Sleep-waking states develop independently in the isolated forebrain and brain stem following early postnatal midbrain transection in cats.

We report the effects of permanently separating the immature forebrain from the brain stem upon sleeping and waking development. Kittens ranging from postnatal 9 to 27 days of age sustained a mesencephalic transection and were maintained for up to 135 days. Prior to postnatal day 40, the electroencephalogram of the isolated forebrain and behavioral sleep-wakefulness of the decerebrate animal showed the immature patterns of normal young kittens. Thereafter, the isolated forebrain showed alternating sleep-wakefulness electrocortical rhythms similar to the corresponding normal patterns of intact, mature cats. Olfactory stimuli generally changed forebrain sleeping into waking activity, and in cats with the section behind the third nerve nuclei, normal correlates of eye movements-pupillary activity with electrocortical rhythms were present. Behind the transection, decerebrate animals showed wakefulness, and after 20 days of age displayed typical behavioral episodes of rapid eye movements sleep and, during these periods, the pontine recordings showed ponto-geniculo-occipital waves, which are markers for this sleep stage, together with muscle atonia and rapid lateral eye movements. Typically, but with remarkable exceptions suggesting humoral interactions, the sleep-waking patterns of the isolated forebrain were dissociated from those of the decerebrate animal. These results were very similar to our previous findings in midbrain-transected adult cats. However, subtle differences suggested greater functional plasticity in the developing versus the adult isolated forebrain. We conclude that behavioral and electroencephalographic patterns of non-rapid eye movement sleep and of rapid eye movement sleep states mature independently in the forebrain and the brain stem, respectively, after these structures are separated early postnatally. In terms of waking, the findings strengthen our concept that in higher mammals the rostral brain can independently support wakefulness/arousal and, hypothetically, perhaps even awareness. Therefore, these basic sleeping-waking functions are intrinsic properties of the forebrain/brain stem and as such can develop autochthonously. These data help our understanding of some normal/borderline sleep-waking dissociations as well as peculiar states of consciousness in long term patients with brain stem lesions.

Tumor volume and growth kinetics in hypothalamic-chiasmatic pediatric low grade gliomas.

Pediatric low grade gliomas evidence a tendency towards quiescent growth, thus complicating the clinical management of nonresected tumors whose clinical behavior may be difficult to predict. We decided to explore the hypothesis of possible correlation in pediatric low grade glioma between tumor volume and growth rate. We identified 6 children with hypothalamic chiasmatic lesions. Five of these patients were treated only with biopsy and 1 with repeated partial tumor resection. All of 6 patients had 10-15 sequential brain MRI over a time span of 3-8 years. Tumor volume was determined using Sigma Scan Image software. The results were analyzed utilizing two equations for modeling tumor growth: exponential and Gompertz. In 4 patients whose tumor volume was approximately 80-100 cm(3) at the time of diagnosis, slow spontaneous partial regression was observed. In the other patients deceleratory or exponential tumor growth was volume-dependent. Our results suggest that growth of pediatric low grade glioma decelerates as tumor becomes large and that the Gompertz model for tumor growth is useful for understanding the growth kinetics of pediatric low grade glioma.

Limited (L4-S1, L5-S1) selective dorsal rhizotomy for reducing spasticity in cerebral palsy.

Selective posterior rhizotomy is effective for relieving spasticity associated with cerebral palsy. In current techniques dorsal roots from L1/L2 to S1/S2 are selectively divided. With transoperative electromyography (EMG) significant sensory loss has been prevented, but postoperative hypotonia following excessive reduction of the fusimotor drive is still of concern for surgeons and therapists. To decrease the volume of deafferentiated rootlets we proposed a limited selective posterior rhizotomy (LPSR) that limits the extent of the surgery to three (L4-S1) or two (L5-S1) dorsal roots. We present the results of two group of spastic children; group 1 (n = 59, 32 quadriplegic and 27 diplegic) who had a L4-S1 LPSR, and group 2 (n = 12) in whom L5 and S1 were selectively rhizotomized. Posture, passive movilization, range of joint movement, and muscle tone in hip flexors, adductors, leg flexors and plantar flexors were graded according to the method proposed by Sindou and Jeanmonod. In all groups these was a significant reduction of the mentioned parameters (Friedman test p < 0.001) at 6, 12 and 18 months after surgery. The preoperative and postoperative ability to ambulate was classified into five grades. In all groups there was a significant (chi 2 between p < 0.01 and p < 0.001) improvement in the quality of their gait. A third of the patients achieved some form of independent ambulation. Our results suggest that extensive selective deafferentation of the lower limbs is not an absolute requisite for reducing muscle tone or achieving functional improvement in spastic children.

