The rationale and methodology for intra-arterial chemotherapy with BCNU as treatment for glioblastoma.

The rationale for, methodology of, and experience with intra-arterial BCNU infusion therapy of malignant glioma are described. This approach achieves tumor levels of drug four times greater than equal doses infused intravenously, and has been used to treat 79 patients over the course of 4 years. The drug was given in 192 infraophthalmic and 66 supraophthalmic carotid artery infusions. Patients who were treated via infraophthalmic carotid artery infusion following tumor recurrence (after both operation and irradiation) survived 54 additional weeks (92 weeks after initial diagnosis). Patients who were treated with BCNU immediately after initial irradiation therapy survived 64 weeks (infraophthalmic carotid artery infusion) and 49.5 weeks (supraophthalmic carotid artery infusion). The major ocular complications (pain and diminished visual acuity) associated with infraophthalmic carotid artery infusion are avoided by selective balloon-guided supraophthalmic carotid artery administration. However, both approaches were associated with white-matter changes, seen as diminished absorption on computerized tomography scans, in 20% of patients treated following irradiation therapy. This toxicity appears to preclude intra-arterial BCNU treatment in the immediate postirradiation period. Better results are being achieved with our current therapy, which involves four infusions of BCNU (400 mg every 4 weeks) into the infraophthalmic or supraophthalmic carotid artery in advance of irradiation. Cisplatin infusions (60 to 90 mg/sq m every 5 weeks) are offered for recurrent glioblastoma.

High dose naloxone produces cerebral vasodilation.

In this study, 12 dogs were anesthetized with sodium pentobarbital, and blood flows were determined using the radioactive microsphere technique. Ten dogs were first made acutely hypertensive by the infusion of norepinephrine and demonstrated preserved cerebral autoregulation. The administration of naloxone, 10 mg/kg i.v., in these animals produced a significant increase in cerebral blood flow and a proportional drop in cerebrovascular resistance with no change in the cerebral metabolic rate of oxygen or the electroencephalogram. Two additional spontaneously hypertensive dogs demonstrated a similar response to naloxone. These results suggest that high dose naloxone produces cerebrovasodilation either directly or through the inhibition of cerebral autoregulation.

Effects of naloxone on cerebral blood flow and metabolism in isoflurane/nitrous oxide-anesthetized dogs.

The purpose of this study was to document the changes in the cerebral and systemic circulations that result from various doses of naloxone. Twenty-four dogs were anesthetized with 0.8% isoflurane and 70% nitrous oxide (1.3 minimal anesthetic concentration). Thirteen of the dogs received bolus injections of naloxone at logarithmically increasing doses 30 minutes apart. Blood flow to the brain and other organs was determined using the radioactive microsphere technique. Electrical activity was measured by electroencephalography (EEG). High dose naloxone increased both cerebral blood flow (CBF) and cerebral metabolism. The changes in CBF were most pronounced in structures containing a large amount of gray matter, particularly the cerebral cortex, brain stem, and cervical spinal cord. The increase in blood flow was proportionately greater than the increase in the cerebral metabolic rate of oxygen, and EEG activity was unchanged. Naloxone did not produce any significant cardiovascular changes or alterations in myocardial, renal, hepatic, stomach, jejunum, or temporalis and paraspinous muscle flow. Accordingly, it seems that naloxone may have direct cerebral vasodilator properties.

Cerebral and systemic vascular effects of naloxone in pentobarbital-anesthetized normal dogs.

In this study, 10 mongrel dogs were anesthetized with sodium pentobarbital and nitrous oxide. Blood flow was determined using the radioactive microsphere technique before and after the bolus intravenous injection of naloxone (10 mg/kg). Naloxone significantly increased cerebral blood flow to cerebral cortex and the total cerebral hemisphere without an associated change in the cerebral metabolic rate of oxygen. The increase in cerebral blood flow was proportional to the elevation in mean arterial pressure. There were no consistent changes in electrical activity as measured by electroencephalography (EEG) and Fourier analysis of EEG. Systemically, naloxone induced a proportional rise in mean arterial pressure and peripheral vascular resistance and also stimulated the myocardium, as evidenced by an improved cardiac index and stroke volume. These data suggest that naloxone may interfere with cerebral autoregulation or have direct vasodilatory effects on cerebral blood vessels that are not associated with opiate receptor blockade or changes in cerebral metabolism. In addition, naloxone did not appear to reverse the cerebral depressive effects of pentobarbital. Systemically, naloxone seemed to potentiate pentobarbital-induced vasoconstriction and reverse myocardial depression.

