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Distinguishing between primary (PID) and secondary (SID) immunodeficiencies, particularly in relation to hematological B-cell lymphoproliferative disorders (B-CLPD), poses a major clinical challenge. We aimed to analyze and define the clinical and laboratory variables in SID patients associated with B-CLPD, identifying overlaps with late-onset PIDs, which could potentially improve diagnostic precision and prognostic assessment. We studied 37 clinical/laboratory variables in 151 SID patients with B-CLPD. Patients were classified as "Suspected PID Group" when having recurrent-severe infections prior to the B-CLPD and/or hypogammaglobulinemia according to key ESID criteria for PID. Bivariate association analyses showed significant statistical differences between "Suspected PID"- and "SID"-groups in 10 out of 37 variables analyzed, with "Suspected PID" showing higher frequencies of childhood recurrent-severe infections, family history of B-CLPD, significantly lower serum Free Light Chain (sFLC), immunoglobulin concentrations, lower total leukocyte, and switch-memory B-cell counts at baseline. Rpart machine learning algorithm was performed to potentially create a model to differentiate both groups. The model developed a decision tree with two major variables in order of relevance: sum κ + λ and history of severe-recurrent infections in childhood, with high sensitivity 89.5%, specificity 100%, and accuracy 91.8% for PID prediction. Identifying significant clinical and immunological variables can aid in the difficult task of recognizing late-onset PIDs among SID patients, emphasizing the value of a comprehensive immunological evaluation. The differences between "Suspected PID" and SID groups, highlight the need of early, tailored diagnostic and treatment strategies for personalized patient management and follow up., (© 2024. The Author(s).)

Background: Unilateral subthalamic nucleus (STN) ablation using magnetic resonance-guided focused ultrasound (MRgFUS) is being explored as a new treatment for asymmetric Parkinson's disease (PD)., Objectives: The aims were to study the efficacy and safety of this treatment in asymmetric PD patients and to characterize the lesions., Methods: This prospective, single-center, open-label study evaluated asymmetric PD patients at 6 (n = 20) and 12 months (n = 12) after MRgFUS lesion of the STN. The primary outcome was the change in the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, Part III (MDS-UPDRS III), score in off medication on the treated side and the adverse events (AEs) at 6-month follow-up. We also evaluated cognitive-neuropsychological changes, self-assessment of clinical improvement, and the correlation of the lesion volume with the motor outcomes., Results: On the treated side, the MDS-UPDRS III score (mean difference = 13.8) and the scores in rigidity, bradykinesia, and tremor improved (P < 0.001) throughout the follow-up compared to baseline (at 6 months: rigidity mean difference = 2.8, improvement: 83.5%; bradykinesia mean difference = 6.0, improvement: 69.4%; tremor mean difference = 4.7, improvement: 91.5%). One patient had severe weakness in the treated hemibody, 1 had moderate dyskinesia, and 1 was in moderate confusional state that became mild (weakness) or completely resolved (dyskinesia and confusional state) at 6 months. The rest of the AEs were mild. We observed no clinically relevant changes in cognitive-neuropsychological tests. The percentage of ablation of the STN correlated with the improvement in the total MDS-UPDRS III and contralateral tremor scores (P < 0.05)., Conclusion: Unilateral MRgFUS lesion of the STN resulted in a significant motor improvement. We observed no persistent severe AEs, although mild, mostly transient AEs were frequent. