Inherited cavernous malformations of the central nervous system: clinical and genetic features in 19 Swiss families.

Cavernous malformations (CCMs) are benign, well-circumscribed, and mulberry-like vascular malformations that may be found in the central nervous system in up to 0.5% of the population. Cavernous malformations can be sporadic or inherited. The common symptoms are epilepsy, hemorrhages, focal neurological deficits, and headaches. However, CCMs are often asymptomatic. The familiar form is associated with three gene loci, namely 7q21-q22 (CCM1), 7p13-p15 (CCM2), and 3q25.2-q27 (CCM3) and is inherited as an autosomal dominant trait with incomplete penetrance. The CCM genes are identified as Krit 1 (CCM1), MGC4607 (CCM2), and PDCD10 (CCM3). Here, we present the clinical and genetic features of CCMs in 19 Swiss families. Furthermore, surgical aspects in such families are also discussed.

Psychiatric co-morbidity in 75 patients undergoing epilepsy surgery: lack of correlation with pathological findings.

BACKGROUND: Psychiatric disorders may occur in patients with intractable partial epilepsy after surgical treatment. Previous reports attributed the presence of psychological adverse events to specific pathological entities such as dysembryoplastic neuroepithelial tumors (DNETs) and gangliogliomas. The rationale for the present study is to evaluate the importance of the surgical pathology in individuals undergoing epilepsy surgery. METHODS: The patients were separated into three groups based on the surgical pathology: group I ganglioglioma (N=25), group II DNETs (N=25), and group III mesial temporal sclerosis (N=25). Thirteen of the 75 patients (17.3%) had a preexisting psychiatric disorder. The most common preoperative psychiatric diagnosis was depression (N=4). Sixty-three of the lesions (84%) were restricted to the temporal lobe. The operative strategy included resection of the lesion and epileptogenic cortex. Sixty-two of the 75 patients (83%) were rendered seizure-free. RESULTS: Eight of the 75 patients (10.7%) had an acquired psychiatric illness following surgical treatment. A mood disorder developed in three patients after surgery. No statistical difference emerged in preoperative psychiatric co-morbidity (no group difference; p=1.0) or in newly diagnosed postoperative psychiatric disease (group I vs. II, p=0.67; group I vs. III, p=1.0; and group II vs. III, p=0.67) within the three surgical pathology groups. CONCLUSION: This study indicates that the presence of psychiatric disease before and after surgery for intractable partial epilepsy, predominantly of temporal lobe origin, was independent of the pathological findings.

ERBIN deficiency links STAT3 and TGF-ß pathway defects with atopy in humans.

Nonimmunological connective tissue phenotypes in humans are common among some congenital and acquired allergic diseases. Several of these congenital disorders have been associated with either increased TGF-ß activity or impaired STAT3 activation, suggesting that these pathways might intersect and that their disruption may contribute to atopy. In this study, we show that STAT3 negatively regulates TGF-ß signaling via ERBB2-interacting protein (ERBIN), a SMAD anchor for receptor activation and SMAD2/3 binding protein. Individuals with dominant-negative STAT3 mutations (STAT3mut ) or a loss-of-function mutation in ERBB2IP (ERBB2IPmut ) have evidence of deregulated TGF-ß signaling with increased regulatory T cells and total FOXP3 expression. These naturally occurring mutations, recapitulated in vitro, impair STAT3-ERBIN-SMAD2/3 complex formation and fail to constrain nuclear pSMAD2/3 in response to TGF-ß. In turn, cell-intrinsic deregulation of TGF-ß signaling is associated with increased functional IL-4Rα expression on naive lymphocytes and can induce expression and activation of the IL-4/IL-4Rα/GATA3 axis in vitro. These findings link increased TGF-ß pathway activation in ERBB2IPmut and STAT3mut patient lymphocytes with increased T helper type 2 cytokine expression and elevated IgE.

Biomechanical evaluation of a veterinary suture anchor in the canine cadaver pelvis and femur.

