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.

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.

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.

Familial versus sporadic cavernous malformations: differences in developmental venous anomaly association and lesion phenotype.

BACKGROUND AND PURPOSE: CCMs are commonly associated with DVAs, but the incidence of association in familial CCM is unknown. The presence of a DVA significantly complicates surgical management of a CCM because of the risk of compromised venous drainage. In this investigation, we compared the incidence of a DVA in the presence of a CCM in sporadic and familial CCM cases comprising predominantly familial CCM with the Southwestern US common Hispanic mutation (or Q455X mutation) of CCM1. MATERIALS AND METHODS: Retrospective review was performed of 112 patients identified with CCM. MR imaging review included the presence or absence of a DVA and number, location, size, and signal-intensity characteristics of CCMs. Record review included patient and family history and documented genetic mutations. Statistical analysis was performed by using the Fisher exact and 2-sample t tests. RESULTS: Eighty-one cases were familial, 18 were sporadic, and 13 were indeterminate. There were a total of 2212 CCMs: 2176, 21, and 15 in the familial, sporadic, and indeterminate groups, respectively. There was a close association of CCM and DVA (an apparent combined vascular lesion) in 8 of 18 (44%) sporadic cases and only 1 possible such association in the familial cases. The difference was highly statistically significant (P < .0001). CONCLUSIONS: Familial CCMs are unlikely to be associated with DVAs, and sporadic CCMs have a high rate of association with DVA. This difference in imaging features of familial and sporadic CCMs suggests the possibility of a different developmental mechanism.

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.

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.

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.

Evaluation of cervical spine in intensive care patients following blunt trauma.

The aim of this study was to review a Level 1 trauma center's use of early (< 72 hours from injury) limited MRI to "clear" cervical spine extradural soft tissue injuries in ICU patients sustaining blunt trauma. A retrospective review of the records of patients meeting entry criteria during 1997 was performed. Demographic data, cervical spine radiographic and imaging evaluation, results, and follow-up information were gathered. One hundred and fifty patients met criteria. Forty-one patients had initial static radiographs that revealed cervical spine trauma. Twenty-seven of the 108 patients with normal initial static radiographs had evidence of extradural soft tissue injury on MRI indicating potential spinal column instability. Twenty-one of the 108 patients had negative MRI and were liberated from cervical spine precautions at a mean of 2.9 +/- 0.9 days from injury. The remaining patients were cleared of cervical spine precautions by plain radiographs and reliable clinical examinations, or by dynamic radiographs, or they died before complete evaluation. The diagnosis of acute injury to the cervical spine from blunt trauma in ICU patients must include evaluation of the osseous spine and extradural soft tissues. Dynamic studies such as flexion and extension views place the obtunded ICU patient at risk of potential neurologic injury. MRI is a noninvasive imaging technique that allows evaluation of extradural soft tissue injury with potentially less patient risk and with fewer personnel. MRI allows early liberation of cervical spine precautions in those patients with negative studies. Further studies are needed to compare specific ligamentous injury patterns by MRI with dynamic studies of the C-spine to further define MRI injury patterns indicating risk of acute spinal instability.

Effects of chronic haloperidol and clozapine treatments on frontal and caudate neurochemistry in schizophrenia.

N-Acetyl-aspartate (NAA), a marker of neuronal integrity, has been found to be reduced in frontal regions in schizophrenia. However, the impact of antipsychotic drug type on NAA has not been carefully evaluated. We studied outpatients with schizophrenia/schizoaffective disorders chronically treated with haloperidol or clozapine and normal controls with single-voxel 1H-MRS of the caudate nuclei and the left frontal lobe. Concentrations of NAA, choline containing compounds (Cho) and creatine plus phosphocreatine (Cre) were determined and corrected for the proportion of cerebrospinal fluid (CSF) in each voxel. The haloperidol-treated group had significantly lower CSF-uncorrected and CSF-corrected left frontal NAA than the normal controls, with the clozapine group having intermediate concentrations. The haloperidol-treated group had significantly lower CSF-uncorrected caudate NAA than the normal controls, but the three groups did not differ after correcting for CSF fraction. Performance times in the Grooved Pegboard, a measure of motor dexterity and proxy for parkinsonism, were correlated with CSF-uncorrected and CSF-corrected left frontal NAA. Demographic and illness-related variables were not related to NAA. Exposure to haloperidol-like drugs may in part account for the frontal NAA reductions previously reported in schizophrenia. Adjustment for proportion of voxel CSF should be considered in 1H-MRS studies.

