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Biomedical subjects

Andrea Bernasconi

Publications and source records attributed to Andrea Bernasconi.

16 recordsLinked to original sources
PubMed2006

Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation.

STAT5 proteins are components of the common growth hormone and interleukin 2 family of cytokines' signaling pathway. Mutations in the STAT5b gene, described in 2 patients, lead to growth hormone insensitivity that resembles Laron syndrome. Clinical immunodeficiency was also present, although immunologic defects have not been well characterized thus far. Here we describe a 16-year-old girl who suffered generalized eczema and recurrent infections of the skin and respiratory tract since birth. She also suffered severe chronic lung disease and multiple episodes of herpetic keratitis. Clinical features of congenital growth hormone deficiency were observed, such as persistently low growth rate, severely delayed bone age, and postnatal growth failure resulting from growth hormone resistance. This combined phenotype of growth hormone insensitivity and immunodeficiency was attributable to a homozygous C-->T transition that resulted in a nonsense mutation at codon 152 in exon 5 of the STAT5b gene. This novel mutation determined a complete absence of protein expression. The main immunologic findings were moderate T-cell lymphopenia (1274/mm3), normal CD4/CD8 ratio, and very low numbers of natural killer (18/mm3) and gammadelta T (5/mm3) cells. T cells presented a chronically hyperactivated phenotype. In vitro T-cell proliferation and interleukin 2 signaling were impaired. CD4+ and CD25+ regulatory T cells were significantly diminished, and they probably contributed to the signs of homeostatic mechanism deregulation found in this patient. This new case, in accordance with 2 previously reported cases, definitely demonstrates the significant role of the STAT5b protein in mediating growth hormone actions. Furthermore, the main immunologic findings bring about an explanation for the clinical immunodeficiency features and reveal for the first time the relevant role of STAT5b as a key protein for T-cell functions in humans.

Adolescent↗
PubMed2006

Sensorimotor organization in double cortex syndrome.

Subcortical band heterotopia is a diffuse malformation of cortical development related to pharmacologically intractable epilepsy. On magnetic resonance imaging (MRI), patients with "double cortex" syndrome (DCS) present with a band of heterotopic gray matter separated from the overlying cortex by a layer of white matter. The function and connectivity of the subcortical heterotopic band in humans is only partially understood. We studied six DCS patients with bilateral subcortical band heterotopias and six healthy controls using functional MRI (fMRI). In controls, simple motor task elicited contralateral activation of the primary motor cortex (M1) and ipsilateral activation of the cerebellum and left supplementary motor area (SMA). All DCS patients showed task-related contralateral activation of both M1 and the underlying heterotopic band. Ipsilateral motor activation was seen in 4/6 DCS patients. Furthermore, there were additional activations of nonprimary normotopic cortical areas. The sensory stimulus resulted in activation of the contralateral primary sensory cortex (SI) and the thalamus in all healthy subjects. The left sensory task also induced a contralateral activation of the insular cortex. Sensory activation of the contralateral SI was seen in all DCS patients and secondary somatosensory areas in 5/6. The heterotopic band beneath SI became activated in 3/6 DCS patients. Activations were also seen in subcortical structures for both paradigms. In DCS, motor and sensory tasks induce an activation of the subcortical heterotopic band. The recruitment of bilateral primary areas and higher-order association normotopic cortices indicates the need for a widespread network to perform simple tasks.

Adolescent↗
PubMed2006

In vivo profiling of focal cortical dysplasia on high-resolution MRI with computational models.

PURPOSE: On MRI, focal cortical dysplasia (FCD) is characterized by a combination of increased cortical thickness, hyperintense signal within the dysplastic lesion, and blurred transition between gray and white matter (GM-WM). The visual identification of these abnormal characteristics may be difficult, and it is unclear to what degree these features occur among different FCD lesions. Our purpose was to investigate the pattern of occurrence of abnormal MRI characteristics in FCD by using a set of computational models and to generate quantitative lesion profiling. METHODS: A set of voxel-wise operators was applied to high-resolution 3D T1-weighted MRI in 23 patients with histologically proven FCD and 39 healthy controls, creating maps of GM thickness, maps of relative intensity highlighting areas with hyperintense signal, and maps of gradient magnitude modeling the GM-WM transition. All FCD lesions were segmented manually on the T1-weighted MRI. RESULTS: FCD volumes ranged from 734 mm3 to 80,726 mm3 (mean, 8,629 mm3 +/- 16,238). The manually segmented FCD lesions were used to estimate features in the lesional area and to determine possible local variations of each feature by means of a histogram. In 78% of the patients, FCD lesions were characterized by simultaneous GM thickening, hyperintense signal, and blurring of the GM-WM transition. Moreover, in all patients, the FCD lesion had at least two of these three characteristics. CONCLUSIONS: The three features occurred regardless of the lesion volume, and they characterized not only large FCD lesions, but also subtle ones that had been overlooked by conventional radiologic inspection before surgery.

