Phosphonomycin, a new antibiotic produced by strains of streptomyces.

Phosphonomycin is a newly discovered antibiotic produced by streptomycetes. It is effective, when administered by the oral route, to mice infected with Gram-positive or Gram-negative microorganisms. The antibiotic is bactericidal and inhibits cell-wall synthesis.

Avoidance behavior and ileum motility post-cingulumotomy in monkey.

Two experiments were conducted utilizing rhesus monkeys to determine (i) the effects of cingulumotomy on conditioned-avoidance acquisition and extinction and (ii) the effects of avoidance learning on distal ileum motility in control- and cingulum-lesioned animals. Active (AAR) and passive (PAR) avoidance schedules singly or in combination were employed during short daily periods (less than 2 hr) of "shaping," training, acquisition, and extinction. The data indicated that the control-lesion and cingulum groups did not differ in the acquisition or extinction of an AAR. The cingulum group, however, showed a significant deficit in the acquisition of a PAR and a noticeably slower rate of lever pulling during avoidance trials in the combined avoidance training sessions. The results also suggested that ileum motility and avoidance behavior parallel on another, i.e., if either changed the other often changed in the same direction; that cingulum monkeys seemed to be less "reactive" than control-lesion monkeys; and that cingulum animals may been somewhat more regular in their percent daily motility patterns than the control animals.

Evaluation of signal detection theory on the effects of psychotropic drugs on critical flicker-fusion frequency in normal subjects.

Critical flicker-fusion frequency (CFF) has often been applied to psychotropic drug evaluation as a measure of cortical arousal. There are several variables that must be considered for proper conclusions to be obtained from CFF experimental data. Psychological variables such as subject response bias are especially difficult to control. We studied the effects of single oral doses of 10 mg diazepam and 10 mg amphetamine sulfate on CFF values obtained by a block up-down spatial forced-choice method on 13 healthy volunteers (seven males and six females). Signal detection theory was also used to obtain the non-parametric value P(A) as a measure of sensory function and B as a measure of the psychological function of response bias. As a group, amphetamine increased CFF (Hz) and P(A) and diazepam decreased CFF (Hz) and P(A), with the most significant effects observed at 2 and 3 h after drug administration. B scores showed more individual variation with a trend towards a low score, or a tendency to report more flicker responses after diazepam. Separated by sex, the males had a higher percentage of subjects that demonstrated a reduction of CFF after diazepam, while the females had a higher percentage that demonstrated an increase in CFF after amphetamine. The results suggest that CFF changes following diazepam and amphetamine are mostly changes in sensory function and not changes in response bias. It is possible to apply signal detection theory to flicker-fusion studies and the accounting of bias by controlling, measuring or eliminating it is essential in interpretation of CFF data.

Cortical CSF volume fluctuations by MRI in brain aging, dementia and hydrocephalus.

Dynamic MR imaging has revealed dramatic fluctuations in the appearance of CSF in the cortical sulci and cortical subarachnoid spaces in aging individuals and patients with hydrocephalus, dementia and Down syndrome in contrast to young healthy volunteers. The changes have been interpreted as volume fluctuations that represent undamped CSF hydrodynamics and have implications with respect to the origin of CSF in the cortical regions and with respect to the similarity between aging and dementia and edematous states of the brain.

The effects of a new thromboxane synthetase inhibitor, CGS-13080, in man.

CGS-13080 is a new potent selective inhibitor of thromboxane synthetase. This study reports the results of a safety and efficacy study of single oral doses in normal healthy volunteers. The compound was well tolerated by all subjects without evidence of any adverse reactions. Serum thromboxane B2 levels (the stable metabolic product of thromboxane A2) were significantly reduced after administration of the compound, with the maximal effect of a 99 per cent reduction occurring at 0.5 and 1 hour after administration. There was a concomitant increase in PGE2 and 6-keto-PGF1 alpha (the stable metabolic product of PGI2), suggesting a shunting of cyclic endoperoxide metabolism. The apparent half-life of the compound is about 1 hour, but return to 50 per cent of the original thromboxane B2 levels was achieved between 4 and 6 hours. Platelet aggregation to collagen and bleeding times failed to demonstrate significant changes after drug administration. Bleeding times showed a slight increase 2 hours after administration of the compound.

Double compartment hydrocephalus--a new clinical entity.

