High Prevalence of Spinal Cord Cavernous Malformations in the Familial Cerebral Cavernous Malformations Type 1 Cohort.

BACKGROUND AND PURPOSE: Cavernous malformations occur most often in the brain but can occur in the spinal cord. Small studies of patients with familial cerebral cavernous malformations suggested a prevalence of spinal cord cavernous malformations of 20%-42%. We aimed to review our familial cohort and prospectively estimate the prevalence of spinal cord cavernous malformations. MATERIALS AND METHODS: We initially reviewed our familial cerebral cavernous malformations cohort for spinal cord cavernous malformations and reviewed clinical spine MR imaging examinations for sequence sensitivity. We then prospectively performed research MR imaging of the spinal cord in 29 patients from the familial cohort to estimate the prevalence. RESULTS: Gradient-based sequences identified the most spinal cord cavernous malformations on clinical MR images, forming the basis for developing our screening MR imaging. Screening spinal cord MR imaging demonstrated a prevalence of 72.4%, and a positive correlation with patient age and number of cerebral cavernous malformations. CONCLUSIONS: Spinal cord cavernous malformations occur commonly in the familial cerebral cavernous malformation population. Gradient-based sequences are the most sensitive and should be used when spinal cord cavernous malformations are suspected. This study establishes the prevalence in the familial population at around 70% and supports the idea that this condition is a progressive systemic disease that affects the entire central nervous system.

Testosterone regulation of sexual reflexes in spinal male rats.

Castrated male rats with complete midthoracic spinal transections were maintained on exogenous testosterone; they showed intermittent clusters of genital responses consisting of erections, quick flips, and long flips of the penis when gentle pressure was con stantly applied to its base. The number of these genital responses per 30-minute test was markedly influenced by withdrawal or administration of testosterone.

Neonatal castration: influence on neural organization of sexual reflexes in male rats.

Most male rats castrated 4 days after birth and given exogenous testosterone in adulthood were sexually motivated but incapable of completing the mating sequence with an ejaculatory response. When tested for sexual reflexes after spinal transection, these animals displayed impairment of genital responses. Similarly treated 12-day castrates exhibited a complete mating sequence and had normal sexual reflexes. Thus neonatal testicular androgen appears to have an organizational influence at the spinal level on neural tissue mediating sexual reflexes.

An approach to canine behavioural genetics employing guide dogs for the blind.

The purpose of this study was to attempt to find related variables of the canine genome with behavioural traits of dogs maintained and tested in a guide dog facility which provided a relatively uniform environment. The study involved 81 Labrador Retrievers that were being trained as guide dogs. Each dog was taken on walk-out sessions in which the trainer weekly recorded observations that were related to behavioural traits. The records were subjected to key-word analysis of 14 behaviour-related words. A factor analysis on the appearance rate of the 14 key words or phrases resulted in the extraction of six factors that accounted for 67.4% of the variance. Factor 1, referred to as aggressiveness, was significantly related to the success or failure of the dog in qualifying as a guide dog, and was also related to the variable of litter identification. Factor 2, referred to as distraction, was related to the variable of trainer. Factor 3, activity level, was related to the variable of sex, and was significantly related to the polymorphisms of c.471T>C in the solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter) member 2 gene and c.216G>A in the catechol-O-methyltransferase gene. The involvement of polymorphisms c.471T>C and c.216G>A in behavioural patterns related to activity level is similar to comparable genetic studies in other mammalian species. These results contribute to a greater understanding of the role of these genes in behaviour.

Association analysis between canine behavioural traits and genetic polymorphisms in the Shiba Inu breed.

The relationships between behavioural trait data and the genotype of 15 polymorphisms in eight neurotransmitter-related genes were analysed in 77 dogs of the Shiba Inu breed, an indigenous Japanese dog. The data were obtained from a 26-item questionnaire on the dog's behaviour, distributed to the dog's owners, through veterinary hospitals and the Shiba Inu breed magazine. A factor analysis of the questionnaire items extracted eight factors accounting for 66.8% of the variance. An association analysis between these factors and genetic polymorphisms indicated that the polymorphism of c.471T>C in the solute carrier family 1 (neuronal/epithelial high-affinity glutamate transporter) member 2 (SLC1A2) gene was significantly associated with Factor 1, referred to as 'aggression to strangers'. This association remained stable in separate analyses of data from surveys obtained from the hospitals and those obtained from the magazine. The results suggest that the c.471T>C polymorphism is associated with some types of aggressive behaviour in the Shiba Inu. Further studies using other dog breeds are necessary to extend these findings to dogs in general.

