eight of 40 patients had one or more other aneurysms and/or associated arteriovenous malformations. Aneurysms were treated with intramural thrombosis (21), neck occlusion (7), trapping (10), proximal parent artery ligation (1), and aneurysmorrhaphy (1). After as much as 8 years of follow-up, 32 patients (80%) showed complete or marked improvement in signs and symptoms; two patients (5%) had a poor recovery. There were six surgical mortalities (15%). Giant aneurysms can be treated with respectable results if the surgeon selects the technique best suited to the particular aneurysm. In general, neck occlusion, trapping, and aneurysmorrhaphy are best for giant aneurysms of the anterior circulation, and intramural thrombosis is best for those of the posterior circulation. Extra- and intracranial vascular anastomotic techniques are also of value. For success, a flexible approach is essential.

Electrothrombosis of carotid-cavernous fistula.

The author describes a technique for directly closing a carotid cavernous fistula with electrothrombosis while preserving the intracranial arterial circulation. Copper wires are introduced through the superior ophthalmic vein or a frontotemporal craniotomy, and thus directly into the portion of the sinus into which the fistula drains; if posterior, into the posterior segment of Parkinson's triangle, if inferior, into the pterygoid plexus, and if anterior, through the sphenoparietal sinus and/or middle cerebral vein to the anterior-inferior portion of the sinus. A direct current is applied until a thrombus is confirmed angiographically and the wires are left in place. Four patients treated by this method are presented.

Cavernous sinus fistula caused by intracavernous rupture of a persistent primitive trigeminal artery. Case report.

A persistent carotid-basilar anastomosis (primitive trigeminal artery), identified by four-vessel vertebral angiography, was shown to be the cause of a cavernous sinus fistula in a 51-year-old woman. The fistula, but not the primitive artery, was identified on a carotid arteriogram. Because of the flow contribution from the posterior circulation, balloon embolization via the carotid system failed, and the fistula was repaired through a direct surgical approach. The operative technique is described and the hemodynamic aspects of a cavernous sinus fistula that is related to this primitive anastomosis are reviewed.