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.

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.

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.

Large germline deletions and duplication in isolated cerebral cavernous malformation patients.

Cerebral cavernous malformations (CCM) are vascular lesions that predispose to headaches, seizures, and hemorrhagic stroke. Hereditary CCMs are usually associated with the occurrence of multiple CCMs and occur with a frequency of 1:2,000 to 1:10,000. In this study, eight isolated cases with multiple CCMs but no CCM1-3 point mutation were analyzed using the multiplex ligation-dependent probe amplification assay. Four genomic rearrangements were identified including a previously unreported large duplication within the CCM1 gene and a novel deletion involving the entire coding region of the CCM2 gene. Consequently, systematic screening for CCM deletions/duplications is recommended.

Surgical outcome and predictive factors in adult patients with intractable epilepsy and focal cortical dysplasia.

OBJECTIVES: To determine the surgical outcome and prognostic factors in adult patients with intractable epilepsy and focal cortical dysplasia (FCD). MATERIALS AND METHODS: We retrospectively studied the operative outcome in 21 consecutive adult patients with FCD who underwent surgical treatment for intractable partial epilepsy. RESULTS: The mean age at surgery was 32.7 years (range, 18-58 years). The median post-operative follow-up was 2.5 years. The FCD was extratemporal in 11 patients, involved the temporal lobe in 10 patients, and was multilobar in eight patients. Eleven patients (52%) were rendered seizure-free, four patients (19%) had >95% reduction in seizures, and two patients (10%) had an 80-94% reduction in seizures. A seizure-free outcome was associated with shorter duration of epilepsy (P = 0.02). CONCLUSION: Adult patients with FCD may be candidates for surgical treatment of intractable partial epilepsy. Most individuals have neocortical, extrahippocampal seizures and approximately 50% of patients are rendered seizure-free.

CCM3 mutations are uncommon in cerebral cavernous malformations.

Cerebral cavernous malformations (CCMs) are characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. Mutations in the gene PDCD10 have been found in CCM families linked to the CCM3 locus. The authors screened this gene in 15 families that did not have a CCM1 or CCM2 mutation. Only two novel mutations were found, suggesting that mutations in this gene may only account for a small percentage of CCM familial cases.

Adult-onset epilepsy in focal cortical dysplasia of Taylor type.

Focal cortical dysplasia of Taylor type (FCDT) usually presents with seizures at an early age, whereas adult onset of epilepsy is uncommon. We reviewed the medical records of 213 patients with FCDT. In 21 patients (10%), age at seizure onset ranged from 18 to 55 years (mean 25.3). The outcome of seizures in patients with FCDT and adult-onset epilepsy seems favorable vs childhood-onset seizures.

[Familial cavernous malformations of the central nervous system. A clinical and genetic study of 15 German families]. / Familiäre Kavernome des Zentralnervensystems. Eine klinische und genetische Studie an 15 deutsche Familien.

In 1928, Hugo Friedrich Kufs reported on a family with cerebral, retinal, and cutaneous cavernous malformations. Since then, more than 300 families with inherited cavernous malformations have been reported. Genetic studies showed three loci, on chromosomes 7q21-q22 (with the gene CCM1), 7p15-p13 (CCM2), and 3q25.2-q27 (CCM3). The gene product of CCM1 is Krit 1 (Krev interaction trapped 1), a protein interacting with angiogenesis by various mechanisms. Recently, CCM2 has also been identified; its product is a protein which might have a function similar to that of Krit 1. However, the CCM3 gene has still not been found. In this study, we present clinical and genetic findings on 15 German families.

Thoracolumbar intradural extramedullary bronchiogenic cyst.

Intradural extramedullary bronchiogenic cysts are rare findings. All five reported cases were located cervically or upper thoracically. To our knowledge, we describe the first case of an intraspinal bronchiogenic cyst in a thoracolumbar location. We present the case of a 41-year-old patient with a known spina bifida occulta who suffered from a continuous, sharp, and therapy-refractory pain in the left leg. Magnetic resonance imaging of the thoracic and lumbar vertebra revealed an intradural extramedullar mass at T12 to L1 level. After laminectomy T-12 through L-1/L-2 and longitudinal opening of the dura mater, the cystic mass was shown to be attached to the conus medullaris and the cauda equina, and therefore could be removed only partially. Histopathological examination revealed the diagnosis of bronchiogenic cyst. We therefore conclude that intradural extramedullary bronchiogenic cysts may appear also at thoracolumbar levels. Surgical resection can be achieved with good outcome.

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.

Resective reoperation for failed epilepsy surgery: seizure outcome in 64 patients.

