Feasibility of Focal Transcranial DC Polarization with Simultaneous EEG Recording: Preliminary Assessment in Healthy Subjects and Human Epilepsy

We aimed to investigate the feasibility of an experimental system for simultaneous transcranial DC stimulation(tDCS) and EEG recording in human epilepsy. We report tolerability of this system in a cross-over controlled trial with 15 healthy subjects and preliminary effects of its use, testing repeated tDCS sessions, in two patients with drug-refractory Continuous Spike-Wave Discharges During Slow Sleep (CSWS). Our system combining continuous recording of the EEG with tDCS allows detailed evaluation of the interictal activity during the entire process. Stimulation with 1 mA was well‐tolerated in both healthy volunteers and patients with refractory epilepsy. The large reduction in interictal epileptiform EEG discharges in the two subjects with epilepsy supports further investigation of tDCS using this combined method of stimulation and monitoring in epilepsy. Continuous monitoring of epileptic activity throughout tDCS improves safety and allows detailed evaluation of epileptic activity changes induced by tDCS in patients.

Decreased Vascular Endothelial Growth Factor (VEGF) Expression in Focal Segmental Glomeruloesclerosis Lesions of Patients Under Sirolimus

Background: Proteinuria (PT) with SRL appears not only after conversion from a calcineurin inhibitor (CI), but also in de novo patients. The PT may be related to a hemodynamic effect of CI withdrawal or to a direct effect of SRL in glomerulus (GL). Recently an association between PT in SRL patients and FSGS lesions has been described. It is also known that SRL decrease VEGF synthesis and experimental data suggest that VEGF is essential to podocyte survival and differentiation. Aim: To determine if glomerular lesions and PT in SRL patients could be related to altered glomerular VEGF expression. Material and methods: We evaluated glomerular VEGF expression in 10 biopsies: A-allograft kidney in backtable (n=3); B-native normal kidney (n=1); C-native kidney with FSGS lesions (n=2); D-allograft kidney with FSGS lesions from proteinuric patients under SRL after conversion from CI (n=3); E-allograft kidney in proteinuric patient under SRL with a membranous glomerulonephritis (n=1). We employed indirect immunohistochemistry in paraffin-embedded sections using a mouse monoclonal antibody against human VEGF-C1 (Santa Cruz). Results: The controls biopsies (A; B) showed normal global VEGF expression, with strong podocyte staining. The VEGF expression in the group C was similar to the controls, although no FSGS lesions were observed in the stained GL. The group D showed normal VEGF expression in the apparently normal GL, hypertrophied podocytes with reduction of VEGF in anomalous GL, and no staining in slcerotic lesions. We observed a gradual reduction of VEGF expression with progressive dedifferentiation of podocytes. In the group E the VEGF was globally reduced, with some hypertrophied podocytes expressing decreased VEGF. Conclusion: We confirmed the diminished VEGF expression in injured podocytes of SRL patients.This decreased expression may result from a direct effect of SRL and precede the appearance of FSGS lesions and PT. Further studies are needed with greater number of cases and controls, including early biopsies of patients under SRL.

Focal Malignant Liver Lesions: Diagnosis by Dynamic Incremental CT, Early Phase

The purpose of our study was to evaluate the accuracy of dynamic incremental bolus-enhanced conventional CT (DICT) with intravenous contrast administration, early phase, in the diagnosis of malignancy of focal liver lesions. A total of 122 lesions were selected in 74 patients considering the following criteria: lesion diameter 10 mm or more, number of lesions less than six per study, except in multiple angiomatosis and the existence of a valid criteria of definitive diagnosis. Lesions were categorized into seven levels of diagnostic confidence of malignancy compared with the definitive diagnosis for acquisition of a receiver-operator-characteristic (ROC) curve analysis and to determine the sensitivity and specificity of the technique. Forty-six and 70 lesions were correctly diagnosed as malignant and benign, respectively; there were 2 false-positive and 4 false-negative diagnoses of malignancy and the sensitivity and specificity obtained were 92 and 97%. The DICT early phase was confirmed as a highly accurate method in the characterization and diagnosis of malignancy of focal liver lesions, requiring an optimal technical performance and judicious analysis of existing semiological data.