Armies of pestilence: CNS infections as potential weapons of mass destruction.

Infectious agents have been investigated, developed, and used by both governments and terrorist groups as weapons of mass destruction. CNS infections, though traditionally considered less often than respiratory diseases in this scenario, may be very important. Viruses responsible for encephalitides can be highly infectious in aerosol form. CNS involvement in anthrax is ominous but should change treatment. Brucellosis, plague, Q fever, and other bacteria can uncommonly manifest with meningoencephalitis and other findings. Emerging diseases may also pose threats. We review infectious agents of particular concern for purposes of biowarfare with respect to CNS manifestations and imaging features.

Increased number of white matter lesions in patients with familial cerebral cavernous malformations.

BACKGROUND AND PURPOSE: Familial cerebral cavernous malformations, an autosomal dominant disorder, result in excess morbidity and mortality in affected patients. The disorder is most prevalent in the Southwest United States, where the affected families are most often carriers of the CCM1-KRIT1 Common Hispanic Mutation. The brain and spinal cord parenchyma in these individuals is usually affected by multiple cavernous malformations. Previous studies have shown abnormalities of endothelial cell junctions and the blood-brain barrier in cerebral cavernous malformations. Endothelial cell abnormalities have also been described in pathologic studies of white matter hyperintensities. We compared the prevalence of white matter hyperintensities in a population with known familial cerebral cavernous malformations. MATERIALS AND METHODS: We examined 191 subjects with familial cerebral cavernous malformations who were enrolled into an institutional review board-approved study. All carry the same Common Hispanic Mutation in the CCM1 gene. Each subject underwent 3T MR imaging, including gradient recalled-echo, SWI, and FLAIR sequences. The number of cavernous malformations and the number of nonhemorrhagic white matter hyperintensities were counted. Subjects older than 60 years of age were excluded due to the high prevalence of white matter lesions in this population, and children younger than 6 were excluded due to potential sedation requirements. Logistic regression analysis was performed to determine the prevalence of abnormal white matter hyperintensities in those with familial cerebral cavernous malformations compared with healthy controls or those with sporadic cerebral cavernous malformation within the familial cerebral cavernous malformations group; it was also performed to evaluate the associations between abnormal white matter hyperintensities and age, sex, headaches, thyroid disease, diabetes, hypertension, hyperlipidemia, seizure history, or modified Rankin Scale score. RESULTS: Familial CCM1 carriers have a higher prevalence of abnormal white matter hyperintensities (15.4%) compared with both control populations (2.1% and 2.5%, respectively) (P < .05). Logistic regression showed no statistical association with sex, headaches, hyperlipidemia, hypertension, thyroid disease, seizure history, number of cerebral cavernous malformations, or modified Rankin Scale score among those with familial cerebral cavernous malformation. An expected correlation with age was shown. CONCLUSIONS: Familial CCM1 carriers have not only an increased number of cerebral cavernous malformations but also an increased number of white matter T2 hyperintensities, spatially distinct from cerebral cavernous malformations, which exceeded that of a healthy population. Clinical findings did not explain the association with abnormal white matter hyperintensities in the familial cerebral cavernous malformation population. To our knowledge, these relationships have not been previously reported. This finding suggests an additional manifestation of endothelial abnormalities in this population.

Behavioral adaptations to pathogens and parasites: five strategies.

The ever present threat of viral, bacterial, protozoan and metazoan parasites in the environment of wild animals is viewed as responsible for the natural selection of a variety of behavioral patterns that enable animals to survive and reproduce in this type of environment. Several lines of research, some quite recent, point to five behavioral strategies that vertebrates utilize to increase their personal or inclusive fitness in the face of parasites (broadly defined to include pathogens). These are: 1) avoidance of parasites; 2) controlled exposure to parasites to potentiate the immune system; 3) behavior of sick animals including anorexia and depression to overcome systemic febrile infections; 4) helping sick animals; 5) sexual selection for mating partners with the genetic endowment for resistance to parasites. The point is made that to consider a behavioral pattern as having evolved to serve a parasite control function the parasite or causative agent should be shown to adversely impact the animal's fitness and the behavior in question must be shown to help animals, or their offspring or group mates, in combating their exposure, or reducing their vulnerability, to the parasite.

Biological basis of the behavior of sick animals.

The most commonly recognized behavioral patterns of animals and people at the onset of febrile infectious diseases are lethargy, depression, anorexia, and reduction in grooming. Findings from recent lines of research are reviewed to formulate the perspective that the behavior of sick animals and people is not a maladaptive response or the effect of debilitation, but rather an organized, evolved behavioral strategy to facilitate the role of fever in combating viral and bacterial infections. The sick individual is viewed as being at a life or death juncture and its behavior is an all-out effort to overcome the disease.