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Introduction: Patients with subjective memory complaints (SMC) may include subgroups with different neuropsychological profiles and risks of cognitive impairment., Methods: Cluster analysis was performed on two datasets (n: 630 and 734) comprising demographic and neuropsychological data from SMC and healthy controls (HC). Survival analyses were conducted on clusters. Bayesian model averaging assessed the predictive utility of clusters and other biomarkers., Results: Two clusters with higher and lower than average cognitive performance were detected in SMC and HC. Assignment to the lower performance cluster increased the risk of cognitive impairment in both datasets (hazard ratios: 1.78 and 2.96; P log-rank : 0.04 and <0.001) and was associated with lower hippocampal volumes and higher tau/amyloid beta 42 ratios in cerebrospinal fluid. The effect of SMC was small and confounded by mood., Discussion: This study provides evidence of the presence of cognitive clusters that hold biological significance and predictive value for cognitive decline in SMC and HC., Highlights: Patients with subjective memory complaints include two cognitive clusters. Assignment to the lower performance cluster increases risk of cognitive impairment. This cluster shows a pattern of biomarkers consistent with incipient Alzheimer's disease pathology. The same cognitive cluster structure is found in healthy controls. The effect of memory complaints on risk of cognitive decline is small and confounded., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Despite advancements in genetic and functional studies, the timely diagnosis of common variable immunodeficiency (CVID) remains a significant challenge. This exploratory study was designed to assess the diagnostic performance of a novel panel of biomarkers for CVID, incorporating the sum of κ+λ light chains, soluble B-cell maturation antigen (sBCMA) levels, switched memory B cells (smB) and the VISUAL score. Comparative analyses utilizing logistic regression were performed against established gold-standard tests, specifically antibody responses. Our research encompassed 88 subjects, comprising 27 CVID, 23 selective IgA deficiency (SIgAD), 20 secondary immunodeficiency (SID) patients and 18 healthy controls. We established the diagnostic accuracy of sBCMA and the sum κ+λ, achieving sensitivity (Se) and specificity (Spe) of 89% and 89%, and 90% and 99%, respectively. Importantly, sBCMA showed strong correlations with all evaluated biomarkers (sum κ+λ, smB cell and VISUAL), whereas the sum κ+λ was uniquely independent from smB cells or VISUAL, suggesting its additional diagnostic value. Through a multivariate tree decision model, specific antibody responses and the sum κ+λ emerged as independent, signature biomarkers for CVID, with the model showcasing an area under the curve (AUC) of 0.946, Se 0.85, and Spe 0.95. This tree-decision model promises to enhance diagnostic efficiency for CVID, underscoring the sum κ+λ as a superior CVID classifier and potential diagnostic criterion within the panel., (© 2024. The Author(s).)

Background: Factors predicting clinical outcomes after MR-guided focused ultrasound (MRgFUS)-thalamotomy in patients with essential tremor (ET) are not well known., Objective: To examine the clinical outcomes and their relationship with patients' baseline demographic and clinical features and lesion characteristics at 6-month follow-up in ET patients., Methods: A total of 127 patients were prospectively evaluated at 1 (n = 122), 3 (n = 102), and 6 months (n = 78) after MRgFUS-thalamotomy. Magnetic resonance imaging (MRI) was obtained at 6 months (n = 60). Primary outcomes included: (1) change in the Clinical Rating Scale of Tremor (CRST)-A+B score in the treated hand and (2) frequency and severity of adverse events (AEs) at 6 months. Secondary outcomes included changes in all subitems of the CRST scale in the treated hand, CRST-C, axial tremor (face, head, voice, tongue), AEs, and correlation of primary outcomes at 6 months with lesion characteristics. Statistical analysis included linear mixed, standard, and logistic regression models., Results: Scores for CRST-A+B, CRST-A, CRST-B in the treated hand, CRST-C, and axial tremor were improved at each evaluation (P < 0.001). Five patients had severe AEs at 1 month that became mild throughout the follow-up. Mild AEs occurred in 71%, 45%, and 34% of patients at 1, 3, and 6 months, respectively. Lesion volume was associated with the reduction in the CRST-A (P = 0.003) and its overlapping with the ventralis intermedius nucleus (Vim) nucleus with the reduction in CRST-A+B (P = 0.02) and CRST-B (P = 0.008) at 6 months., Conclusions: MRgFUS-thalamotomy improves hand and axial tremor in ET patients. Transient and mild AEs are frequent. Lesion volume and location are associated with tremor reduction. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Problem: Recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF) represent distinct clinical conditions with established definitions, both of which have been linked to an underlying pro-inflammatory state. This study aimed to explore the levels of monocytic-myeloid-derived suppressor cells (M-MDSCs) and regulatory T cells (T Reg ) in a cohort of RPL and RIF women and their potential contribution to RPL and RIF., Method of Study: One hundred and eight non-pregnant women were evaluated: 40 RPL, 41 RIF, and 27 fertile healthy controls (HC). A multiparametric flow cytometry approach was utilized to measure and quantify the frequency of M-MDSCs and T Reg cells. Cytokine levels in plasma samples were evaluated through a multiplex assay. M-MDSCs levels were significantly higher in RPL and RIF patients compared to HC., Results: M-MDSCs levels were significantly higher in RPL (9.4% [7-11.6]) and RIF (8.1% [5.9-11.6]) patients compared to HC (6% [4.2-7.6]). An optimal cut-off of 6.1% for M-MDSCs disclosed a sensitivity of 75.6% and 89.7% and a specificity of 57.7% and 57.7% in RIF and RPL groups, respectively. A significant negative correlation was observed between M-MDSCs and T Reg (p = .002, r = -.51)., Conclusions: Our preliminary data allowed us to build a predictive model that may aid as a potential diagnostic tool in the clinic. These findings could provide a better understanding of these pathologies and a better definition of patients that could benefit from personalized treatments to promote pregnancy. Additional exploration and confirmation in distinct study groups are needed to fully assess the diagnostic capabilities of this biomarker., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Patients with antibody deficiency disorders, such as primary immunodeficiency (PID) or secondary immunodeficiency (SID) to B-cell lymphoproliferative disorder (B-CLPD), are two groups vulnerable to developing the severe or chronic form of coronavirus disease caused by SARS-CoV-2 (COVID-19). The data on adaptive immune responses against SARS-CoV-2 are well described in healthy donors, but still limited in patients with antibody deficiency of a different cause. Herein, we analyzed spike-specific IFN-γ and anti-spike IgG antibody responses at 3 to 6 months after exposure to SARS-CoV-2 derived from vaccination and/or infection in two cohorts of immunodeficient patients (PID vs. SID) compared to healthy controls (HCs). Pre-vaccine anti-SARS-CoV-2 cellular responses before vaccine administration were measured in 10 PID patients. Baseline cellular responses were detectable in 4 out of 10 PID patients who had COVID-19 prior to vaccination, perceiving an increase in cellular responses after two-dose vaccination ( p < 0.001). Adequate specific cellular responses were observed in 18 out of 20 (90%) PID patients, in 14 out of 20 (70%) SID patients and in 74 out of 81 (96%) HCs after vaccination (and natural infection in some cases). Specific IFN-γ response was significantly higher in HC with respect to PID (1908.5 mUI/mL vs. 1694.1 mUI/mL; p = 0.005). Whereas all SID and HC patients mounted a specific humoral immune response, only 80% of PID patients showed positive anti-SARS-CoV-2 IgG. The titer of anti-SARS-CoV-2 IgG was significantly lower in SID compared with HC patients ( p = 0.040), without significant differences between PID and HC patients ( p = 0.123) and between PID and SID patients ( p =0.683). High proportions of PID and SID patients showed adequate specific cellular responses to receptor binding domain (RBD) neoantigen, with a divergence between the two arms of the adaptive immune response in PID and SID patients. We also focused on the correlation of protection of positive SARS-CoV-2 cellular response to omicron exposure: 27 out of 81 (33.3%) HCs referred COVID-19 detected by PCR or antigen test, 24 with a mild course, 1 with moderate symptoms and the remaining 2 with bilateral pneumonia that were treated in an outpatient basis. Our results might support the relevance of these immunological studies to determine the correlation of protection with severe disease and for deciding the need for additional boosters on a personalized basis. Follow-up studies are required to evaluate the duration and variability in the immune response to COVID-19 vaccination or infection.