Optimization of fMRI Processing Parameters for Simutaneous Acquisition of EEG/fMRI in Focal Epilepsy

In the context of focal epilepsy, the simultaneous combination of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) holds a great promise as a technique by which the hemodynamic correlates of interictal spikes detected on scalp EEG can be identified. The fact that traditional EEG recordings have not been able to overcome the difficulty in correlating the ictal clinical symptoms to the onset in particular areas of the lobes, brings the need of mapping with more precision the epileptogenic cortical regions. On the other hand, fMRI suggested localizations more consistent with the ictal clinical manifestations detected. This study was developed in order to improve the knowledge about the way parameters involved in the physical and mathematical data, produced by the EEG/fMRI technique processing, would influence the final results. The evaluation of the accuracy was made by comparing the BOLD results with: the high resolution EEG maps; the malformative lesions detected in the T1 weighted MR images; and the anatomical localizations of the diagnosed symptomatology of each studied patient. The optimization of the set of parameters used, will provide an important contribution to the diagnosis of epileptogenic focuses, in patients included on an epilepsy surgery evaluation program. The results obtained allowed us to conclude that: by associating the BOLD effect with interictal spikes, the epileptogenic areas are mapped to localizations different from those obtained by the EEG maps representing the electrical potential distribution across the scalp (EEG); there is an important and solid bond between the variation of particular parameters (manipulated during the fMRI data processing) and the optimization of the final results, from which smoothing, deleted volumes, HRF (used to convolve with the activation design), and the shape of the Gamma function can be certainly emphasized.

Dispersão da Refractariedade Auricular como Substrato Electrofisiológico da Vulnerabilidade Auricular em Doentes com Fibrilhação Auricular Paroxística

Atrial electrical remodeling plays a part in recurrence of atrial fibrillation (AF). It has been related to an increase in heterogeneity of atrial refractoriness that facilitates the occurrence of multiple reentry wavelets and vulnerability to AF. AIM: To examine the relationship between dispersion of atrial refractoriness (Disp_A) and vulnerability to AF induction (A_Vuln) in patients with clinical paroxysmal AF (PAF). METHODS: Thirty-six patients (22 male; age 55+/-13 years) with > or =1 year of history of PAF (no underlying structural heart disease--n=20, systemic hypertension--n=14, mitral valve prolapse--n=1, surgically corrected pulmonary stenosis--n=1), underwent electrophysiological study (EPS) while off medication. The atrial effective refractory period (AERP) was assessed at five different sites--high (HRA) and low (LRA) lateral right atrium, high interatrial septum (IAS), proximal (pCS) and distal (dCS) coronary sinus--during a cycle length of 600 ms. AERP was taken as the longest S1-S2 interval that failed to initiate a propagation response. Disp_A was calculated as the difference between the longest and shortest AERP. A_Vuln was defined as the ability to induce AF with 1-2 extrastimuli or with incremental atrial pacing (600-300 ms) from the HRA or dCS. The EPS included analysis of focal electrical activity based on the presence of supraventricular ectopic beats (spontaneous or with provocative maneuvers). The patients were divided into group A--AF inducible (n=25) and group B--AF not inducible (n=11). Disp_A was analyzed to determine any association with A_Vuln. Disp_A and A_Vuln were also examined in those patients with documented repetitive focal activity. Logistic regression was used to determine any association of the following variables with A_Vuln: age, systemic hypertension, left ventricular hypertrophy, left atrial size, left ventricular function, duration of PAF, documented atrial flutter/tachycardia and Disp_A. RESULTS: There were no significant differences between the groups with regard to clinical characteristics and echocardiographic data. AF was inducible in 71% of the patients and noninducible in 29%. Group A had greater Disp_A compared to group B (105+/-78 ms vs. 49+/-20 ms; p=0.01). Disp_A was >40 ms in 50% of the patients without A_Vuln and in 91% of those with A_Vuln (p=0.05). Focal activity was demonstrated in 14 cases (39%), 57% of them with A_Vuln. Disp_A was 56+/-23 ms in this group and 92+/-78 ms in the others (p=0.07). Using logistic regression, the only predictor of A_Vuln was Disp_A (p=0.05). CONCLUSION: In patients with paroxysmal AF, Disp_A is a major determinant of A_Vuln. Nevertheless, the degree of nonuniformity of AERP appears to be less important as an electrophysiological substrate for AF due to focal activation.