The effect of somatostatin on the intestinal transport of glucose in vivo and in vitro in the rat.

The possibility that somatostatin has a direct inhibitory effect on intestinal D-glucose absorption was studied in rats using intact intestinal loops and everted jejunal segments. Somatostatin infusion in vivo produced a significant fall in plasma glucose concentration (P less than 0.001) and a fall in pooled plasma insulin concentration to 51% of control values. However, somatostatin infusion did not alter significantly from control values the rate of glucose disappearance from the perfused jejunal lumen in vivo or the appearance of gut-derived plasma glucose. The lack of an inhibitory effect of somatostatin on glucose absorption in vivo was confirmed using two in vitro studies. When increasing concentrations of somatostatin (0-10(4) ng/ml-1) were added to both mucosal and serosal solutions, no significant differences were seen for net transmural flux or unidirectional flux of D-glucose in everted jejunal segments. These studies suggest that somatostatin in the rat does not influence plasma glucose concentration by inhibiting intestinal glucose transport at physiological concentrations of glucose and over a wide range of somatostatin concentrations.

Evidence for cerebellar-frontal subsystem changes in children treated with intrathecal chemotherapy for leukemia: enhanced data analysis using an effect size model.

BACKGROUND: Following brain insult in early childhood, the later maturing neocerebellum and frontal lobes frequently show abnormalities. OBJECTIVE: To investigate the morphologic characteristics and function of a proposed cerebellar-frontal subsystem in children treated for acute lymphoblastic leukemia (ALL) with intrathecal methotrexate using quantitative magnetic resonance imaging, neuropsychological measures, nonlinear multiple regression analysis, and a statistical effect size model that augments interpretive validity of nonsignificant statistical findings, particularly from small sample size studies. DESIGN: Comparison and relationship of magnetic resonance imaging morphometry of cerebellar lobuli I-V and VI-VII and prefrontal cortices, and performance on 5 neuropsychological tests assessing visual-spatial attention, short-term memory, and visuomotor organization and coordination between childhood survivors of ALL and a matched control group. PARTICIPANTS: Ten childhood survivors of ALL treated between 1982 and 1989 with standard 3-year intrathecal chemotherapy, and matched control subjects. MAIN OUTCOME MEASURES: Morphometric results of cerebellar lobuli I-V and VI-VII and prefrontal cortices, and results of Trail-Making Tests, Rey-Osterreith Complex Figure Test, WISC-III Coding. RESULTS: Significant effect size model values for outcome measures in the ALL group support deficits in lobuli VI-VII and prefrontal cortices, and neuropsychological performance. Multiple regression analysis results were consistent with hypothesized involvement of a cerebellar-frontal brain subsystem. CONCLUSION: Treatment of children with ALL with intrathecal methotrexate before 5 years of age has structural and functional effects on the developing neocerebellar-frontal subsystem.

Hypoplasia of the cerebellar vermis and cognitive deficits in survivors of childhood leukemia.

BACKGROUND: Neurodevelopmental evidence of the cerebellum's protracted course of postnatal development suggests that it is particularly sensitive to early toxic insult from cancer therapy. If this is the case, one would expect that there is a relationship between the pattern of neuropsychological and magnetic resonance imaging deficits and that both may indicate cerebellar abnormalities. OBJECTIVE: To investigate the profiles of neuropsychological functions and the morphologic features of the cerebellum, using in vivo magnetic resonance imaging planimetry in survivors of acute lymphoblastic leukemia (ALL) treated with radiation and chemotherapy. DESIGN: Thirteen survivors of childhood ALL with onset at age 2 to 5 years and a uniform protocol of treatment involving cranial radiation of 24 Gy and five doses of intrathecal methotrexate sodium participated in the study. Ten controls matched the patients in age and socioeconomic status. Each child was assessed with a comprehensive battery of neuropsychological tests and with magnetic resonance imaging of the brain. MEASUREMENTS: The neuropsychological scores were transformed into z scores and clustered into right and left hemisphere measures. Planimetric measures of the cerebellar vermis and pons were collected in the midsagittal plane. RESULTS: Consistently observed in survivors of ALL were the following: (1) significant cognitive deficits in visual-spatial-motor coordination and figural memory, functions commonly related to the right side of the brain; and (2) hypoplasia of the cerebellar vermis, lobuli I through V and particularly VI to VII. Lateralization of the neurobehavioral deficits was not reflected in structural brain abnormalities. CONCLUSIONS: Coexistence of the cerebellar hypoplasia and visual-motor coordination and memory deficits supports the neurodevelopmental approach to brain sequelae in survivors of ALL; it also suggests significance of the cerebellum for both motor and complex nonmotor cognitive processing.