A commercially available veterinary suture anchor was tested in the acetabula and femurs of canine cadavers. Size #2 suture anchor constructs were compared to a traditional screw and Teflon spiked washer constructs in a model of coxofemoral luxation repair. The screw/washer constructs failed at a higher maximum load than the #2 anchor constructs. In the acetabulum, significant differences in strength were also found in the position of the implant and in the direction of pull. The constructs in a more caudal position, and constructs pulled 90 degrees to the axis of insertion, failed at higher loads. The predominant mode of failure of the constructs was a suture failure. In the femur, size #5 suture anchors were used in a model of cranial cruciate ligament repair and collateral ligament repair. The anchor constructs failed predominantly by anchor pull-out in the distal femur. The constructs pulled 90 degrees to the axis of insertion were stronger than construcs pulled at 0 degrees to the axis of insertion. Varying the location of the implant in the femur did not affect the maximum load to failure.

Generalised peliosis hepatis mimicking metastases after long-term use of oral contraceptives.

Peliosis hepatis (PH) is a rare vascular condition of the liver characterised by the presence of cystic blood-filled cavities distributed randomly throughout the liver parenchyma. PH should be considered in the differential diagnosis of women with a long history of use of oral contraceptives with suspected hypervascular lesions diagnosed by imaging, but with an unknown primary tumour. Because of the extensive use of oral contraceptives in the general female population worldwide, PH should be added to the differential diagnosis of suspected hypervascular liver lesions.

Cerebral cavernous malformations: mutations in Krit1.

OBJECTIVE: To find mutations in the recently identified additional exons of the Krit1 gene that causes CCM1, a disease characterized by the formation of cerebral cavernous malformations (CCM). To determine the relative frequency with which Krit1 mutations cause CCM as well as recharacterize the mutations reported in the literature. METHODS: Twenty-seven families and 11 apparently sporadic individuals affected with CCM were screened for mutations in the Krit1 gene. The gene was screened by single stranded conformation polymorphism, and variants were sequenced. Familial segregation of the mutations was determined. RESULTS: In familial samples, two new mutations in the novel upstream exons and six additional mutations in the previously identified exons were identified. No mutation was found in any of the sporadic individuals. CONCLUSIONS: Results demonstrate that the frequency of mutations found in Krit1 is 47% in the families studied and the frequency may increase as more mutations are detected. Mutations are evenly distributed in the gene and do not seem to be limited to structural domains present in Krit1. This is in accordance with the model that Krit1 could be a tumor suppressor gene.

CCM1 gene mutations in families segregating cerebral cavernous malformations.

Cerebral cavernous malformations (CCM) are vascular anomalies, sometimes inherited as an autosomal dominant trait, which can cause strokes and seizures. Recently, mutations of the CCM1 gene (chromosome 7q) have been found in a subset of families. The authors found 10 new mutations by screening 29 families and five seemingly sporadic cases of CCM. The mutations predicted truncation of the Krit1 mRNA encoded by CCM1, supporting the contention that CCM result from loss of Krit1 protein function and the possibility that this protein acts as a tumor suppressor.

Learning and retention of words and designs following excision from medial or lateral temporal-lobe structures.

We sought to elucidate the contributions of the amygdala, hippocampus and temporal neocortex to learning and memory for verbal and visuospatial material. Two matched learning tasks, using abstract words versus abstract designs, were administered to patients with unilateral neocorticectomy (NCE; Dublin), selective amygdalohippocampectomy (AHE; Zurich) or anterior temporal-lobe resection invading the amygdala and hippocampus (ATL; Montreal). Data were analysed according to side and type of resection. Learning and recall for words was impaired in groups with resection from the left temporal lobe, irrespective of whether mediobasal structures were spared or temporal neocortex was spared. All right-resection groups were unimpaired. Learning for abstract designs was impaired across all trials in the right AHE and NCE groups, and on the last two trials in the right ATL group. Restricted deficits of lower magnitude were observed on some trials in left-resection groups. These results show a partial dissociation between side of excision and type of material, but the finding of similar deficits in all resection types was unexpected. We propose that excision from either the hippocampal region or temporal neocortex may result in a disconnection, giving a similar functional outcome, as both types of resection interrupt a circuit likely to be essential for normal storage and retrieval of information.

Does performing image registration and subtraction in ictal brain SPECT help localize neocortical seizures?