OBJECTIVE: To determine the surgical outcome and factors of predictive value in patients undergoing reoperation for intractable partial epilepsy. METHODS: The authors retrospectively studied the operative outcome in 64 consecutive patients who underwent reoperation for intractable partial epilepsy. Demographic data, results of comprehensive preoperative evaluations, and the seizure and neurologic outcome after reoperation were determined. All patients were followed a minimum of 1 year subsequent to their last operative procedure. RESULTS: Fifty-three patients had two surgeries, and 11 patients had three or more operations. The first surgery involved a lesionectomy (n = 33), "nonlesional" temporal lobe resection (n = 28), and a "nonlesional" extratemporal resection (n = 3). The mean duration between the first and second procedure was 5.5 years. Fifty-five patients underwent an intralobar reoperation, whereas nine had a resection of a different lobe. After reoperation, 25 patients (39%) were free of seizure, 6 patients (9%) had rare seizures, 12 patients (19%) had a worthwhile improvement, and 21 patients (33%) failed to respond to surgery. Predictors of seizure-free outcome were age at seizure onset >15 years (p = 0.01), duration of epilepsy < or =5 years at the time of initial surgery (p = 0.03), and focal interictal discharges in scalp EEG (p = 0.03). Using a logistic regression model, two significant predictors emerged: duration of epilepsy < or =5 years (odds ratio, 3.18; p = 0.04) and preoperative focal interictal discharge (odds ratio, 4.45; p = 0.02). Complications of reoperation included visual field deficits (n = 9), wound infection (n = 2), subdural hematoma (n = 1), and hemiparesis (n = 1). CONCLUSION: Reoperation may be an appropriate alternative form of treatment for selected patients with intractable partial epilepsy who fail to respond to initial surgery.

CCM1 mutation screen of sporadic cases with cerebral cavernous malformations.

Cerebral cavernous malformations (CCM) are CNS vascular anomalies associated with seizures, headaches, and hemorrhagic strokes. The CCM1 gene was screened in 35 sporadic cases with either single or multiple CCM. It was found that 29% of the individuals with multiple CCM have a CCM1 mutation, whereas cases with only one malformation have none. Sporadic cases with multiple malformations warrant the same approach as individuals who have a familial history of CCM.

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.

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.

Bedside functional imaging of the premature infant brain during passive motor activation.

BACKGROUND: Changes in regional brain blood flow and hemoglobin oxygen saturation occur in the human cortex in response to neural activation. Traditional functional radiologic methods cannot provide continuous, portable measurements. Imaging methods, which use near-infrared light allow for non-invasive measurements by taking advantage of the fact that hemoglobin is a strong absorber at these wavelengths. AIMS: To test the feasibility of a new optical functional imaging system in premature infants, and to obtain preliminary brain imaging of passive motor activation in this population. METHODS: A new optical imaging system, the Diffuse Optical Tomography System (DOTS), was used to provide real-time, bedside assessments. Custom-made soft flexible fiberoptic probes were placed on two extremely ill, mechanically ventilated 24 week premature infants, and three healthier 32 week premature infants. Passive motor stimulation protocols were used during imaging. RESULTS: Specific movement of the arm resulted in reproducible focal, contralateral changes in cerebral absorption. The data suggest an overall increase in blood volume to the imaged area, as well as an increase in deoxyhemoglobin concentration. These findings in premature infants differ from those expected in adults. CONCLUSIONS: In the intensive care setting, continuous non-invasive optical functional imaging could be critically important and, with further study, may provide a bedside monitoring tool for prospectively identifying patients at high risk for brain injury.

Medically intractable, localization-related epilepsy with normal MRI: presurgical evaluation and surgical outcome in 43 patients.

PURPOSE: High-resolution magnetic resonance imaging (MRI) plays a crucial role in the presurgical evaluation of patients with medically refractory partial epilepsy. Although MRI detects a morphologic abnormality as the cause of the epilepsy in the majority of patients, some patients have a normal MRI. This study was undertaken to explore the hypothesis that in patients with normal MRI, invasive monitoring can lead to localization of the seizure-onset zone and successful epilepsy surgery. METHODS: A series of 115 patients with partial epilepsy who had undergone intracranial electrode evaluation (subdural strip, subdural grid, and/or depth electrodes) between February 1992 and February 1999 was analyzed retrospectively. Of these, 43 patients (37%) had a normal MRI. RESULTS: Invasive monitoring detected a focal seizure onset in 25 (58%) patients, multifocal seizure origin in 12 (28%) patients, and in six patients, no focal seizure origin was found. Of the 25 patients with a focal seizure origin, cortical resection was performed in 24, of whom 20 (83%) had a good surgical outcome with respect to seizure control. Six of the 12 patients with multifocal seizure origin underwent other forms of epilepsy surgery (palliative cortical resection in two, anterior callosotomy in two, and vagal nerve stimulator placement in two). CONCLUSIONS: Successful epilepsy surgery is possible in patients with normal MRIs, but appropriate presurgical evaluations are necessary. In patients with evidence of multifocal seizure origin during noninvasive evaluation, invasive monitoring should generally be avoided.