Effect of gonadectomy on subsequent development of age-related cognitive impairment in dogs.

OBJECTIVE: To determine whether gonadectomy predisposes dogs to development of age-related behavioral changes linked to cognitive impairment. DESIGN: Cohort study. ANIMALS: 29 sexually intact male dogs, 63 spayed female dogs, and 47 castrated male dogs 11 to 14 years old. PROCEDURE: Information on possible impairments in 4 behavioral categories linked to cognitive impairment (orientation in the home and yard, social interactions, house training, and sleep-wake cycle) was obtained from owners of the dogs by use of a structured telephone interview format. A second interview was performed 12 to 18 months after the initial interview, and differences in responses were evaluated. RESULTS: Sexually intact male dogs were significantly less likely than neutered dogs to progress from mild impairment (i.e., impairment in 1 category) to severe impairment (i.e., impairment in > or = 2 categories) during the time between the first and second interviews. This difference was not attributable to differences in ages of the dogs, duration of follow-up, or the owners' perceptions of the dogs' overall health. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that the presence of circulating testosterone in aging sexually intact male dogs may slow the progression of cognitive impairment, at least among dogs that already have signs of mild impairment. Estrogens would be expected to have a similar protective role in sexually intact female dogs; unfortunately, too few sexually intact female dogs were available for inclusion in the study to test this hypothesis. There may be a need to evaluate possible methods for counteracting the effects of loss of sex hormones in gonadectomized dogs.

Prevalence of behavioral changes associated with age-related cognitive impairment in dogs.

OBJECTIVE: To determine the prevalence of age-related behavioral changes, namely impairment, in a randomly chosen population of dogs. DESIGN: Age-stratified cohort study. ANIMALS: 97 spayed female and 83 castrated male dogs that were 11 to 16 years old. PROCEDURE: Data on possible impairment in 4 behavioral categories (ie, orientation in the home and yard, social interaction, house training, and sleep-wake cycle) linked to cognitive dysfunction were obtained from dog owners, using a structured telephone interview. Hospital records of dogs had been screened to exclude dogs with dysfunction in organ systems that may cause behavioral changes. Dogs with behavioral impairment were those with > or = 2 signs of dysfunction within a category. Dogs with impairment in 1 category were considered mildly impaired and those with impairment in > or =2 categories were considered severely impaired. RESULTS: Age by sex interactions for dogs with impairment in any category were not significant, and, therefore, data on castrated males and spayed females were pooled for analyses across ages. The prevalence of age-related progressive impairment was significant in all categories. The percentage of 11- to 12-year-old dogs with impairment in > or = 1 category was 28% (22/80), of which 10% (8/80) had impairment in > or = 2 behavioral categories. Of 15- to 16-year-old dogs, 68% (23/34) had impairment in > or =1 category, of which 35% (12/34) had impairments in > or = 2 categories. There were no significant effects of body weight on the prevalence of signs of dysfunction in the behavioral categories. CONCLUSIONS AND CLINICAL RELEVANCE: Data collected provide estimates of the prevalence of various degrees of age-related behavioral changes associated with cognitive dysfunction in dogs. Age-related behavioral changes may be useful indicators for medical intervention for dogs with signs of cognitive impairment.

Predicting behavioral changes associated with age-related cognitive impairment in dogs.