UNLABELLED: Ictal brain SPECT (IS) findings in neocortical epilepsy (patients without mesiotemporal sclerosis) can be subtle. This study is aimed at assessing how the seizure focus identification was improved by the inclusion of individual IS and interictal brain SPECT (ITS)-MRI image registration as well as performing IS - ITS image subtraction. METHODS: The study involved the posthoc analysis of 64 IS scans using 99mTc-ethyl cysteinate dimer that were obtained in 38 patients without mesiotemporal sclerosis but with or without other abnormalities on MRI. Radiotracer injection occurred during video-electroencephalographic (EEG) monitoring. Patients were injected 2-80 s (median time, 13 s) after clinical or EEG seizure onset. All patients had sufficient follow-up to correlate findings with the SPECT results. All patients had ITS and MRI, including a coronal volume sequence used for registration. Image registration (IS and ITS to MRI) was performed using automated software. After normalization, IS - ITS subtraction was performed. The IS, ITS, and subtraction studies were read by 2 experienced observers who were unaware of the clinical data and who assessed the presence and localization of an identifiable seizure focus before and after image registration and subtraction. Correlation was made with video-EEG (surface and invasive) and clinical and surgical follow-up. RESULTS: Probable or definite foci were identified in 38 (59%) studies in 33 (87%) patients. In 52% of the studies, the image registration aided localization, and in 58% the subtraction images contributed additional information. In 9%, the subtraction images confused the interpretation. In follow-up after surgery, intracranial EEG or video-EEG monitoring (or both) has confirmed close or reasonable localization in 28 (74%) patients. In 6 (16%) patients, SPECT indicated false seizure localization. CONCLUSION: Image registration and image subtraction improve the localization of neocortical seizure foci using IS, but close correlation with the original images is required. False localizations occur in a minority of patients.

Risk factors for infection with Toxoplasma gondii for residents and workers on swine farms in Illinois.

Risk factors for Toxoplasma gondii infection in workers and residents of swine farms were studied on 43 farms in Illinois. Blood samples were collected from 174 adults in 1993. The T. gondii seroprevalence was 31%. An interview was conducted with each participant, obtaining information on demographic characteristics and behaviors suspected to affect the risk of T. gondii infection. Factors associated with increased risk of T. gondii seropositivity were a higher number of seropositive cats trapped on the farm, male sex, rearing pigs on pasture, and gardening. Factors associated with a decreased risk were handling of pig feed and presence of cats inside the pig facilities. Thus, infection of cats with T. gondii increased the risk of human infection, and contact with soil was a likely mechanism for transmission. The increased risk of seropositivity in males is attributed to less attention paid to cleanliness in food preparation and eating.

Psychopathology in urban female minority adolescents with suicide attempts.

This study examines the level of psychopathology in 53 African-American females who attempted suicide by ingestion. Parents completed a measure of adolescent psychopathology, and the youths completed measures of depression and psychopathology. Overall, the results suggested that these youths were not experiencing significant emotional distress. However, after classifying the youths into four groups by their self-reported level of depression, the incidence of parent- and youth-reported psychopathology varied. More significant levels of depression corresponded to significant internalizing difficulties, as reported by the adolescent, and myriad psychopathological difficulties, as reported by the parents. These results are discussed from a clinical perspective with a developmentally and culturally sensitive focus. Disposition decisions must consider the level of psychopathology reported by child and parent, the family's willingness to participate in outpatient treatment, and the degree to which the adolescent and her family acknowledge the significance of the suicide attempt.

Relationships between MR-imaged total amount of tissue removed, resection scores of specific mediobasal limbic subcompartments and clinical outcome following selective amygdalohippocampectomy.