Pediatric low-grade gliomas: prognosis with proton magnetic resonance spectroscopic imaging.

OBJECTIVE: Our aim was to assess the correlation between the low-grade glioma (LGG) metabolic profile and tumor progression. Using in vivo proton magnetic resonance spectroscopic imaging, we specifically asked whether and which metabolic features are associated with tumor regrowth or recurrence. METHODS: Eleven pediatric patients with histologically proven partially resected (<20% resection) midline LGG were treated and followed up for a period of 2 years. All patients underwent proton magnetic resonance spectroscopic imaging studies before any management was determined. Tumor progression was defined as radiological evidence of mass enlargement (>25%) during the follow-up period. Proton magnetic resonance spectroscopic imaging was performed using a PRESS-CSI sequence on a General Electric 1.5-tesla scanner (General Electric Medical System, Waukesha, WI). The signal intensities of N-acetylaspartate, choline (CHO), and creatine from the tumor and the normal brain were used to calculate normalized metabolite intensities and metabolite ratios. RESULTS: Tumors that progressed during a 2-year period displayed higher normalized CHO than those that remained stable (Mann-Whitney test, P < 0.03). The majority (five of six) of the rapidly growing LGG showed values of normalized CHO of at least 1, whereas the nonprogressors had a normalized CHO value of less than 1. CONCLUSION: In association with pediatric LGG, high normalized CHO values seem to herald the potential for rapid tumor growth. These observations may be valuable for defining subsets of patients with LGG who may benefit from early therapeutic interventions.

Reduced bovine leukaemia virus proviral load in genetically resistant cattle.

The bovine leukaemia virus (BLV) is an exogenous retrovirus that is closely related to the human T cell leukaemia viruses. Genetic resistance and susceptibility to persistent lymphocytosis (PL), an advanced subclinical stage of infection characterized by a polyclonal expansion of the infected B cell population, have been mapped to structural motifs in bovine MHC DRB3 (class II) alleles. To determine whether alleles of DRB3 influence the number of BLV-infected B cells in peripheral blood, seven pairs of Holstein cows naturally infected with BLV were matched on the basis of DRB3 genotype (resistance or susceptibility to PL), age, and year of seroconversion. Flow cytometry was used to separate B cell populations that then were tested for the presence of provirus by a single-cell PCR methodology. Animals with the PL-resistance associated DRB3.2*11 allele had significantly fewer BLV-infected B cells than did age- and seroconversion-matched cows with DRB3 alleles associated with susceptibility to PL. Our results demonstrate that DRB3 or a closely linked gene may play a direct role in controlling the number of BLV-infected peripheral B cells in vivo. Association of MHC class II alleles with resistance to disease progression in cattle naturally infected with BLV provides a unique immunogenetic model for the study of host resistance to human and other animal retroviral infections.

Multiple shunt failures: an analysis of relevant factors.

Ventricular shunts that require multiple revisions are familiar to pediatric neurosurgeons. We conducted a retrospective study to determine whether patients who require repeated shunt revisions represent a particular cohort within shunted hydrocephalic children. The clinical records of 244 children who had undergone shunt procedures between January 1990 and January 1996 were examined. They were divided into group 1: children with no shunt failure (n=136), group 2: children with one shunt revision (n=52), group 3: children with 2 or 3 shunt revisions (n=34), and group 4: patients who had 4 or more shunt revisions (n=22). Patients in groups 3 and 4 accounted for 54.8% of the total of 531 shunt procedures. Etiology of hydrocephalus, nature of the dysfunction, CSF characteristics, and variables related to the surgical procedure were analyzed for each group. We observed a progressive shortening of the intervals between revisions as the numbers of surgeries increased, indicating that shunts that tended to fail repeatedly did so sooner than those that did not. A Kaplan-Meier shunt survival curve showed that group 2 had a slower rate of failure than either group 3 (chi2=7.13, P<0.01) or group 4 (chi2=4.76, P<0.05). The etiologies of the hydrocephalus were not randomly distributed among the four groups (chi2=81.4, P<0.001); there was a predominance of congenital conditions in group 1. Repeated shunt revisions were associated with a progressive increase in the concentration of monocytes in the CSF (Kruskal-Wallis, P<0.05). Our data suggest that multiple shunt revisions constitute a phenomenon that may be caused by specific, still unidentified, biological factors.