We are reporting eight patients who demonstrated double compartment hydrocephalus, i.e., supratentorial and infratentorial hydrocephalus in clinical sequence and separately. One infant with veil occlusion of the aqueduct was operated on to remove the veil and then later demonstrated panhydrocephalus. Six patients had been treated months to years earlier by the performance of a ventriculoperitoneal shunt for aqueductal hydrocephalus and then developed characteristic cerebellar-brain stem deficits from 4th ventricle enlargement. The work-up included computed tomographic scan, air study, isotope cerebrospinal fluid flow study, and direct 4th ventricle pressure studies. Operation with removal of a veil occlusion of the upper 4th ventricle aqueduct produced immediate recovery in five of six patients. The conversion of aqueductal stenosis to veil occlusion is postulated as the mechanism of "primary" veil obstruction found in infants. This new clinical entity is more common than realized. We report one patient with compartmental 4th ventricular hydrocephalus.

Acute negative intracranial pressure effects on the auditory evoked response in rabbits.

Recent clinical experience has shown that significant neurological symptoms and deficits occur in patients who have been shunted for hydrocephalus when "overshunting" produces unusual negative intracranial pressure (ICP). Therefore, the effect of acute negative ICP .on the early auditory evoked response (AER) was studied in the normal New Zealand rabbit. ICP was reduced to -50, -100, and -150 mm H2O below base line pressure. The AER after rarefaction auditory stimulation was obtained from ongoing electroencephalographic activity at the base line ICP and at each of the three negative ICP levels. Off-line statistical evaluation of the AER showed minimal changes in the absolute and interpeak latencies of N-0 to P-5 at some negative pressures. However, no statistically significant changes were observed for any of the measures for grouped data. At the negative ICP levels studied, the cerebrospinal fluid (CSF) pulse pressure was considerably augmented over base line measures. Such augmentation of the CSF pulse pressure may be the cause of the minimal effects observed on the AER, which may be due to a neuropraxic effect rather than ischemia from cerebral perfusion pressure changes.

Cerebrospinal fluid bulk flow study: radioiodinated serum albumin (R131ISA) and technetium-99m-labeled diethylenetriaminepentaacetic acid (DTPA) retention in the ventricles of normal and hydrocephalic dogs.

Eight normal dogs were studied and then made hydrocephalic (kaolin induced) to demonstrate and compare the use of R131ISA and 99mTcDTPA in cerebrospinal fluid (CSF) bulk flow studies. The radioisotopes were simultaneously injected into the CSF space in the cisterna magna of normal dogs and into the lateral ventricles of hydrocephalic dogs after an equal volume of CSF had been removed. The average dose of RISA was 100 muCi, and for TcDTPA it was 7 mCi. A bag of lactated Ringer's solution (500 ml) was used as a control phantom after being injected with the same dose of isotope as used in the animals. Brain scans were obtained with the gamma ray camera at 4 and 24 hours after injection. We used four criteria to evaluate results: clinical state of the animal, CSF ventricular pressures with challenges, percentage of retained isotope in counts per minute, and ventricular size at postmortem examination. The results demonstrate that the amount of isotope retention over 20 hours and the clinical state of the dog are better correlated when RISA is used than when TcDTPA is used. The study indicates that RISA is more reliable than TcDTPA as an indicator of CSF bulk flow in both normal and hydrocephalic dogs.

Hydrocephalus: increased intracranial pressure and brain stem auditory evoked responses in the hydrocephalic rabbit.

The auditory evoked response (AER) was used to study the effect of increased intracranial pressure (ICP) on the auditory pathway in normal New Zealand rabbits and in those made hydrocephalic by intracisternal injections of kaolin. AERs were studied: (a) in the normal and then in the hydrocephalic animal; and (b) in the hydrocephalic animal during further ICP elevation by cerebrospinal fluid infusion. The AER was obtained from ongoing electroencephalographic activity after rarefaction auditory clicks presented at 90 dB sound pressure equivalent. In comparing base line normal AERs to those found in hydrocephalic conditions, a statistically significant increase in latency for AER components N2, P2, and P5 was noted in hydrocephalic rabbits. Increased ICP in the hydrocephalic model showed an increase in the latencies of AER components for P0 and P1 at 250 mm H2O, and a prolongation of P3-P5 central conduction time at 700 mm H2O above base line cerebrospinal fluid pressure. In addition, a decrease in the P4/N5 amplitude and an increase in P1-P3 central conduction times at 700 mm H2O was observed. The differences between normal and hydrocephalic rabbit AER base lines may be the result of the chronically increased ICP and presumed chronic anatomical changes within the auditory pathway due to kaolin itself. The differences in the AER from base line hydrocephalus to acute increased ICP may indicate that the hydrocephalic system is more sensitive to acute neuropraxic pressure effects on the brain stem auditory structures than is the normal brain.

Malignant hyperthermia.