Adult↗
PubMed2005

Progression in temporal lobe epilepsy: differential atrophy in mesial temporal structures.

OBJECTIVE: To determine the relationship between hippocampal, amygdalar, and entorhinal cortex atrophy and duration of epilepsy, presence of secondary generalized seizures, and prolonged childhood febrile convulsions in patients with pharmacologically intractable temporal lobe epilepsy (TLE). METHODS: Volumetric MRI of the hippocampus, amygdala, and entorhinal cortex were performed in 86 consecutive patients with TLE and 44 age- and sex-matched healthy control subjects. Linear regression analysis was used to explore the relation between the volumetric measurements and the clinical parameters. RESULTS: In simple regressions, duration of epilepsy but not age at seizure onset was related to hippocampal (r2 = 0.19, p < 0.001), entorhinal cortex (r2 = 0.11, p = 0.002), and amygdalar (r2 = 0.15, p < 0.001) atrophy ipsilateral to the seizure focus. Prediction of the regression function to time of onset of recurrent seizures (time = 0) resulted in a y intercept of < 0 for the hippocampus and the entorhinal cortex but was not different from 0 for the amygdala. Patients with a positive history of febrile convulsions had smaller hippocampal volumes ipsilateral to the seizure (p < 0.001). No relationship was found between febrile convulsions and entorhinal cortex and amygdalar volumes or between secondary generalization of seizures and any mesial temporal volume. CONCLUSION: Progressive volume loss in the mesial temporal lobe in relation to duration of epilepsy is not limited to the hippocampus but affects the entorhinal cortex and the amygdala.

Adolescent↗
PubMed2005

Characteristics of headache associated with intractable partial epilepsy.

PURPOSE: The association between headache (HA) and epilepsy is well known. However, few previous studies characterized HA types and head sensations (HSens) in large populations of individuals with well-defined forms of epilepsy. METHODS: To analyze the incidence of HA in such a group, we compare HA and non-HA patients to identify special predictive factors for HAs or migraine. We also investigate the pathologically verified group for possible correlations with HAs or migraine. One hundred consecutive patients undergoing presurgical evaluation for pharmacologically intractable partial epilepsy were interviewed. For each HA type, we inquired about lateralization, localization, quality of HA, and results of treatment. RESULTS: Periictal HAs were reported by 47 patients. Of those, 11 had preictal HA (PIHA), and 44 had postictal HA (PostHA). Eight patients had both PIHA and PostHA. Interictal HAs (InterHAs) were reported by 31 patients. Twenty-nine (62%) of 47 patients had frontotemporal HAs. Twenty-five patients had migraine-like HA without aura: 18 (60%) of 30 patients with temporal lobe epilepsy (TLE) and seven (41%) of 17 with extratemporal epilepsy (ETE). No correlation between pathology and presence of HA was found in 59 pathologically verified patients, except in four who had arteriovenous malformations (AVMs): three had and one did not have HAs. Eighteen patients had, in addition, poorly localized and ill-described HSens other than HAs. CONCLUSIONS: We confirm an association between focal epilepsy and HAs, including migraine without aura. This is true for both TLE and ETE. PIHA and even prodromal HA may be related to the epileptic discharge and may have lateralizing value. This association is not recognized by the current International Headache Society (IHS) classification. The presence of HA and migraine is not related to the underlying epileptogenic pathology except in patients with AVMs.

Adolescent↗
PubMed2004

Quantitative analysis of temporal lobe white matter T2 relaxation time in temporal lobe epilepsy.