An enzyme immunoassay for neuron-specific enolase in cerebrospinal fluid.

A direct (as opposed to competitive) enzyme immunoassay (EIA) was developed to detect neuron-specific enolase (NSE) in cerebrospinal fluid (CSF). Most common methods of evaluating NSE levels have utilized radioimmunoassay. These are highly sensitive, but cannot be employed in laboratories not equipped or licensed for the use of radioisotopes. The EIA developed here shows sensitivity within the physiological range of values for CSF-NSE (> I ng/ml) and can be used in laboratories with appropriate densitometric scanning capabilities. The assay was applied to CSF samples obtained from patients with a variety of diagnoses at the time of surgical intervention for their respective disorders. While there were no diagnostically significant differences between the level of NSE in CSF from patients with different neurological disorders utilized in the development of this procedure, we were able to differentiate between marginally different levels of NSE. We conclude that we have developed a safe, fast, reliable, and sensitive assay for NSE in the CSF that can be used to study NSE levels in a variety of neurological cases.

The prevalence of proviral bovine leukemia virus in peripheral blood mononuclear cells at two subclinical stages of infection.

The bovine leukemia virus (BLV) is an oncogenic retrovirus that is associated with the development of persistent lymphocytosis (PL) and lymphoma in cattle. While B lymphocytes have been shown to be the primary cellular target of BLV, recent studies suggest that some T lymphocytes and monocytes may be infected by the virus. Because virally altered functions of monocytes and/or T cells could contribute to the development of lymphoproliferative disease, we sought to clarify the distribution of the BLV provirus in subpopulations of peripheral blood mononuclear cells in seropositive cows with and without PL. CD2+ T cells, monocytes, and CD5+ and CD5- B cells were sorted by flow cytometry and tested for the presence of BLV by single-cell PCR. We did not obtain convincing evidence that peripheral blood monocytes or T lymphocytes contain the BLV provirus in seropositive cows with or without PL. In seropositive cows without PL (n=14), BLV-infected CD5+ and CD5- B cells accounted for 9.2% +/- 19% and 0.1% +/- 1.8% of circulating B lymphocytes, respectively. In cows with PL (n=5), BLV-infected CD5+ and CD5- B cells accounted for 66% +/- 4.8% and 13.9% +/- 6.6% of circulating B lymphocytes, respectively. The increase in lymphocyte numbers in cows with PL was entirely attributable to the 45-fold and 99-fold expansions of infected CD5+ and CD5- B-cell populations, respectively. Our results demonstrate that B cells are the only mononuclear cells in peripheral blood that are significantly infected with BLV. On the basis of the absolute numbers of infected cells in seropositive, hematologically normal animals, there appear to be differences in susceptibility to viral spread in vivo that may be under the genetic control of the host.

Proton magnetic resonance spectroscopic imaging of pediatric low-grade astrocytomas.

Despite their uniform histologic appearance, pediatric low-grade astrocytomas (LGA) often exhibit a rather unpredictable clinical course. It is presently unclear whether certain specific genetic, immunologic and/or metabolic features underlie these observed variations. In order to address this question we examined the tumor distribution of choline compounds (Cho), creatine (Cr) and N-acetyl aspartate (NAA) in seven children with midline LGA by means of proton magnetic resonance spectroscopy imaging (H-MRSI). Studies were performed with a 1.5 T GE Signa Scanner equipped with the standard head coil; nominal voxel size was 7.5 x 7.5 x 15 mm. This spatial resolution allowed us to select and independently evaluate multiple regions of interest (ROI) in the tumor as well as in areas of normal brain from the same individual. Normalized values of the observed signal intensities demonstrated a lower NAA and Cr content in the tumors than in the surrounding normal brain. Intratumoral Cho signals were also below normal values in all but one patient. The average Cho:NAA ratio was consistently higher in the tumor than in the normal brain. However, there was a wide variation (up to fourfold) in the Cho:NAA ratios of different ROIs, even within the same tumor. Our results clearly indicate that pediatric LGAs are metabolically heterogeneous, a feature that may be relevant to the understanding of their variable biologic behavior. Inasmuch as unique metabolic patterns were observed in some LGAs, we believe that systematic HMRSI studies of these patients may help define subsets within the group with specific therapeutic requirements.