Lesões do Sistema Nervoso Central na Síndroma de Adams-Oliver

Reportam-se dois casos de doentes do sexo feminino com dois anos de idade e síndrome Adams-Oliver, que se caracteriza por um defeito congénito do escalpe e alterações malformativas congénitas dos membros, a que se associaram malformações e complicações do SNC. O diagnóstico foi feito à nascença e a aplasia cútis congénita caracterizava-se não só por extenso defeito no escalpe, mas também no osso subjacente, com exposição dos seios durais. A variabilidade das duas situações clinicas, traduziu-se essencialmente pela exetnsão e gravidade das lesões osteocutâneas dos membros e do crânio, pelas anomalias do SNC e pelo tipo de intercorrências. Numa criança detectou-se por TC e RM hemimegalencefalia focal do hemisfério direito e a outra apresentou durante o decuros da doença lesões encefaloclásticas e herniação encefálica, que necessitou de correcção cirúrgica. Ambas sobreviveram, mas o diagnóstico de lesão malformativa do SNC e a ocorrência de lesões encefaloclásticas modificaram de forma determinante o prognóstico inicial.

Localized Abdominal Idiopathic Lipodystrophy

Localized loss of subcutaneous tissue can occur after panniculitis, injections of corticosteroids and other drugs, or associated with infectious, autoimmune or neurologic diseases. The "idiopathic lipoatrophies" are a group of poorly characterized diseases, with focal disappearance of subcutaneous fat, and usually the thighs, abdomen or the ankles are affected. Three subtypes have been described based on clinical presentation: lipoatrophia semicircularis, annular lipoatrophy of the ankles and centrifugal lipodystrophy. We describe a 52-year-old female patient who developed a localized atrophy of the abdominal areas over a period of 3 months without any inflammatory signs over the evolution of the disease. The patient denied any previous local trauma or medication of any type. The atrophy stabilized, showing no progression over the last 6 years. The histopathological examination was normal except for the absence of subcutaneous fat, although the biopsy was taken down to the fascia. There was no clinical or serologic evidence of autoimmune diseases and laboratory testing for Borrelia burgdorferi infection was negative. Other causes of localized lipoatrophies were excluded and the final diagnosis was localized idiopathic lipodystrophy. Our patient is the second report on an abdominal lipodystrophy, with no previous inflammatory signs, absence of subcutaneous fat and no associated pathogenic factor. There is no established treatment for idiopathic lipodystrophy, and the lesions do not tend to resolve spontaneously.

Intraorbital Abducens Nerve Schwannoma

BACKGROUND: Schwannomas of the abducens nerve are extremely rare tumors. The tumor may be located within the cavernous sinus or more often at the prepontine region. However, literature research has identified only one case of isolated schwannoma of the orbit, arising from the terminal branches of the abducens nerve to the lateral rectus muscle. This is only the second report of an abducens nerve schwannoma located entirely intraconal. CASE DESCRIPTION: We report a case of an intraorbital abducens nerve schwannoma in a 42-year-old man with no signs of neurofibromatosis. The lesion resulted in progressive diplopia and focal abducens palsy. The clinical, radiologic, and pathologic features are presented. RESULTS: We point the particular aspects and discuss the possible treatments and approaches to preserve nerve function. CONCLUSIONS: Being a benign lesion, one of the goals has always been total removal. The knowledge of the correct anatomic features made us believe that the VI nerve function could be preserved. Our case is the first example of a total removal with eye abduction preserved. Because of that, we believe that it is reasonable to aim for these goals in future cases.