The authors report the case of an infant with noncommunicating hydrocephalus, Arnold-Chiari malformation, and a lumbar myelomeningocele, in whom malignant hyperthermia occurred. The genetics and presumed etiology of this unusual problem are reviewed. The management is directed toward establishing effective cooling measures, reversing tissue hypoxia, and correcting respiratory and metabolic acidosis.

Craniosynostosis.

The authors review the embryopathology and clinical manifestations of craniosynostosis and analyze a series of 27 children. The operative procedure of linear craniectomy and immediate cranioplasty is described and evaluated. Since few children with craniosynostosis have neurological deficits that can be ascribed to the skull anomalies, surgery to prevent neurological complications is only rarely justified. However, it is often possible to ameliorate the cosmetic deformity in many of these patients if operative intervention is undertaken in early infancy.

Symptomatic low intracranial pressure in shunted hydrocephalus.

Fourteen patients with ventricular cerebrospinal fluid shunts in place for chronic hydrocephalus presented with a history and neurological deficits usually associated with high intracranial pressure (ICP) caused by an obstructed shunt system. However, the symptoms were characteristically present when the patient was upright and active, and were usually relieved by lying down. The symptoms of intermittent headache, nausea, emesis, lethargy, and diplopia were associated with paresis of upward gaze or minimal strabismus. Measurement of ICP showed unexpected dramatically low levels with a marked drop in pressure when the patient was in the upright position, whereas ICP was near normal when the patient was supine. The low ICP was corrected by insertion of a high-pressure Flo-Control valve into the shunt system already in place. Postoperatively, the immediate clinical improvement and more normal ICP measurements were striking. The important clinical finding in this group of patients was the presence of disabling symptoms which occurred when the patients were up and active and which were relieved by lying down. Measurements of ICP with the patient in the supine and then in the upright position were critical in establishing an accurate diagnosis of symptomatic low ICP in these hydrocephalic patients with indwelling shunts. With the patient in the Trendelenburg position, ICP showed a marked increase, as expected; in some patients this position was prescribed as treatment for several days before surgery.

Follow-up comparison of hydrocephalus with and without myelomeningocele.

A series of 454 hydrocephalic patients with and without myelomeningocele and with and without treatment is reviewed. The survival rates for hydrocephalus alone and for hydrocephalus with myelodysplasia are comparable. The authors reach the conclusion that treatment of the hycrocephalic process and its complications is the most critical therapeutic consideration. Mental retardation is the major unalterable cause for failure to develop independence; some lesser emotional causes can be modified by encouragement. Repeated reassessment of the patient's condition and adjustment are important. Before treatment is started parents or guardians should be fully informed of the child's future potential for independent life and mental development.

CSF pulsatility in hydrocephalus: respiratory effect on pulse wave slope as an indicator of intracranial compliance.

The effect of inspiration and expiration on the systolic slope of the cerebrospinal fluid (CSF) pulse wave has been studied in 83 shunted and non-shunted patients undergoing diagnostic tests for suspected hydrocephalus. A ratio of the systolic CSF pulse slope on inspiration to the same in expiration (I/E ratio or index) has proved statistically valid in identifying non-hydrocephalic patients from hydrocephalic patients and in separating hydrocephalic patients into arrested, communicating and aqueductal stenosis hydrocephalus. The I/E ratio depends on the comparative damping effect of intracranial venous venting on the systolic CSF pulse slope during inspiration (I) when venous volume is evacuated from the cranium by negative mediastinal pressure, and during expiration (E) when cranial venous volume flow to heart is minimal due to positive mediastinal pressure. The low cranial venous outflow on expiration produces little effect on the normal damping of the systolic CSF pulse slope. The high venous outflow on inspiration produces a loss of damping, causing a high systolic CSF pulse slope. Therefore, exhausted cranial venous volume, or exhausted intracranial compliance, produces an I/E ratio approaching 1.0, whereas a normal I/E ratio is between 2.0 and 3.0. The I/E ratio can presumably be used to assess intracranial compliance changes occurring before the dangerous late intracranial pressure (ICP) upward surge related to the volume-pressure curve in all clinical problems of increasing ICP. The I/E ratio may be used likewise to assess the urgency of treatment for any hydrocephalus and increased intracranial pressure problem, i.e. the closer to unity the greater the urgency.

Hydrocephalus: slit ventricles, shunt obstructions, and third ventricle shunts: a clinical study.