The objective of this study was to assess temporal lobe white matter (WM) quantitatively using T2 relaxometry in patients with pharmacologically intractable temporal lobe epilepsy (TLE). T2 relaxometry was performed using a dual-echo sequence with 23 contiguous oblique coronal slices in 56 consecutive TLE patients and in 30 healthy subjects. Averages of six slices were chosen to calculate T2 relaxation time in the temporal lobe WM (WM-T2) and the hippocampus (Hippo-T2). Twenty-seven patients had unilateral hippocampal atrophy (HA), and twenty-nine patients had normal hippocampal volumes (NV) on volumetric MRI. Mean WM-T2 was increased ipsilateral to the seizure focus in TLE patients with HA and those with NV (P < 0.001). Contralateral mean WM-T2 was increased in left and right TLE with HA (P < 0.001) and in right TLE with NV (P = 0.001). There was a positive correlation between WM-T2 and Hippo-T2. Individual analysis showed a prolongation of WM-T2 in about 70% of TLE patients with HA and NV. In half of the patients, WM-T2 increase was bilateral and symmetric. However, in 33% of patients with NV and bilateral symmetric increase in Hippo-T2, WM-T2 provided a correct lateralization of the seizure focus. Regardless of the pattern of T2 abnormalities, that is, bilateral symmetric or ipsilateral, the majority of patients with HA became seizure-free after surgery, while those with NV did not have a favorable outcome. In patients with NV, WM-T2 measurement may provide additional lateralizing information compared to Hippo-T2.

Adolescent↗
PubMed2004

Quantitative MR imaging of the neocortex.

This article provides an overview of novel MR image analysis methods applied to the quantitative assessment of the neocortex in various forms of epilepsy. Postacquisition processing methods, such as voxel-based morphometry and texture analysis, involve the use of computer software to manipulate, enhance, and classify image information in a digital format. These techniques have the potential to demonstrate subtle abnormalities that are not identified by eye because of anatomic variability. Information provided by quantitative MR imaging of the neocortex may be important for the identification of accurate predictors of surgical outcome and may refine the selection of surgical candidates, particularly those with "nonlesional" neocortical epilepsy.

Epilepsies, Partial↗
PubMed2003

MRI volumetry of the thalamus in temporal, extratemporal, and idiopathic generalized epilepsy.

OBJECTIVE: To examine the specificity of thalamic atrophy in epilepsy. METHODS: Thalamic volume measurements were carried out using high-resolution MRI in 40 patients with pharmacologically intractable temporal lobe epilepsy (TLE), 16 patients with extratemporal lobe epilepsy (ETE), and 17 with idiopathic generalized epilepsy (IGE). Thalamic volumes of patients were compared with those of 21 neurologically normal control subjects. Volumes were correlated with duration of epilepsy. The effect of prolonged febrile seizures and generalized seizures on thalamic volumes was examined. RESULTS: Compared with normal control subjects, patients with TLE had a reduction in thalamic volume ipsilateral to the seizure focus. Thalamic volumes in patients with ETE and IGE were not significantly different from those of normal control subjects. In TLE patients, thalamic volumes ipsilateral to the seizure focus were negatively correlated with duration of epilepsy. Patients with a history of prolonged febrile seizures had more severe thalamic atrophy ipsilateral to the seizure focus than those without febrile seizures. CONCLUSIONS: Thalamic atrophy ipsilateral to the seizure focus is found in TLE but not in other forms of focal epilepsy or IGE. In TLE, thalamic atrophy is correlated with duration of disease. Patients with a history of prolonged febrile seizures had smaller thalamic volumes ipsilateral to the seizure focus than those without.

Adolescent↗
PubMed2003

Nonsyndromic mental retardation and cryptogenic epilepsy in women with doublecortin gene mutations.

DCX mutations cause mental retardation in male subjects with lissencephalypachygyria and in female subjects with subcortical band heterotopia (SBH). We observed four families in which carrier women had normal brain magnetic resonance imaging (MRI) and mild mental retardation, with or without epilepsy. Affected male subjects had SBH or pachygyria-SBH. In two families, the phenotype was mild in both genders. In the first family, we found a tyr138his mutation that is predicted to result in abnormal folding in the small hinge region. In the second family, we found an arg178cys mutation at the initial portion of R2, in the putative beta-sheet structure. Carrier female subjects with normal MRI showed no somatic mosaicism or altered X-inactivation in lymphocytes, suggesting a correlation between mild mutations and phenotypes. In the two other families, with severely affected boys, we found arg76ser and arg56gly mutations within the R1 region that are predicted to affect DCX folding, severely modifying its activity. Both carrier mothers showed skewed X-inactivation, possibly explaining their mild phenotypes. Missense DCX mutations may manifest as non-syndromic mental retardation with cryptogenic epilepsy in female subjects and SBH in boys. Mutation analysis in mothers of affected children is mandatory, even when brain MRI is normal.