Of 204 patients who underwent a selective amygdalohippocampectomy at our hospital, we studied 30 in whom special pre- and postoperative MR imaging was carried out and who were followed up for at least 1 year postoperatively. We measured the total size of the resection and the extent to which the following specific mediobasal temporal lobe structures had been removed: amygdala, hippocampus, pes hippocampi, dentate gyrus, parahippocampal gyrus, uncus and subiculum. Postoperative seizure control was correlated with the overall size of the resection as well as with the resection scores of the above mentioned limbic subcompartments. The mean size of the removed tissue was 7.2 cm3 (range: 2.1-17.7). The mean resection scores of the limbic subcompartments (in percentages) are: amygdala 92%, hippocampus 46%, pes hippocampi 92%, dentate gyrus 45%, parahippocampal gyrus 32%, uncus 92%, subiculum 40%. Although a small resection did not exclude a good outcome, the general tendency was that a better outcome was obtained from a larger resection. With regard to the resection scores of the limbic subcompartments, a positive correlation emerged between good postoperative outcome and the radicality of the removal of the parahippocampal gyrus (and the subiculum, which has been evaluated separately). These findings support our previously formulated amplifier hypothesis for the parahippocampal gyrus.

Epilepsy and trisomy 19q--different seizure patterns in a brother and a sister.

In symptomatic epilepsies due to chromosomal aberrations, epileptogenesis may be either the direct consequence of deletion or duplication of a gene causing seizures or may have a more complex etiology caused by the disturbance of the interaction of several genes and environmental factors. We report on a brother and a sister with trisomy 19q13.3-->qter who present different epileptologic features and discuss epileptogenesis in this syndrome with respect to genes known to be located on the distal part of chromosome 19q. Both patients share mental retardation and several dysmorphic features. The boy was hypoxic at birth and showed an extremely delayed psychomotor development. The girl, however, had no significant neonatal problems, and her psychomotor development was better. Although the male had an abnormal EEG in childhood, his first partial seizures occurred only as late as at age 31 years. He subsequently became seizure-free with carbamazepine (CBZ). In contrast, the girl already suffered from absence-like seizures during childhood and became seizure-free under ethosuccimide (ESM). A photoparoxysmal response, however, is still visible in her EEG. The difference between the epileptologic features in these siblings points to epileptogenic mechanisms placed far downstream on the way from genotype to phenotype. The photoparoxysmal response--otherwise a facultative finding in genetically determined epilepsies--in the EEG of the sister, however, points to a closer relationship between the duplicated genes and epileptogenesis. The fact that genes encoding potassium channels are located on 19q13.3-q13.4 may also support the latter assumption.

Endothelial proliferation, neoangiogenesis, and potential de novo generation of cerebrovascular malformations.

OBJECT: To date, both arteriovenous malformations (AVMs) and cavernomas have been considered to be congenital malformations. A recent survey of the literature has shown the potential for de novo generation of both familial and sporadic cavernomas as well as AVMs. Therefore, it was of interest to determine the biological behavior of these lesions in detail. METHODS: The proliferative and angiogenic capacities of the endothelium of 13 cavernomas and 25 AVMs obtained in patients recently treated (1997-1998) at one institution were studied. Immunohistochemical staining for proliferating cell nuclear antigen (PCNA), MIB-1, and vascular endothelial growth factor (VEGF) and its receptor Flk-1 was performed using standard staining procedures. Positive immunostaining of the nuclei of endothelial cells was observed in specimens of both AVMs and cavernomas for PCNA (80% of AVMs and 85% of cavernomas), and Flk-1 (80% of AVMs and 31% of cavernomas). Endothelial expression of VEGF in the 18 incompletely embolized AVMs was found in 72% of cases but only in 28% of the seven cases in which patients did not undergo endovascular treatment: it was found in 38% of cavernomas. Endothelial expression of MIB-1 was found in 12% of AVMs but in no cavernomas. CONCLUSIONS: These results indicate that there is endothelial proliferation as well as neoangiogenesis in cerebral cavernomas and AVMs. The increased level of angiogenesis in only partially obliterated AVMs underscores the need for radical and complete occlusion of cerebral AVMs to avoid recurrences and further risks of morbidity.

Parietal lobe epilepsy.