Objective: Stereoelectroencephalography (SEEG) is a technique for preoperative evaluation of patients with difficult-to-localise refractory focal epilepsy (DLRFE), enabling the study of deep cortical structures. The procedure, which is increasingly used in international epilepsy centres, has not been fully developed in Spain. We describe our experience with SEEG in the preoperative evaluation of DLRFE., Material and Methods: In the last 8 years, 71 patients with DLRFE were evaluated with SEEG in our epilepsy centre. We prospectively analysed our results in terms of localisation of the epileptogenic zone (EZ), surgical outcomes, and complications associated with the procedure., Results: The median age of the sample was 30 years (range, 4-59 years); 27 patients (38%) were women. Forty-five patients (63.4%) showed no abnormalities on brain MR images. A total of 627 electrodes were implanted (median, 9 electrodes per patient; range, 1-17), and 50% of implantations were multilobar. The EZ was identified in 64 patients (90.1%), and was extratemporal or temporal plus in 66% of the cases. Follow-up was over one year in 55 of the 61 patients undergoing surgery: in the last year of follow-up, 58.2% were seizure-free (Engel Epilepsy Surgery Outcome Scale class I) and 76.4% had good outcomes (Engel I-II). Three patients (4.2%) presented brain haemorrhages., Conclusion: SEEG enables localisation of the EZ in patients in whom this was previously impossible, offering better surgical outcomes than other invasive techniques while having a relatively low rate of complications., (Copyright © 2019 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)

Objective: Stereoelectroencephalography (SEEG) is a technique for preoperative evaluation of patients with difficult-to-localise refractory focal epilepsy (DLRFE), enabling the study of deep cortical structures. The procedure, which is increasingly used in international epilepsy centres, has not been fully developed in Spain. We describe our experience with SEEG in the preoperative evaluation of DLRFE., Material and Methods: In the last 8 years, 71 patients with DLRFE were evaluated with SEEG in our epilepsy centre. We prospectively analysed our results in terms of localisation of the epileptogenic zone (EZ), surgical outcomes, and complications associated with the procedure., Results: The median age of the sample was 30 years (range, 4-59 years); 27 patients (38%) were women. Forty-five patients (63.4%) showed no abnormalities on brain MR images. A total of 627 electrodes were implanted (median, 9 electrodes per patient; range, 1-17), and 50% of implantations were multilobar. The EZ was identified in 64 patients (90.1%), and was extratemporal or temporal plus in 66% of the cases. Follow-up was over one year in 55 of the 61 patients undergoing surgery: in the last year of follow-up, 58.2% were seizure-free (Engel Epilepsy Surgery Outcome Scale class I) and 76.4% had good outcomes (Engel I-II). Three patients (4.2%) presented brain haemorrhages., Conclusion: SEEG enables localisation of the EZ in patients in whom this was previously impossible, offering better surgical outcomes than other invasive techniques while having a relatively low rate of complications., (Copyright © 2019 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Purpose: We hypothesized that epilepsy associated with temporal pole encephaloceles (ETPE) could be the consequence and an unrecognized manifestation of idiopathic intracranial hypertension (IIH). To test this hypothesis in patients with ETPEs we evaluated: 1) the frequency of two radiological signs of IIH and 2) whether these patients develop over time clinical manifestations suggestive of elevated intracranial pressure (ICP)., Methods: Case-control study comparing two cardinal radiological signs of IIH pituitary gland height (PGH) and the diameter of the two optic nerve sheaths (ONS) between 29 patients with ETPEs (TPE group) and 29 patients with focal epilepsy of other etiologies (control group), adjusted by age, sex, body mass index (BMI), age at epilepsy onset and epilepsy duration. Analysis was performed using conventional and ordinal logistic regression. The measurements in both groups were compared with validated radiological criteria of IIH., Results: Of the patients 17 (63%) in the TPE group had all three measurements over the cut-off values for IIH, while no patients in the control group had all three findings. The TPE group patients had lower PGH (3.2 ± 1.0 mm vs. 4.9 ± 1.3 mm, p < 0.001) and larger diameter of ONS than controls (p < 0.001), being similar to validated data of IIH. No patient with TPE had clinical manifestations of elevated ICP (mean follow-up 15.1 ± 11.7 years)., Conclusion: Patients with ETPEs frequently had radiological signs of IIH while not developing typical manifestations of elevated ICP over time. In this way, ETPEs could be an unrecognized manifestation of IIH, and temporal lobe seizures the only clinical expression of this epilepsy syndrome., (© 2020. Springer-Verlag GmbH Germany, part of Springer Nature.)

The broad and heterogeneous clinical spectrum that characterizes common variable immunodeficiency (CVID) is associated with quite different disease course and prognosis, highlighting the need to develop tools that predict complications. We developed a multianalyte VISUAL score (variable immunodeficiency score upfront analytical link) aimed to predict severity using individual CVID patient data at baseline of a cohort of 50 CVID patients from two different centers in Portugal and Spain. We retrospectively applied VISUAL to the CVID clinical severity scores proposed by Ameratunga and Grimbacher after 15 years follow-up of our cohort. VISUAL score at CVID diagnosis showed adequate performance for predicting infectious and non-infectious severe complications (Cluster B). Compared to switched memory B lymphocyte phenotype alone, VISUAL provided a more accurate identification of clinically meaningful outcome, with significantly higher sensitivity (85% vs 55%, p = 0.01), and negative predictive value (77% vs 58%) and AUC of the ROC curves (0.72 vs 0.64), with optimal cut-off level of 10. For every increase of 1 point in the VISUAL scale, the odds of being in the higher risk category (Cluster B) increased in 1.3 (p = 0.005) for Ameratunga's severity score and 1.26 (p = 0.004) for Grimbacher's severity score. At diagnosis of CVID, VISUAL score ≥ 10 showed 8.94-fold higher odds of severe prognosis than below this threshold. Kaplan-Meier estimates for the VISUAL ≥ 10 points showed significantly earlier progression to Cluster B than those with VISUAL < 10 (p = 0.0002). This prognostic laboratory score might allow close monitoring and more aggressive treatment in patients with scores ≥ 10 on a personalized basis approach. Further studies are needed to prospectively validate VISUAL score.