OBJECTIVE: To monitor the progression of age-related behavioral changes in dogs during a period of 6 to 18 months and to determine whether signs of dysfunction in any of 4 behavioral categories can be used to predict further impairment. DESIGN: Age-stratified cohort study. ANIMALS: 63 spayed female and 47 castrated male dogs 11 to 14 years of age. PROCEDURE: Data were collected from randomly selected dog owners who were interviewed by telephone twice at a 12- to 18-month interval; data were included if the dog had lived > or = 6 months between interviews. The interview focused on signs of impairment in the following behavioral categories: orientation in the home and yard, social interactions with human family members, house training, and the sleep-wake cycle. Dogs were determined to have impairment in 0 behavioral categories (on the basis of < or = 1 sign for each category), impairment in 1 category (> or = 2 signs of dysfunction in that category), or impairment in > or = 2 categories. RESULTS: Between interviews, 22% (16/73) of dogs that did not have impairment in a category at the time of the first interview developed impairment in that category by the time of the second interview. Forty-eight percent (13/27) of dogs that had impairment in 1 category at the time of the first interview developed impairment in > or = 2 categories by the time of the second interview and were significantly more likely to develop impairment in > or = 2 categories, compared with dogs that initially had impairment in 0 categories. Dogs with 1 sign of dysfunction in orientation were significantly more likely to develop impairment in that category, compared with dogs that had 0 signs of dysfunction in orientation. CONCLUSIONS AND CLINICAL RELEVANCE: Age-related behavioral changes in dogs are progressive. Clinicians should consider trying to predict which dogs are most likely to become progressively impaired during the subsequent 6 to 18 months.

Causes of urine marking in cats and effects of environmental management on frequency of marking.

OBJECTIVE: To evaluate effects of environmental management alone on marking frequency in cats with urine marking and to obtain demographic data on cats with urine marking and data on owner-perceived factors that contributed to urine marking behavior. DESIGN: Single-intervention study. ANIMALS: 40 neutered male and 7 spayed female cats. PROCEDURE: During a 2-week baseline phase, owners maintained a daily record of the number of urine marks. This phase was followed by a 2-week environmental management phase during which owners cleaned recently deposited urine marks daily, scooped waste from the litter box daily, and changed the litter and cleaned the litter box weekly while continuing to record urine marks. RESULTS: Male cats and cats from multicat households were significantly overrepresented, compared with the general pet cat population in California. The most commonly mentioned causative factors for urine marking were agonistic interactions with other cats outside or inside the home. Environmental management procedures resulted in an overall reduction in urine marking frequency. Among cats that marked > or = 6 times during the baseline phase, females were significantly more likely to respond to treatment (> or = 50% reduction in marking frequency) than were males. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that male cats and cats from multicat households are more likely to exhibit urine marking behavior than females and cats from single-cat households. Results also suggest that attention to environmental and litter box hygiene can reduce marking frequency in cats, regardless of sex or household status of the cats, and may come close to resolving the marking problem in some cats.

Gerstmann syndrome in systemic lupus erythematosus: neuropsychological, neuroimaging and spectroscopic findings.

Gerstmann syndrome (GS) comprises four interlaced neuropsychological symptoms including finger agnosia, right-left confusion, agraphia, and acalculia. While GS is commonly associated with focal lesions to the region of the left angular gyrus, it has also been associated with numerous diffuse etiologies including atrophy, alcoholism, carbon monoxide poisoning, lead intoxication and anaphylactic shock. Thus, a vigorous debate has emerged as to whether GS represents a syndrome arising from general brain decline or a distinct and localizing lesion. We report a right-handed patient who developed neuropsychological dysfunction secondary to systemic lupus erythematosus (SLE). Neuropsychological evaluation found the patient to exhibit symptoms consistent with the GS tetrad, as well as general cognitive decline. Magnetic resonance imaging revealed a distinct focal lesion of the left parieto-occipital white matter underlying the angular gyrus as well as diffuse atrophy. (1)H-magnetic resonance spectroscopy revealed substantial metabolic derangement in a voxel placed within the visible lesion, although substantial metabolic derangement was observed in regions remote from the focal pathology. Thus, GS in this first case in SLE would appear to comprise a focal neurological tetrad of disorders within a more general pattern of cognitive decline and metabolic derangement.

Effects of a selective serotonin reuptake inhibitor on urine spraying behavior in cats.