Adolescent↗
PubMed2003

Automated detection of focal cortical dysplasia lesions using computational models of their MRI characteristics and texture analysis.

Focal cortical dysplasia (FCD), a malformation of cortical development, is a frequent cause of pharmacologically intractable epilepsy. FCD is characterized on Tl-weighted MRI by cortical thickening, blurring of the gray-matter/white-matter interface, and gray-level hyperintensity. We have previously used computational models of these characteristics to enhance visual lesion detection. In the present study we seek to improve our methods by combining these models with features derived from texture analysis of MRI, which allows measurement of image properties not readily accessible by visual analysis. These computational models and texture features were used to develop a two-stage Bayesian classifier to perform automated FCD lesion detection. Eighteen patients with histologically confirmed FCD and 14 normal controls were studied. On the MRI volumes of the 18 patients, 20 FCD lesions were manually labeled by an expert observer. Three-dimensional maps of the computational models and texture features were constructed for all subjects. A Bayesian classifier was trained on the computational models to classify voxels as cerebrospinal fluid, gray-matter, white-matter, transitional, or lesional. Voxels classified as lesional were subsequently reclassified based on the texture features. This process produced a 3D lesion map, which was compared to the manual lesion labels. The automated classifier identified 17/20 manually labeled lesions. No lesions were identified in controls. Thus, combining models of the T1-weighted MRI characteristics of FCD with texture analysis enabled successful construction of a classifier. This computer-based, automated method may be useful in the presurgical evaluation of patients with severe epilepsy related to FCD.

Adult↗
PubMed2003

Entorhinal cortex MRI assessment in temporal, extratemporal, and idiopathic generalized epilepsy.

PURPOSE: We previously showed a reduction in the volume of the entorhinal cortex (EC) ipsilateral to the seizure focus in patients with intractable temporal lobe epilepsy (TLE). The purpose of this study was to examine the specificity of EC atrophy in epilepsy. METHODS: We performed volumetric measurement of the EC on high-resolution magnetic resonance imaging (MRI) in patients with TLE (n = 70), extratemporal lobe epilepsy (ETE; n = 18), and idiopathic generalized epilepsy (IGE; n = 20). EC volumes of epilepsy patients were compared with those of 48 age- and sex-matched normal controls. Within the TLE group, 63 patients were selected prospectively with hippocampal atrophy ipsilateral to the seizure focus. The remaining seven patients were chosen retrospectively based on normal volumetric MRI of the hippocampus and amygdale, as well as normal histopathologic examination of the resected tissue. RESULTS: Compared with normal controls, EC volume was smaller ipsilateral but not contralateral to the seizure focus in patients with TLE (p < 0.001). No difference in the EC volumes ipsilateral and contralateral to the seizure focus was seen in patients with ETE and IGE compared with normal controls. The individual analysis showed that the EC was atrophic in 73% of TLE patients with hippocampal atrophy. Three of the seven TLE patients with normal volumetric MRI of the hippocampus and amygdala and normal histopathologic examination had EC atrophy ipsilateral to the seizure focus. In no patient with ETE or IGE was the EC found to be atrophic. CONCLUSIONS: EC atrophy ipsilateral to the seizure focus appears to be specific to mesial temporal lobe structural damage associated with TLE.

Adolescent↗
PubMed2003

Advanced MRI analysis methods for detection of focal cortical dysplasia.

In many patients, lesions of focal cortical dysplasia (FCD) may go unrecognized by standard radiological analysis. This is due to the fact that identification of many of these malformations on visual inspection of conventional MRI is difficult due to their subtlety and the complexity of the brain's convolutions. Quantitative MR image processing methods have the potential to help identify lesions that may be overlooked by conventional radiological evaluation. To increase the sensitivity of MRI for the detection of subtle lesions of FCD, we recently developed voxel-based image post-processing methods, including first-order texture analysis and morphological processing modeled on known MRI features of FCD. Using these methods we were able to increase the sensitivity over conventional MRI analysis by more than 30%, while maintaining a high degree of reliability. The image processing methods we developed improve visual detection of FCD, even in cases where no lesion is obvious on MRI. Therefore, these techniques could allow a more precise evaluation of patients with partial epilepsy who could benefit from surgery.