C4d Presence in Kidney Allograft Biopsy: Sensitivity and Specifity of Immunoperoxidase vs Immunofluorescence

OBJECTIVES: Evaluate the sensitivity/specificity of immunoperoxidase method in comparison with the standard immunofluorescence. MATERIAL AND METHODS: Retrospective review of 87 biopsies made for allograft dysfunction. Immunofluorescence (IF) was performed in frozen allograft biopsies using monoclonal antibody anti-C4d from Quidel®. The indirect immunoperoxidase (IP) technique was performed in paraffin-embebbed tissue with polyclonal antiserum from Serotec®. Biopsies were independently evaluated by two nephropathologist according Banff 2007 classification. RESULTS: By IF, peritubular C4d deposition were detected in 60 biopsies and absent in 27 biopsies. The evaluation of biopsy by IP was less precise due to the presence of background and unspecific staining. We find 13.8% (12/87) of false negative and Banff classification concordance in 79.3% (69/87) of cases (table1). The ROC curve study reveal a specificity of 100% and sensitivity of 80.0 % of IP method in relation to the gold standard (area under curve:0.900; 95% Confidence interval :0.817-0.954; p=0.0001). Banff Classification C4d Cases Immunofluorescence Immunoperoxidase n =87 Diffuse Negative 3 (3.4%) Focal Negative 9 (10.3%) Negative Negative 27 (31.0%) Diffuse Diffuse 33 (37.9%) Focal Focal 9 (10.3%) Diffuse Focal 6 (6.9%) CONCLUSION: The IP method presents a good specificity, but lesser sensitivity to C4d detection in allograft dysfunction. The evaluation is more difficult, requiring more experience of the observer than IF method. If frozen tissue is unavailable, the use of IP for C4d detection is acceptable.

Clinical and Pathological Findings in Women with Fabry Disease

Introduction. Fabry disease is a rare metabolic disorder caused by the genetic deficiency of the lysosomal hydrolase alpha-galactosidase A, located on chromosome X. Females with the defective gene are more than carriers and can develop a wide range of symptoms. Nevertheless, disease symptoms generally occur later and are less severe in women than in men. The enzyme deficiency manifests as a glycosphingolipidosis with progressive accumulation of glycosphingolipids and deposit of inclusion bodies in lysosomes giving a myelinlike appearance. Patients and Methods. Records of renal biopsies performed on adults from 1st January 2008 to 31st August 2011, were retrospectively examined at the Renal Pathology Laboratory. We retrieved biopsies diagnosed with Fabry disease and reviewed clinical and laboratory data and pathology findings. Results. Four female patients with a mean age of 49.3±4.5 (44-55) years were identified. The mean proteinuria was 0.75±0.3 g/24h (0.4-1.2) and estimated glomerular filtration rate (CKD EPI equation) was 71±15.7 ml/min/1.73m2 (48-83). Three patients experienced extra-renal organ involvement (cerebrovascular, cardiac, dermatologic, ophthalmologic and thyroid) with distinct severity degrees. Leukocyte α-GAL A activity was below normal range in the four cases but plasma and urinary enzymatic activity was normal. Light microscopy showed predominant vacuolisation of the podocyte cytoplasm and darkly staining granular inclusions on paraffin and plastic-embedded semi-thin sections. Electron microscopy showed in three patients the characteristic myelin-like inclusions in the podocyte cytoplasm and also focal podocyte foot process effacement. In one case the inclusions were also present in parietal glomerular cells, endothelial cells of peritubular capillary and arterioles. Conclusion. Clinical signs and symptoms are varied and can be severe among heterozygous females with Fabry disease. Intracellular accumulation of glycosphingolipids is a characteristic histologic finding of Fabry nephropathy. Since this disease is a potentially treatable condition, its early identification is imperative. We should consider it in the differential diagnosis of any patient presenting with proteinuria and/or chronic kidney disease, especially if there is a family history of kidney disease.