OBJECTIVE: To determine the effectiveness of a readily available selective serotonin reuptake inhibitor (SSRI), fluoxetine hydrochloride, on reducing problem urine spraying in cats. DESIGN: Randomized placebo-controlled double-blind clinical trial. ANIMALS: 17 neutered cats > 1 year old with objectionable urine spraying behavior. Procedure-Owners recorded urine-spraying events for 2 weeks (baseline). Cats that vertically marked a mean of > or = 3 times per week were treated for 8 weeks with fluoxetine or fish-flavored liquid placebo. If urine spraying was not reduced by 70% by weeks 4 through 5, the dosage was increased by 50% for weeks 7 and 8. After discontinuation of treatment at the end of 8 weeks, owners recorded daily urine marks for another 4 weeks. RESULTS: The mean (+/- SE) weekly rate of spraying episodes in treated cats was 8.6 (+/- 2.0) at baseline, decreased significantly by week 2 (1.7 +/- 0.6), and continued to decrease by weeks 7 and 8 (0.4 +/- 0.2). The mean weekly spraying rate of cats receiving placebo was 7.8 (+/- 1.5) at baseline, decreased only slightly during week 1 (5.5 +/- 1.8), and did not decline further. When treatment was discontinued after 8 weeks, the spraying rate of cats that had received treatment varied. The main adverse reaction to the drug was a reduction in food intake, which was observed in 4 of 9 treated cats. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of fluoxetine hydrochloride for treatment of urine spraying in cats can be expected to considerably reduce the rate of urine marking. The frequency of spraying before treatment is predictive of the spraying rate when the drug is discontinued.

Magnetic source imaging and brain surgery: presurgical and intraoperative planning in 26 patients.

OBJECT: The availability of large-array biomagnetometers has led to advances in magnetoencephalography that permit scientists and clinicians to map selected brain functions onto magnetic resonance images. This merging of technologies is termed magnetic source (MS) imaging. The present study was undertaken to assess the role of MS imaging for the guidance of presurgical planning and intraoperative neurosurgical technique used in patients with intracranial mass lesions. METHODS: Twenty-six patients with intracranial mass lesions underwent a medical evaluation consisting of MS imaging, a clinical history, a neurological examination, and assessment with the Karnofsky Performance Scale. Magnetic source imaging was used to locate the somatosensory cortex in 25 patients, the visual cortex in six, and the auditory cortex in four. The distance between the lesion and the functional cortex was determined for each patient. Twenty-one patients underwent a neurosurgical procedure. As a surgical adjunct, a frameless stereotactic navigational system was used in 17 cases and a standard stereotactic apparatus in four cases. Because of the results of their MS imaging examination, two patients were not offered surgery, four underwent a stereotactic biopsy procedure, 10 were treated with a subtotal surgical resection, and seven were treated with complete surgical resection. One patient deteriorated before a procedure could be scheduled and, therefore, was not offered surgery, and two patients were offered surgery but declined. Three patients experienced surgery-related complications. CONCLUSIONS: Magnetic source imaging is an important noninvasive neurodiagnostic tool that provides critical information regarding the spatial relationship of a brain lesion to functional cortex. By providing this information, MS imaging facilitates a minimum-risk management strategy and helps guide operative neurosurgical technique in patients with intracranial mass lesions.

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.

Biochemical markers of cognition: a proton MR spectroscopy study of normal human brain.

In the current study we explored the relationship between neurometabolites measured by proton magnetic resonance spectroscopy (1H-MRS) and cognitive ability assessed with a battery of neuropsychological tests. Forty-five participants were recruited from the local college community, and examined utilizing neuropsychological testing and 1H-MRS. Our central finding was that N-acetylaspartate (NAA) was associated with overall neuropsychological performance (F(1,42) = 23.16, p < 0.0001], r2 = 0.35. We found an even stronger association between timed neuropsychological measures and NAA (F(1,42) = 31.15, p < 0.0001], r = 0.43. These results reveal the specific relationship of NAA to neuropsychological functioning in normal human brain. The current observations in healthy individuals are consistent with the hypothesis that variability in NAA levels and neuropsychological performance may be related to mitochondrial function.