Objective: This study aimed to evaluate the access to advanced diagnostic tests in patients with epilepsy and intellectual disability, with special focus on genetics., Methods: Patients with epilepsy and intellectual disability evaluated between 2016 and 2018 at the Epilepsy Unit of two hospitals in Madrid, Spain were included. The main inclusion criterion was an undetermined etiological diagnosis after clinical assessment, neuroimaging, and electroencephalogram (EEG)., Results: Two hundred and five patients with epilepsy and intellectual disability were evaluated, with 124 fulfilling the inclusion criteria (mean age: 33.9 years). Regarding the etiological workup, advanced neuroimaging, prolonged video-EEG, and any type of genetic test had been performed in 58%, 41%, and 40%, respectively. An etiological diagnosis was reached in 18.5%. The workup was considered incomplete in 67%. Variables that showed the strongest association with an incomplete diagnostic workup in the multivariate analysis were current age and seizure freedom., Conclusions: Despite the multiple implications of modern diagnostic techniques, especially genetic testing, there is a large proportion of patients with epilepsy and intellectual disability who do not have access to them. Older age and seizure freedom seem to be associated with the highest diagnostic gap., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To assess the effectiveness and tolerability of perampanel (PER) monotherapy in routine clinical practice for the treatment of focal onset and generalized tonic-clonic seizures (GTCS)., Methods: This multicenter, retrospective, observational study was conducted in patients aged ≥12 years treated with PER as primary monotherapy or converted to PER monotherapy by progressive reduction of background antiepileptic drugs. Outcomes included retention, responder, and seizure-free rate after 3, 6, and 12 months and tolerability throughout the follow-up., Results: A total of 98 patients (mean age = 49.6 ± 21.7 years, 51% female) with focal seizures and/or GTCS were treated with PER monotherapy for a median exposure of 14 months (range = 1-57) with a median dose of 4 mg (range = 2-10). The retention rates at 3, 6, and 12 months and last follow-up were 93.8%, 89.3%, 80.9%, and 71.4%, respectively. The retention rates according to the type of monotherapy (primary vs conversion) did not differ (log-rank P value = .57). Among the 98 patients, 61.2% patients had seizures throughout the baseline period, with a median seizure frequency of 0.6 seizures per month (range = 0.3-26). Responder rates at 3, 6, and 12 months were 79.6%, 70.1%, and 52.8%, respectively, and seizure freedom rates at the same points were 62.7%, 56.1%, and 41.5%. Regarding the 33 patients who had GTCS in the baseline period, 87.8% were seizure-free at 3 months, 78.1% at 6 months, and 55.1% at 12 months. Over the entire follow-up, PER monotherapy was generally well tolerated, and only 16% of patients discontinued PER due to adverse events (AEs). Female patients were found to be at a higher risk of psychiatric AEs (female vs male odds ratio = 2.85, 95% confidence interval = 1-8.33, P = .046)., Significance: PER demonstrated good effectiveness and a good safety profile when used as primary therapy or conversion to monotherapy at relatively low doses, in a clinical setting with patients with focal seizures and GTCS., (© 2020 International League Against Epilepsy.)