Familial cerebral cavernous angiomas: clinical and radiologic studies.

Cavernous angiomas are well-circumscribed cerebrovascular malformations whose natural history is poorly understood. We reviewed 5,000 cranial MRI reports of studies performed between 1986 and 1993 and retrospectively evaluated the histories and imaging studies of 29 patients whose lesions were suggestive of cavernous angiomas. Patients ranged from 3 to 66 years and 27 were of Hispanic origin. The number of malformations per patient ranged from one to 30, and 24 patients had more than one lesion. In our series, the number of lesions per patient increased at a rate of one lesion per decade of age, but the mean size of the lesions was smaller with advancing decade (p < 0.05). All patients had MRI evidence of old or recent hemorrhage confined only to the malformation and adjacent brain. In only one patient was it deemed necessary to remove the malformation. Two excluded patients with typical lesions on MRI had small arteriovenous malformations found at surgery. Thus, MRI or CT cannot identify cavernous angiomas with certainty. This study supports studies that propose that cavernous angioma-like lesions, as identified by MRI or CT, are more common in Hispanics. It is possible that patients may not be born with MRI-identifiable malformations, but with advancing age the malformations become MRI-visible through malformation growth, hemorrhage, or both. The declining size by decade favors hemorrhage rather than growth. Cavernous angiomas may be more benign than previously thought.

Quantitative proton MRS predicts outcome after traumatic brain injury.

OBJECTIVE: To determine whether proton MRS (1H-MRS) neurochemical measurements predict neuropsychological outcome of patients with traumatic brain injury (TBI). BACKGROUND: Although clinical indices and conventional imaging techniques provide critical information for TBI patient triage and acute care, none accurately predicts individual patient outcome. METHODS: The authors studied 14 patients with TBI soon after injury (45+/-21 days postinjury) and again at 6 months (172+/-43 days) and 14 age-, sex-, and education-matched control subjects. N-acetylaspartate (NAA), creatine, and choline were measured in normal-appearing occipitoparietal white and gray matter using quantitative 1H-MRS. Outcome was assessed with the Glasgow Outcome Scale (GOS) and a battery of neuropsychological tests. A composite measure of neuropsychological function was calculated from individual test z-scores probing the major functional domains commonly impaired after head trauma. RESULTS: Early NAA concentrations in gray matter predicted overall neuropsychological performance (r = 0.74, p = 0.01) and GOS (F = 11.93, p = 0.007). Other metabolite measures were not related to behavioral function at outcome. CONCLUSION: 1H-MRS provides a rapid, noninvasive tool to assess the extent of diffuse injury after head trauma, a component of injury that may be the most critical factor in evaluating resultant neuropsychological dysfunction. 1H-MRS can be added to conventional MR examinations with minimal additional time, and may prove useful in assessing injury severity, guiding patient care, and predicting patient outcome.

Cerebellar hypoplasia and frontal lobe cognitive deficits in disorders of early childhood.

A developmental chronometry hypothesis of early brain damage is suggested in which regions of the brain with a protracted course of postnatal development will be more vulnerable than earlier maturing areas to deleterious effects of early insult and, therefore, may become common sites of abnormality across many disorders originating in early childhood. Initial investigations of the cerebellum and frontal lobes are presented using MRI and neuropsychological measures. Planimetric measures of the cerebellar vermis (lobuli I-V and VI-VII) and pons, and neuropsychological frontal lobe measures were obtained from high functioning individuals with autism (A), survivors of acute lymphoblastic leukemia (ALL) with brain sequelae following radiation and chemotherapy, and from rigorously selected healthy controls (C). The neuropsychological results were clustered according to functions commonly related to frontal brain, posterior brain, and left and right hemispheres. The A and ALL groups, as compared to C, yielded modest but consistently reduced MRI measures for vermal lobuli I-V and VI-VII. Hypoplasia of lobuli VI-VII was more marked than I-V. Performance on neuropsychological tests for frontal lobe functions was generally depressed in both groups, with more severe deficits in A. Between-group differences in verbal, visual-spatial, and emotional-social skills are discussed. The cerebellar and frontal brain deficits that are present in both clinical groups (A and ALL) may be common to other developmental and acquired disorders of early childhood. Such joint manifestation of cerebellar and frontal lobe abnormalities is in agreement with the concept of cerebellar significance for the development of higher cognitive functions.

Hydranencephaly in an infant with vascular malformations.