Metabolic responses of the neonatal rabbit brain to hydrocephalus and shunting.

The metabolic changes that occur in the neonatal brain as a result of hydrocephalus, and the response to ventriculoperitoneal shunting, vary with the maturational stage of the brain. In this study, local glucose utilization (LCMRglu) and oxidative metabolic capacity were estimated using 2-deoxyglucose autoradiography and cytochrome oxidase histochemistry, respectively. Hydrocephalus was induced in rabbit pups via intracisternal kaolin injections at 4-6 days of age. Shunting occurred at 19-26 days of age and the animals were sacrificed at ages ranging from 33 to 331 days. In normal animals there was a high glucose demand early in life which showed a decrease at about 60 days of age. In rabbits sacrificed prior to 60 days of age the controls showed the highest LCMRglu with significant decreases in both the hydrocephalic and shunted animals. After 60 days of age the shunted animals had higher LCMRglu than both the hydrocephalic and control subjects. Oxidative metabolic capacity peaked before 50 days of age in normal animals. At the youngest age, both the hydrocephalic and shunted animals showed higher cytochrome oxidase density rates than the control rabbits. In the older group, the hydrocephalic animals remained high while the shunted animals approximated the control densities. Neither the changes seen in the LCMRglu nor the oxidative metabolic capacity were correlated with changes in cell packing density or increased intracranial pressure. These data suggest that when the brain is compromised by hydrocephalus, there is an initial compensatory increase in oxidative metabolic capacity. The development of the glycolytic pathway appears to be retarded by hydrocephalus, but with shunting and the passage of time, the LCMRglu rebounds to levels above that of controls.

Neuroamine related compounds in the CSF of hydrocephalic rabbits.

The effects of neonatal hydrocephalus on the levels of tyrosine, tryptophan, 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) in CSF were determined by high-performance liquid chromatography (HPLC) with fluorometric detection in normal and chronically hydrocephalic rabbits. The hydrocephalic rabbits showed a highly significant increase in both the serotonin metabolite 5-HIAA and the dopamine metabolite HVA. There were no significant effects of the hydrocephalus on either tyrosine or tryptophan levels. There was a significant positive correlation between the intracranial pressure (ICP) and the increase in 5-HIAA and HVA, but not with the two precursor amino acids. There was a significant decrease in these amino acid precursors with age in both groups. A trend towards higher levels of 5-HIAA and HVA in older rabbits was also evident, however this change was not to the degree found in the hydrocephalics. These data indicate that increased ICP affects the mechanism of removal of 5-HIAA and HVA from the cerebrospinal fluid.

Hypothalamic dysthermia in persons with brain damage.

Brain injury causing dysthermia has appeared to be not uncommon in institutionalized people with mental retardation. We sought to determine the characteristics and risks of patients of one institution. Of 1100 residents surveyed over 10 years 92 were reported to have unexplained high or low body temperatures, and 48 were monitored. Core temperatures were taken by non-invasive thermometers recording continuously for 24 h. Results were related to clinical conditions and aetiologies of mental retardation. Twenty-one per cent of the residents monitored showed hyperthermia, often related to prenatal metabolic or chromosomal abnormalities. Forty-two per cent had hypothermia, related to other causes of brain injury. Seventy-five per cent had abnormal patterns, including flat or exaggerated rhythms, reversed day-night cycle, unusual fluctuations, or sleep phase delay. Sixty-two per cent of 21 deaths to date have occurred in hypothermic patients. Occasional discrepancies between history of dysthermia and monitored results are best explained by fluctuations of temperature control over several days, probably due to changes in timing of hypothalamic rhythmicity. This could be better delineated by longer periods of monitoring.

Mortality and the acquisition of basic skills by children and adults with severe disabilities.