When symptoms such as lateralized paresthesias or pain occur prominently and early in partial seizures, parietal lobe seizure origin should be suspected. Most patients with parietal lobe seizures, however, have no symptoms or signs suggesting the parietal lobe. In the absence of detectable epileptogenic lesions, these patients without clinical seizure characteristics suggesting parietal lobe origin can present with misleading findings, resulting in erroneous localization, which can, in turn, lead to ineffective surgical intervention (23,25). Although ictal SPECT might provide vital evidence of parietal lobe seizure origin (25), as noted previously, this technology also can produce misleading data in some patients (52). Even when parietal lobe seizure origin is suspected, in the absence of a structural lesion, documenting this with invasive monitoring can be difficult. The parietal lobes, like the frontal lobes, are large, diffuse structures, and the potential for sampling error is high (19). Spread patterns are unpredictable and can result in false localization (23). Even with extensive and repetitive invasive studies, localization can prove elusive (53). No well-documented series of patients with non-lesional parietal lobe epilepsy in the modern literature who have been cured by surgery have been reported as a result of a combination of the rarity of the condition, the lack of correct recognition, as well as the difficulty of localization. Patients with medically intractable parietal lobe seizures, however, can experience excellent surgical results (23,24). Postoperative parietal lobe symptoms and signs, even when extreme, are usually not enduring (patient 3). One of our patients, however, did develop a chronic pain syndrome (48).

Treatment-induced neoangiogenesis in cerebral arteriovenous malformations.

We investigated the angiogenetic and proliferative activity of the endothelium of 30 consecutive surgical cases of AVM treated at our institution by immunohistochemical detection of the PCNA, MIB-1, Flk-1 and VEGF antibodies. Endothelial positive immunostaining was observed in 87% of the cases for PCNA, in 20% for MIB-1, and in 80% for Flk-1. Of 22 individuals treated with incomplete embolization prior to surgery, 17 showed an expression of VEGF (77%), but only two of the eight patients (25%) who were treated without prior embolization exhibited such an immunoreaction (P=0.0086). The proliferation and growth of cerebral AVMs is documented by endothelial expression of PCNA and MIB-1. The statistically significantly higher expression of VEGF in partially obliterated (embolized) AVMs is most likely caused by transient regional hypoxia within the AVM nidus that mediates neoangiogensis. It points out the clinical relevance of a complete occlusion in order to avoid neovascularization associated with subsequent morbidity and mortality.

Evaluation of the sensitivity and specificity of two diagnostic tests for antibodies to pseudorabies virus glycoprotein X.

The diagnostic performance of 2 enzyme-linked immunosorbent assays (gX-T, gX-H) for antibodies to pseudorabies virus (PRV) glycoprotein X (gX) were evaluated using 311 serum samples from a nonvaccinated quarantined herd. When the standardized virus neutralization (VN) test, which uses the Shope strain (VN Shope), was used as the comparative diagnostic standard, the gX-T test had a 7% false-negative rate and a 52% false-positive rate, and the gX-H test had a 19% false-negative rate and a 19% false-positive rate. When the VN test with a Bartha recombinant strain (VN Bartha gIIIKa) was used as the diagnostic standard, the gX-T test had a 9% false-negative rate and a 26% false-positive rate, and the gX-H test had a 24% false-negative rate and a 11% false-positive rate. Thus, the gX-T test was more sensitive and the gX-H test was more specific. Additional diagnostic tests on 79 serum samples from a noninfected herd did not produce false positives for the gX-H test, but there was an 8% false-positive rate for the gX-T test. Previous studies from our laboratory have demonstrated that VN Bartha gIIIKa has higher sensitivity than VN Shope, without losing specificity, and thus is a better comparative diagnostic standard. When adding a suspect range to the gX-T test, using the same criteria as the suspect range for the gX-H test, the false-positive rate of the gX-T test was reduced to 5% when evaluated versus VN Bartha gIIIKa in the infected herd and to 1% for the PRV-negative herd.(ABSTRACT TRUNCATED AT 250 WORDS)

Application of a quantitative algorithm to restriction endonuclease analysis of Aujeszky's disease (pseudorabies) virus from a geographically localized outbreak.