Hydranencephaly is a condition in which cerebral hemispheres are absent and reduced to fluid-filled sacs in a normal skull. Numerous causes have been proposed. We report a male infant with hydranencephaly and congenital vascular malformations (port wine stains, generalized nevus flammeus, anomalous retinal vessels, and absent internal carotid flow). Magnetic resonance imaging of the brain showed absence of most of the cerebrum except for small portions of the occipital cortex and thalami. Magnetic resonance angiography showed flow within the vertebral and basilar arteries without internal carotid intracranial flow above the internal carotid petrous and cavernous portion. This is a report of cutaneous and retinal malformations associated with hydranencephaly. Vascular malformations of larger vessels (e.g., webbing of the carotid arteries and an absent internal carotid arterial system) have been observed in other infants with hydranencephaly, and are proposed to lead to brain destruction. The case reported herein supports the role of primary vascular malformations in the development of some cases of hydranencephaly.

Female and male sexual responses in female cats with ventromedial hypothalamic lesions.

The effects of lesions in the ventromedial hypothalamus (VMH) on male and female sexual behavior in female cats were examined. Following preoperative testing for receptivity, proceptivity, and male mating behavior, 27 female cats received either lesions in the anterior or posterior portion of the VMH or sham lesions. Neither of the VMH lesion placements reduced proceptivity and receptivity scores. However, the female mating pattern was significantly altered in that although females in both lesion groups initially allowed a stud male to mount, they usually did not allow the male to intromit. As in rodents, the VMH in the cat appears to be an important neural area for the display of normal female sexual behavior. Low levels of male sexual behavior were seen in the three groups preoperatively, and no changes were observed in the levels of male behavior following lesion placement. Thus, because lesions that disrupted female behavior did not affect male sexual behavior, it appears that the neural areas controlling homotypical and heterotypical sexual behaviors are not necessarily neurally linked.

Female sexual responses in male cats facilitated by olfactory bulbectomy and medial preoptic/anterior hypothalamic lesions.

Bilateral lesions of the medial preoptic/anterior hypothalamic area and olfactory bulbectomies were performed sequentially in sexually active male cats, with the order of operations balanced. Male sexual behavior was virtually eliminated by the combined operations in all cats. Increased levels of female proceptive behavior were seen following either type of lesion alone, and combined operations resulted in increased levels of receptivity. The results support the concept that there exists, within the brains of male animals, the neural basis for the display of female as well as male sexual responses and that certain brain operations may potentiate the display of female responses. However, it does not appear that the reduction of male behavior is necessarily coupled with an increase in female behavior since no correlation was seen between the degree of enhancement of female behavior and the decrement in male behavior.

MRI morphometry of mamillary bodies, caudate nuclei, and prefrontal cortices after chemotherapy for childhood leukemia: multivariate models of early and late developing memory subsystems.

Neurotoxic intrathecal chemotherapy for childhood acute lymphoblastic leukemia (ALL) affects developing structures and functions of memory and learning subsystems selectively. Results show significant reductions in magnetic resonance imaging morphometry of mamillary bodies, components of the corticolimbic-diencephalic subsystem subserving functionally later developing, single-trial memory, nonsignificant changes in bilateral heads of the caudate nuclei, components of the corticostriatal subsystem subserving functionally earlier developing, multitrial learning, significant reductions in prefrontal cortical volume, visual and verbal single-trial memory deficits, and visuospatial, but not verbal, multitrial learning deficits. Multiple regression models provide evidence for partial dissociation and connectivity between the subsystems, and suggest that greater involvement of caudate may compensate for inefficient corticolimbic-diencephalic components.

Role of grooming in biological control of ticks.

Although many species of wild bovids live in tick infested environments, tick loads are usually kept to very low levels, primarily by frequent self grooming. Evidence from numerous studies on antelope in Africa strongly support the concept that the delivery of bouts of grooming reflects programmed grooming rather than stimulus driven or reactive grooming. In other words, grooming occurs in response to an endogenous generator that produces grooming bouts at periodic intervals, resulting in removal of ticks before they attach and begin to feed. In the same tick exposure environment, animals that groom most have the fewest ticks. The rate of programmed grooming is modulated by a number of interspecific and intraspecific determinants. Interspecific determinants include adult body size and whether or not the evolutionary habitat is tick dense or tick sparse. Intraspecific determinants include developmental stage of growth, gender (e.g., territorial male vs. female), ectoparasite exposure, and stage of arousal. Some of the intraspecific determinants appear to be mediated by systemic physiological influences suggesting there may be ways to improve grooming activity in weak groomers, such as cattle.