OBJECTIVE: To determine normative data on age-related probabilities of children with severe disabilities acquiring mobility or self-feeding skills, or dying during a 5-year follow-up period. RESEARCH DESIGN: A 5-year follow-up study of three mutually exclusive subgroups formed on the basis of severe, profound, or suspected levels of retardation and incontinence and the following combinations of feeding and mobility skills. PARTICIPANTS: The sample was made up of 7836 children and adults distributed among the three subgroups being served in California between January 1981 and December 1985. MEASUREMENTS/MAIN RESULTS: Subjects who were tube-fed and immobile showed very little likelihood of becoming mobile or feeding themselves and had a high probability of death. Individuals who had some mobility experienced a better outcome. CONCLUSIONS: After age 6 years, the most probable outcome for children who are immobile and cannot feed themselves is death or no improvement in self-help skills.

Maturation of pyrogen-elicited fever in the kitten.

The febrile response to the endotoxin Salmonella typhosa was studied in developing kittens. We found that kittens younger than 30 days of age generated only a small rise in temperature in response to a standardized endotoxin challenge that consistently causes fever in adult cats. Some degree of febrile response was present at birth, but the dose of pyrogen necessary to elicit a fever was 10-15 times greater than that required in the adult. There was a gradual increase in both the magnitude and duration of fever as a function of age with the largest change occurring after 30 days of age. There was a direct relationship between the ability of the kitten to maintain its body temperature (Tbo) at the room ambient (Ta) and the magnitude of the elicited fever. However, increasing the Ta to thermoneutral (Ta = 30-32 degrees C) did not enhance the thermal response indicating that the failure to elicit the fever is not due to passive effects of Ta. These data suggest that the febrile response to an endotoxin develops over the first 6-7 weeks of the kitten's life and are discussed in relation to other physical variables of development.

Neurological and neurobehavioral development of the mutant 'twitcher' mouse.

The present study described the neurological and locomotor development of the mutant 'twitcher' mouse (B57BL/6J-twi), an enzymatically authentic model of globoid cell (Krabbe) leukodystrophy. Comparisons were made on a neurological developmental battery and a series of behavioral tests, including open field, rotorod, and hangtime performance. Homozygous affected (twi/twi), heterozygous carriers (+/twi) and homozygous normals (+/+) were compared. Neurological development was slowed in twi/twi with some subtler differences between +/twi and normals. Twi/twi reached all functional milestones except grasp. There was a rapid deterioration of motor indices after 20 days of age. However, most sensory markers were preserved. On hangtime, there were significant differences from normal for both twi/twi and +/twi at 15 days of age and across the 15-30 day developmental stage, with the +/twi males slightly more impaired. On the rotorod, all animals were equally unable to stay on the rod at 15 days of age and neither male nor female twi/twi showed significant development. Male +/twi lagged significantly behind male +/+. In the open field, all groups were equally inactive at 13-15 days and showed similar increases in activity, rearing, and grooming until weaning. All groups peaked immediately after weaning and declined thereafter, with twi/twi showing the lowest activity. The data were discussed in terms of the relationship between the human disease and the animal model.

Recovery of function after neonatal or adult hemispherectomy in cats: I. Time course, movement, posture and sensorimotor tests.

Cats with removal of the left hemitelencephalon (hemispherectomy) as neonates (n = 12) or in adulthood (n = 14), were compared using a battery of 16 neurological and behavioral tests given when they were young adults (kittens) or at least 5 months after the lesion (adults). The neonatal-lesioned subjects grew normally and performed markedly and significantly better than adult-lesioned cats in 13 tests covering the wide range of movement, posture and sensory functions which were assessed. None of the animals recovered tactile placing of the right forelimb or a normal vision in the right visual field. However, the overall recovery was outstanding for all cats such that the neonatal-lesioned were hard to differentiate from intact controls in their spontaneous, daily activities. Because the lesions were similar in the two age-at-lesion groups, and since numerous functions were followed for prolonged, comparable postlesion time, we conclude that, after hemispherectomy in the cat, there definitely is greater functional recovery if the lesion is sustained early in life. We propose that the enhanced recovery of function in neonatal-lesioned cats is largely due to the extensive anatomical reorganization which we have demonstrated in ongoing studies, and which contrasts with a lesser remodeling in adult-lesioned cats.