In a retrospective 5 year study of patients with ventricle shunts for hydrocephalus (N = 88), studies were developed on slit ventricles in teenagers and in young adults. These studies presented here are (1) time to slit ventricles from first shunt and average upright ICP associated (N = 24); (2) upright ICP in asymptomatic long-term ventricle shunt patients without slit ventricles (N = 21), (3) clinical course of patients with uncorrected slit ventricles and lateral ventricles or third ventricle shunts (N = 31), (4) resolution of slit ventricles by Zero ICP Shunt with normal upright ICP (N = 28), (5) no resolution of slit or large ventricles in shunted patients with normal upright ICP (N = 23), and (6) unreliability of CT ventricle size (slit or enlarged) after normal upright ICP achieved (N = 28; 23). Surprisingly, slit ventricle patients with the ventricular catheter in collapsed lateral ventricles develop shunt obstruction within 20 months (21/31; 71%; 10/31 29%) patients with ventricle catheters incidentally in the third ventricle did not obstruct during the 4 1/2 year follow-up.

Hydrocephalus: overdrainage by ventricular shunts. A review and recommendations.

Selected literature review of the clinical course of patients with ventricular shunts for hydrocephalus shows that the effects of cerebrospinal fluid overdrainage are subdural hematoma, craniosynostosis, slit ventricle syndrome, and low intracranial pressure syndrome. These occur sequentially at different age groups, but approximate averages of incidence and time of occurrence after first shunt reveal an overall incidence of 10%-12% for at least one of these appearing at 6.5 years after shunting. The basic etiology, diagnosis, and variety of treatment modalities available are reviewed, including the need for shunt closing intracranial pressure control. Included is a hydrocephalus program designed to minimize the need for long-term extracranial shunts and to maximize therapeutic intracranial procedures for hydrocephalus.

Diagnosis of hydrocephalus by CSF pulse-wave analysis: a clinical study.

Pulsatility of the cerebrospinal fluid (CSF) is augmented in hydrocephalus. Analysis of pulsatility, including the CSF waveform, may be a more valid criterion for the diagnosis of hydrocephalus than mean CSF pressure. To test this possibility, CSF pressures were measured in 118 patients with presumed hydrocephalus. The pressure measurements included baseline mean pressure and pulse pressure, responses to jugular compression, and CSF wave analysis (amplitude and peak latency). Four groups of pressure recordings were identified and matched with four clinical groups: normal, arrested hydrocephalus, communicating hydrocephalus, and aqueduct stenosis hydrocephalus. The CSF pulse pressure and systolic slope form were highly reliable in the diagnosis of hydrocephalus, whereas mean CSF pressure was not reliable.

Head trauma and nonsurvival--a sample survey.

A retrospective survivor study of 42 patients with severe brain and multisystem injury is presented. All patients were treated with vigorous trauma/neurosurgical techniques. Thirty-seven patients in this series had a Glasgow Coma Score of 3 at the initial examination, and none survived. Since all 37 patients at initial emergency room evaluation showed persistent apnea at 40-60 minutes after injury, a diagnosis of dead on arrival (DOA) might have been appropriate. Cost analysis shows that the direct cost for the 37 cases was $27,000 per patient, or $990,000 for the 37 patients with no survivors. A diagnosis of DOA would have been $200 per patient. Many implications can be derived from these figures.

Shunted hydrocephalus: normal upright ICP by CSF gravity-flow control. A clinical study in young adults.

Hydrocephalic patients with years of ventricle shunts may be disabled by shunt overdrainage. Gravity-induced upright CSF shunt flow produces this overdrainage with abnormally low, upright ICP. Consequently, the concept of a normal level of zero ICP, which ventricle shunts must mimic, was developed. For 4.5 years, this concept has been applied in hydrocephalus patients by using a Siphon Control Device as a Zero Pressure Device in ventricle shunts. The results in 56 patients, including 42 overdrainage problems, were assessed by clinical grading, ICP record analyses, and computed tomographic (CT) ventricle size comparisons. All patients ultimately achieved satisfactory clinical results. This occurred in 80% of the patients on the first insertion. Adjustment of the vertical level of the Zero Pressure Device was necessary in 20%. The optimum clinical result correlated with an upright ICP of -66 mm of H2O. This postoperative ICP correlated within 4 mm of the Zero Pressure Device placement below vertex. Ventricle size correlated poorly with clinical grade and normal ICP. Only 73% of slit ventricles enlarged by 16.5 months. The need to mimic normal upright ICP by maintaining a normal level of zero upright ICP in shunted patients is supported by these results.

Double compartment hydrocephalus in a patient with cysticercosis meningitis.

The authors discuss encystment of the fourth ventricle and upward herniation complicating a case of cysticercosis cerebri. The "double compartment" hydrocephalus followed occlusion of the aqueduct of Sylvius and the foramena of Luschka and Magendie in a patient who had previously received a ventriculo-atrial shunt for communicating hydrocephalus. The clinical presentation of this particular form of double compartment hydrocephalus is discussed.