Visual object naming is a complex cognitive process that engages an interconnected network of cortical regions moving from occipitotemporal to anterior-inferior temporal cortices, and extending into the inferior frontal cortex. Naming can fail for diverse reasons, and different stages of the naming multi-step process appear to be reliant upon the integrity of different neuroanatomical locations. While the neural correlates of semantic errors have been extensively studied, the neural basis of omission errors remains relatively unspecified. Although a strong line of evidence supports an association between anterior temporal lobe damage and semantic errors, there are some studies suggesting that the anterior temporal lobe could be also associated with omissions. However, support for this hypothesis comes from studies with patients in whom damage affected extensive brain regions, sometimes bilaterally. Here, we availed of a group of 12 patients with epilepsy associated with a small lesion at the tip of the left temporal pole. Using an unbiased surface-based morphometry methodology, we correlated two morphological features with errors observed during visual naming. Analyses revealed a correlation between omission errors and reduced local gyrification index in three cortical clusters: one in the left anteromedial temporal lobe region (AMTL) and two in the left anterior cingulate cortex (ACC). Our findings support the view that regions in ACC and AMTL are critical structures within a network engaged in word selection from semantics., (© 2019 The British Psychological Society.)

Introduction: Hippocampal volumetry can discriminate normal subjects from patients with amnestic mild cognitive impairment (MCI) or Alzheimer disease (AD). We have analyzed the effects of different methods of hippocampal volume (HV) adjustment on the diagnostic accuracy of this technique., Methods: Cross-sectional analysis of 148 subjects of the ADNI database (48 normal, 66 MCI, 34 AD). Brain volumes were calculated from 3T MRI scans with gm extractor, a fully automated script based on FSL. A series of logistic regression models was obtained using 9 volumes of reference and 3 methods of adjustment (normalization, covariance, bilinear regression). Diagnostic accuracy was evaluated with the receiver operating characteristic curve method. External validity was assessed with 10-fold cross-validation., Results: The models with the highest area under the curve (AUC) were those including the HV normalized by total intracranial volume (TIV). The differences with bilinear regression and the covariance method adjusted by TIV were minor and not statistically significant. The lowest AUCs corresponded to the models based on raw (unadjusted) HVs. The results were qualitatively similar in two clinical settings (normal versus MCI, and normal versus AD), but the differences were higher in the normal versus MCI context., Conclusion: The accuracy of hippocampal volumetry for the differential diagnosis between normal subjects and patients with MCI or AD was maximized by normalizing the HV by the TIV. Our results do not exclude the potential superiority of non-linear models., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Several lines of research have linked olfactory regions with the pathophysiology of focal epilepsies. Among those regions, the piriform cortex represents the major part of the primary olfactory cortex. According to these data, we raised the hypothesis that in patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis exists an interictal dysfunction of olfactory processing that could be more significant compared to patients with extra-hippocampal focal epilepsy and healthy controls. This could be the consequence of a dysfunctional epileptogenic network that extends beyond the hippocampus and affects other structures, including the piriform cortex. To test this hypothesis, we evaluated the olfactory function with the Sniffin' Sticks test in 32 patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis, 30 patients with extra-hippocampal focal epilepsy, and 22 healthy controls. Compared to the other study groups, patients with temporal lobe epilepsy due to hippocampal sclerosis showed a basal olfactory dysfunction characterized by an impairment in odor discrimination and odor identification. We also found that high seizure frequency had a strong correlation with the evaluated olfactory tasks. Our results are consistent with neuroimaging and neuropathological data that establish a link between olfactory regions and the pathophysiology of temporal lobe epilepsy., Competing Interests: None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Dementia is a syndrome characterised by chronic, multi-domain, acquired cognitive impairment that causes significant functional limitations. MRI is the standard imaging study for these cases, since it enables detection of the atrophy patterns of the various neurodegenerative diseases (Alzheimer's disease, frontotemporal degeneration, Lewy body dementia), the vascular lesions associated with vascular dementia, and various potentially reversible diseases (for example, tumours, hydrocephaly) or diseases that require special management measures (for example, prion diseases). In certain cases other imaging methods can be used, such as CT, functional MRI, HMPAO SPECT or dopaminergic markers and FDG PET, amyloid markers or dopaminergic markers. The indications for these methods have not yet been clearly established, and therefore should be used in multidisciplinary dementia units., (Copyright © 2018. Publicado por Elsevier España, S.L.U.)