Brain Diseases↗
PubMed2002

Computational models of MRI characteristics of focal cortical dysplasia improve lesion detection.

In many patients, focal cortical dysplasia (FCD) is characterized by minor structural changes that may go unrecognized by standard radiological analysis. We previously demonstrated that visual analysis of a composite map based on three simple models of MRI features of FCD increased the sensitivity of FCD lesion detection, compared to visual analysis of conventional MRI. Here we report on the use of improved methods for characterizing FCD which improve contrast in the composite maps: a Laplacian-based metric for measuring cortical thickness, a convolutional kernel to model blurring of the GM-WM interface, and an operator to measure hyperintense T1 signal. To validate these methods, we processed the MRIs of 14 FCD patients with our original set of image processing operators and an improved set of image processing operators. Comparison of the composite maps associated with the two sets of operators revealed that contrast between lesional tissue and nonlesional cortex was significantly increased in the composite maps associated with the set of improved operators. Increasing this contrast is an important step toward the goal of automated FCD lesion detection.

Brain Mapping↗
PubMed2002

Trisomy 3 in two paediatric post-transplant lymphomas.

Few cytogenetic data are available concerning the chromosomal constitution of post-transplant lymphomas. We report two paediatric cases of trisomy 3, as a primary anomaly, in post-transplant lymphoproliferative disease (PTLD) associated with B immunophenotype. Using cytogenetic analysis and fluorescence in situ hybridization on chromosome preparations, we found trisomy 3 in both patients and an extra X chromosome in one. Clinical, histological and immunophenotypical data are presented. Trisomy 3 has been observed in different types of non-Hodgkin's lymphomas but it is relatively rare in B-cell lymphomas, with the exception of marginal zone lymphoma and mantle cell lymphoma. To our knowledge, trisomy 3 is an uncommon cytogenetic finding in PTLD. Further cytogenetic studies of these lymphoproliferative disorders might contribute to evaluate the role of these chromosomal anomalies in the pathogenesis of this disease.

Adolescent↗
PubMed2002

Subcortical band heterotopia (SBH) in males: clinical, imaging and genetic findings in comparison with females.

Subcortical band heterotopia (SBH) or double cortex syndrome is a neuronal migration disorder, which occurs very rarely in males: to date, at least 110 females but only 11 in males have been reported. The syndrome is usually associated with mutations in the doublecortin (DCX) (Xq22.3-q23) gene, and much less frequently in the LIS1 (17p13.3) gene. To determine whether the phenotypic spectrum, the genetic basis and genotype-phenotype correlations of SBH in males are similar to those in females, we compared the clinical, imaging and molecular features in 30 personally evaluated males and 60 previously reported females with SBH. Based on the MRI findings, we defined the following band subtypes: partial, involving one or two cerebral lobes; intermediate, involving two lobes and a portion of a third; diffuse, with substantial involvement of three or more lobes; and pachygyria-SBH, in which posterior SBH merges with anterior pachygyria. Karyo typing and mutation analysis of DCX and/or LIS1 were performed in 23 and 24 patients, respectively. The range of clinical phenotypes in males with SBH greatly overlapped that in females. MRI studies revealed that some anatomical subtypes of SBH, such as partial and intermediate posterior, pachygyria-SBH and diffuse bands with posterior predominance, were more frequently or exclusively present in males. Conversely, classical diffuse SBH and diffuse bands with anterior predominance were more frequent in females. Males had either mild or the most severe band subtypes, and these correlated with the over-representation of normal/borderline intelligence and severe mental retardation, respectively. Conversely, females who had predominantly diffuse bands exhibited mostly mild or moderate mental retardation. Seven patients (29%) had missense mutations in DCX; in four, these were germline mutations, whereas in three there was evidence for somatic mosaicism. A germline missense mutation of LIS1 and a partial trisomy of chromosome 9p were identified in one patient (4%) each. One male each had a possible pathogenic intronic base change in both DCX and LIS1 genes. Our study shows that SBH in males is a clinically heterogeneous syndrome, mostly occurring sporadically. The clinical spectrum is similar to that of females with SBH. However, the greater cognitive and neuroradiological heterogeneity and the small number of mutations identified to date in the coding sequences of the DCX and LIS1 genes in males differ from the findings in females. This suggests other genetic mechanisms such as mutations in the non-coding regions of the DCX or LIS1 genes, gonadal or somatic mosaicism, and finally mutations of other genes.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