Renal Pathology in Portuguese HIV-Infected Patients

HIV-infected patients may be affected by a variety of renal disorders. Portugal has a high incidence of HIV2 infection and a low prevalence of HIV-infected patients under dialysis treatment. The aim of this study was to characterise the type of renal disease in Portuguese HIV-infected patients and to determine if HIV2 infection is associated to renal pathology. Only 60 of the 5158 HIV-infected patients followed in our hospital underwent renal biopsy. Clinical and laboratory data and the type of renal disease were reviewed. Male gender was predominant (76.7%), as was Caucasian race (78.3%). Mean age was 37.9±10.6 years. The majority had criteria for AIDS, 66% were on combined antiretroviral therapy and 18.3% were on dialysis. The predominant lesions were immunecomplex glomerulonephritis (n=19), tubulointerstitial nephropathy (n=12), focal segmental glomerulosclerosis(n=11), followed by HIVAN (n=8). Other patterns(amyloidosis, vasculitis, minimal change lesion) were observed. Only three patients were HIV2 infected, and presented diabetic nephropathy, acute tubular necrosis and tubulointerstitial nephritis. No correlations between clinical findings and renal pathology were found. In conclusion, renal disease in HIV patients has a broad spectrum, and renal biopsy remains the gold standard for establishing the diagnosis and guide treatment. Renal disease is not frequent in HIV2-infected patients, and, when present, is probably not directly associated with HIV infection.

De Novo Hypertension and Decline of Renal Function in a Young Woman with Systemic Lupus Erythematosus and Antiphospholipid Syndrome

Antiphospholipid syndrome nephropathy and lupus nephritis have similar clinical and laboratory manifestations and achieving the accuracy of diagnosis required for correct treatment frequently necessitates a kidney biopsy. We report the case of a 29-year-old woman referred to the nephrology service for de novo hypertension, decline of renal function and proteinuria. She had had systemic lupus erythematosus and antiphospholipid syndrome since the age of 21 and was taking oral anticoagulation. Two weeks later, after treatment of hypertension and achievement of adequate coagulation parameters, a percutaneous renal biopsy was performed. The biopsy revealed chronic lesions of focal cortical atrophy, arterial fibrous intimal hyperplasia and arterial thromboses, which are typical features of antiphospholipid syndrome nephropathy. We describe the clinical manifestations and histopathology of antiphospholipid syndrome nephropathy and review the literature on renal biopsy in patients receiving anticoagulation.

Diabetes Mellitus and Renal Disease: When to Perform a Renal Biopsy?

Background: Several studies suggest that nondiabetic renal disease (NDRD) is common in patients with diabetes mellitus. The aim of this analysis of renal biopsies in diabetic patients was (a) to assess the prevalence and type of NDRD and (b) to identify its clinical and laboratory predictors. Methods: This retrospective study analysed clinical and laboratory data and biopsy findings in diabetic patients observed by a single pathologist over the past 25 years. Based on biopsy findings, patients were categorised as (i) isolated diabetic nephropathy,(ii) isolated NDRD and (iii) NDRD superimposed on diabetic nephropathy. Results: Of the 236 patients studied, 60% were male and the mean age was 56.3 (±14.2) years. Of these, 91% had known diabetes mellitus at the time of biopsy (13% type 1 and 87% type 2). Isolated diabetic nephropathy was found in 125 (53%), isolated NDRD in 89 (38%) and NDRD superimposed on diabetic nephropathy in 22 (9%) patients. The main indication for biopsy in the three groups was nephrotic proteinuria. Patients with isolated NDRD and NDRD superimposed on diabetic nephropathy presented acute deterioration of renal function more frequently (p<0.001) and had more microhaematuria(p<0.001) as indications for renal biopsy. Focal segmental glomerulosclerosis and membranous nephropathy were the most frequent diagnoses in patients with NDRD. Patients with isolated diabetic nephropathy were younger (p=0.02), presented a longer duration of diabetes mellitus (p<0.001) and had more frequent retinopathy (p<0.001). The prevalence of microhaematuria was higher in patients with isolated or superimposed NDRD (p=0.01). Conclusion: The prevalence of NDRD (either isolated or superimposed on diabetes mellitus) is remarkably frequent in diabetic patients in whom nephrologists consider renal biopsy an appropriate measure. Predictors of NDRD were older age, shorter duration of diabetes mellitus, absence of retinopathy and presence of microhaematuria.