The stiff person syndrome is a rare neurological disorder, difficult to diagnose and to treat. Paraneoplastic patients usually present amphiphysin antibodies but the association with anti-Ri antibodies is less known. We present a case report of paraneoplastic SPS, small cell carcinoma of the bladder and anti-Ri antibodies., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Eslicarbazepine acetate (ESL, Aptiom™) is a once-daily anticonvulsant, approved as adjunctive treatment of partial-onset seizures (POS). Historical-controlled trials investigating the use of ESL as monotherapy have demonstrated a favorable efficacy and tolerability profile in patients with POS. This prospective, non-interventional study recruited POS patients in 17 hospitals in Spain. After a 3-month baseline period, ESL therapy was initiated as 400mg QD and up-titrated to an optimal maintenance dose based on clinical response and tolerance. The incidence of seizures was assessed via seizure calendars and the nature and severity of adverse events (AEs) were also recorded. A total of 117 patients (aged 9-87years) enrolled in the study and were treated with ESL at either 400mg/day (3.4% patients), 800mg/day (61% patients), 1200mg/day (27.1% patients) or 1600mg/day (8.5% patients). At 3months, 82.0% (n=72) of patients achieved a ≥50% reduction in seizure frequency, compared to 79.7% (n=67) of patients at 6months and 83.0% (n=49) at 12months. Patients who suffered secondary generalized tonic-clonic (SGTC) seizures had seizure-free rates of 71% (n=27), 69.6% (n=29), and 72.7% (n=16) at 3, 6, and 12months, respectively. Overall, 18 patients (15.3%) reported AEs of instability and dizziness (n=9), somnolence (n=3), mild hyponatremia (n=3), headache (n=1), hypertriglyceridemia (n=1), and allergic reaction (n=1), which caused ESL discontinuation of ESL treatment. ESL is effective and well tolerated as monotherapy for patients with POS, which supports previous findings. Early use is supported by its frequent use as monotherapy in this study and lack of severe side effects., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background/aims: Alzheimer's disease (AD) shows a characteristic pattern of brain atrophy, with predominant involvement of posterior limbic structures, and relative preservation of rostral limbic and primary cortical regions. We aimed to investigate the diagnostic utility of two gray matter volume ratios based on this pattern, and to develop a fully automated method to calculate them from unprocessed MRI files., Patients and Methods: Cross-sectional study of 118 subjects from the ADNI database, including normal controls and patients with mild cognitive impairment (MCI) and AD. Clinical variables and 3T T1-weighted MRI files were analyzed. Regional gray matter and total intracranial volumes were calculated with a shell script (gm&#95;extractor) based on FSL. Anteroposterior and primary-to-posterior limbic ratios (APL and PPL) were calculated from these values. Diagnostic utility of variables was tested in logistic regression models using Bayesian model averaging for variable selection. External validity was evaluated with bootstrap sampling and a test set of 60 subjects., Results: gm&#95;extractor showed high test-retest reliability and high concurrent validity with FSL's FIRST. Volumetric measurements agreed with the expected anatomical pattern associated with AD. APL and PPL ratios were significantly different between groups, and were selected instead of hippocampal and entorhinal volumes to differentiate normal from MCI or cognitively impaired (MCI plus AD) subjects., Conclusion: APL and PPL ratios may be useful components of models aimed to differentiate normal subjects from patients with MCI or AD. These values, and other gray matter volumes, may be reliably calculated with gm&#95;extractor., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Purpose: We aimed to determine the correlation between subjective evaluations of mood and cognitive functions by patients and informants, and the findings of a battery of neuropsychological tests., Methods: We analyzed 74 subjects recruited from a general neurology clinic, comprising 37 patients with cognitive complaints and 37 informants (either relatives or caregivers in close contact with the patients). Four ordinal scales concerning recent memory, verbal expression, initiative, and mood were correlated with the findings of a series of neuropsychological tests and questionnaires using the tau b coefficient., Results: The scores for the patients on the scales were most strongly correlated with scores on the 15-item Geriatric Depression Scale (GDS-15), while the scores for the informants were most strongly correlated with scores on GDS-15, the Informant Questionnaire on Cognitive Decline, and the Functional Activities Questionnaire (FAQ). The most significant correlation was between the initiative scale from informants and FAQ (tau b=-0.591, p<0.001), and it was the only one that remained significant after correcting for multiple testing (p Holm=0.013)., Conclusions: Cognitive complaints from patients mainly reflect their mood, whilst informant reports mainly reflect both the functional ability and mood of the patients., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2017 Korean Neurological Association)