Topography of somatosensory evoked potentials after stimulation of the median nerve.

We studied topography of major negative-positive peaks, NI, PI, NII, PII and NIII, of scalp recorded somatosensory evoked potentials (SEP) after stimulation of the median nerve. Unlike the diffusely distributed P14, NI, PI and NII recorded from contralateral hemisphere after unilateral stimulation normally showed statistically significant latency increase from frontal (N17, P20, N29) to central (N19, P23, N32) and parietal (N20, P26, N34) electrodes. However, NIII (N60) had considerable inter- and intra-individual variations with no consistent antero-posterior latency shift. In contrast to well localized N19 and N32 peaks at the contralateral central electrode, the N17, P20 and N29 peaks were registered over the bifrontal and ipsilateral central regions as well as in the vertex. The parietal N20 peak was also present at the occipital electrodes bilaterally. In patients with localized cerebral lesions, types of SEP abnormalities varied considerably, presumably reflecting complex somatosensory afferent pathways. A small lesion in posterolateral thalamus may totally eliminate NI, NII and NIII components over both hemispheres, sparing only P14 whereas a sizable lesion in the frontal or parietal lobe may affect only NII or NIII. Capsular lesions spare P14 and frontal N17 but may alter all the subsequent SEP components, or NII or NIII selectively. In some cases, the corresponding peaks at the central and parietal electrodes may be affected independently. The complex relationships between the type of SEP abnormalities and the location of cerebral lesions can best be explained by postulating the presence of multiple, at least partially independent, thalamocortical projections mediating regionally specific somatosensory inputs.

Time-dependent changes in cerebral and cardiovascular parameters in isoflurane-nitrous oxide-anesthetized dogs.

The purpose of this study was to examine the time-dependent effects of isoflurane-nitrous oxide anesthesia on cerebral blood flow and metabolism and on cardiovascular parameters. Eleven 15-kg mongrel dogs were anesthetized with 0.8% isoflurane (approximately 1.3 MAC (minimal anesthetic concentration], 70% nitrous oxide, and 30% O2 and were paralyzed with pancuronium. Blood flow (using the radioactive microsphere technique) and cerebrovascular and cardiovascular parameters were measured 6 times at 30-minute intervals beginning 2 hours after the induction of anesthesia. In this experiment, cerebral blood flow was markedly elevated at 2 hours after the induction of anesthesia, but then declined progressively by 40 to 50% over the 2 1/2-hour time period investigated, approaching values for normal awake dogs. The decline was accompanied by a progressive decrease in the cerebral metabolic rate of oxygen and a constant rise in cerebrovascular resistance. Blood flow to organs outside the central nervous system declined progressively, but with more variability between tissues. The mean arterial pressure increased slightly, and the peripheral vascular resistance almost doubled, but cardiac index, cardiac work, and stroke volume all decreased gradually. We conclude that isoflurane-nitrous oxide anesthesia produces significant cerebral vasodilatation in dogs, but that this effect diminishes over time. These time-dependent circulatory changes merit further investigation in humans.

Field distribution of antidromically activated digital nerve potentials: model for far-field recording.

In 20 median nerves, the shift in mean latency of the referentially recorded antidromic sensory potential was 0.22 to 0.38 msec per 1.5 cm across the palm and only 0.03 to 0.05 msec per 1.5 cm along the third digit. In five radial nerves, referential recording from the tip of the second digit detected a stationary positive potential that was coincident with the entry of the sensory impulse into the nerve terminal near the base of the digit. These findings are consistent with the view that, in far-field recording of a traveling impulse, a time peak could result from an abrupt change in current flow that is based on the geometry of the volume conductor without fixed neural discharges.

Seizures due to central nervous system rheumatoid meningovasculitis.

A patient with rheumatoid arthritis and seizures had rheumatoid meningovasculitis on brain biopsy. Infection was excluded as a cause of the seizures and cerebrospinal fluid abnormalities, which resolved with corticosteroids and azathioprine therapy.