A retrospective epidemiologic study was conducted to evaluate the application of an objective quantitative algorithm for estimating genetic similarity from restriction endonuclease analysis data. The analysis was performed to assist the determination of chronologic trends in an Aujeszky's disease viral epidemic in a geographic region. DNA from each viral isolate obtained during the epidemic was digested with 4 restriction endonucleases and molar ratio labeled to generate separate fragment patterns that were simultaneously compared using the algorithm. The resultant estimates of genetic similarity were then used in conjunction with time of virus isolation and specific geographic location of the outbreaks to identify the probable sources of infection and the patterns of spread among swine herds. This type of quantitative analysis enabled a more precise and objective approach than previously has been applied to the interpretation of restriction endonuclease data, thereby demonstrating the benefit of this methodology for the investigation of infectious disease outbreaks.

Herd factors affecting the selection and success of intervention strategies in the program for eradication of pseudorabies (Aujeszky's disease) virus from Illinois swine farms.

The program for eradication of pseudorabies virus (PrV) from swine herds in Illinois was evaluated with respect to compliance with Livestock Conservation Institute (LCI) guidelines for selection of intervention strategies and for the effectiveness of these interventions under different herd conditions. The sample consisted of 395 swine operations quarantined between 1988 and 1994. These herds were followed until the end of 1996. The association of herd characteristics (number of sows, sow PrV seroprevalence, type of housing, number of PrV-seropositive farms within 1.5 mi) at the time of quarantine with the producer's selection of an initial intervention strategy (vaccination, offspring segregation, test-and-removal, depopulation-and-repopulation) was analyzed using logistic multiple regression. The interaction of herd characteristics with intervention strategies to affect the duration of quarantine was analyzed using multivariable Cox regression. Factors favoring selection of vaccination were increased herd size, higher sow PrV seroprevalence, and more PrV-seropositive farms within 1.5 mi. Offspring segregation was preferred when sow PrV seroprevalence was higher, and test-and-removal was preferred when seroprevalence was lower. Depopulation-and-repopulation was more likely in outdoor operations. Except for depopulation-and-repopulation, selection of an intervention strategy was in accordance with LCI guidelines. Vaccination and offspring segregation were associated with longer times under quarantine, and test-and-removal and depopulation-and-repopulation with shorter times. Test-and-removal was more effective in reducing the duration of quarantine when sow PrV seroprevalence was low. Vaccination increased the duration of quarantine less when sow PrV seroprevalence was high. Vaccination increased the duration of quarantine more when there were one or more PrV-seropositive farms within 1.5 mi than when there were no PrV-seropositive farms within 1.5 mi. It is apparent that herd characteristics affect the duration of quarantine and therefore need to be taken into account in the selection of a PrV-intervention strategy.

Sources and reservoirs of Toxoplasma gondii infection on 47 swine farms in Illinois.

Field studies were conducted on 47 swine farms in Illinois during 1992 and 1993 to identify sources and reservoirs of Toxoplasma gondii infection. Blood samples were obtained from swine and from trapped wildlife. Serum antibodies to T. gondii were determined using the modified agglutination test, incorporating mercaptoethanol. Antibodies to T. gondii (titer > or = 25) were found in 97 of 4,252 (2.3%) finishing pigs, 395 of 2,617 (15.1%) sows, 267 of 391 (68.3%) cats, 126 of 188 (67.0%) raccoons, 7 of 18 (38.9%) skunks, 29 of 128 opossums (22.7%), 6 of 95 (6.3%) rats, 3 of 61 (4.9%) white-footed mice (Peromyscus sp.), and 26 of 1,243 (2.1%) house mice (Mus musculus). Brains and hearts of rodents trapped on the farm were bioassayed in mice for the presence of T. gondii. Toxoplasma gondii was recovered from tissues of 7 of 1,502 (0.5%) house mice, 2 of 67 (3.0%) white-footed mice, and 1 of 107 (0.9%) rats. Feces of 274 cats trapped on the farm and samples of feed, water, and soil were bioassayed in mice for the presence of T. gondii oocysts. Toxoplasma gondii was isolated from 2 of 491 (0.4%) feed samples, 1 of 79 (1.3%) soil samples, and 5 of 274 (1.8%) samples of cat feces. All mammalian species examined were reservoirs of T. gondii infection. All farms had evidence of T. gondii infection either by detection of antibodies in swine or other mammalian species, or by detection of oocysts, or by recovery from rodents by bioassay. The possibility of transmission of T. gondii to swine via consumption of rodents, feed, and soil was confirmed.