Background: Gamma knife radiosurgery (GKRS) is one of the alternatives for treatment for classical trigeminal neuralgia (TN)., Objective: To retrospectively analyze long-term outcomes for TN using GKRS achieved at our institution., Methods: One hundred seventeen patients with medically refractory TN treated by GKRS at our institution were followed up between 1993 and 2011. Mean maximum dose was 86.5 Gy (range: 80-90 Gy; median: 90 Gy). Clinical response was defined based on the Burchiel classification. We considered classes I and II as a complete response. For toxicity, we use the Barrow Neurological Institute facial numbness scale. Mean duration of follow-up was 66 months (range: 24-171 months)., Results: Complete response at last follow-up in our patients was 81%, with an excellent response while off medication in 52%. Pain-free rates without medication (class I) were 85% at 3 years (confidence interval [CI]: 78%-94%), 81% at 5 years (CI: 72%-91%), and 76% at 7 years (CI: 65%-90%). Complete response rates (classes I-II) were 91% at 3 years (CI: 86%-97%), 86% at 5 years (CI: 79%-93%), and 82% at 7 years (CI: 72%-93%). Poor treatment response rates differed significantly between patients who had undergone previous surgery and were refractory to management with medication prior to GKRS. New or worsening facial numbness was reported in 32.5% (30% score II and 2.5% score III). No anesthesia dolorosa was reported. Permanent recurrence pain rate was 12%., Conclusion: GKRS achieved favorable outcomes compared with surgery in terms of pain relief and complication rates in our cohort of patients, notwithstanding decreasing pain-free survival rates over time. We consider GKRS to be an initial treatment in the management of medically intractable TN in selected patients., Abbreviations: CI, confidence intervalGKRS, gamma knife radiosurgeryMVD, microvascular decompressionRS, radiosurgeryTN, trigeminal neuralgia.

Objective: Naming difficulties are frequently observed in patients with temporal lobe epilepsy (TLE). Although damage/removal of regions of the anterior temporal neocortex including the temporal pole is considered critical for those difficulties, 1 relevant hypothesis proposes that hippocampal damage also has a role. Our aim was to better understand the specific involvement of temporal pole and hippocampus in visual object naming., Method: We assessed 2 types of patients with TLE on a visual confrontation-naming task: patients with hippocampal sclerosis (HS; n = 16) and patients with a lesion on the tip of the temporal pole that spared the hippocampus entirely (n = 18). A common battery of verbal and nonverbal semantic tasks was administered and used as a semantic memory background. Control group were 20 matched healthy participants., Results: Patients with lesions on their temporal poles differed from patients with HS and control group on naming ability, proportion and rate of error type, and influence of concept familiarity. Of note, naming performance was not affected by hippocampal damage. Using a Bayesian model averaging approach, we found that the number of omission errors distinguished patients with temporal pole damage from patients with HS and controls. This differential pattern occurred despite similar impairment on the semantic memory background in both clinical groups., Conclusion: Current findings provide evidence that temporal pole damage produces or contributes to naming impairment in TLE, while also suggesting that the hippocampus is not critical for naming. They also highlight the importance of error-type analysis when evaluating visual naming in TLE. (PsycINFO Database Record, ((c) 2016 APA, all rights reserved).)

Objective: Small temporal pole encephalocele (STPE) can be the pathologic substrate of epilepsy in a subgroup of patients with noninformative magnetic resonance imaging (MRI). Herein, we analyzed the clinical, neurophysiologic, and radiologic features of the epilepsy found in 22 patients with STPE, and the frequency of STPE in patients with refractory focal epilepsy (RFE)., Methods: We performed an observational study of all patients with STPE identified at our epilepsy unit from January 2007 to December 2014. Cases were detected through a systematic search of our database of RFE patients evaluated for surgery, and a prospective collection of patients identified at the outpatient clinic. The RFE database was also employed to analyze the frequency of STPE among the different clinical subgroups., Results: We identified 22 patients with STPE (11 women), including 12 (4.0%) of 303 patients from the RFE database, and 10 from the outpatient clinic. The median age was 51.5 years (range 29-75) and the median age at seizure onset was 38.5 years (range 15-73). Typically, 12 (80%) of 15 patients with left STPE reported seizures with impairment of language. Among the RFE cases, STPE were found in 9.6% of patients with temporal lobe epilepsy (TLE), and in 0.5% of those with extra-TLE (p = 0.0001). STPEs were more frequent in TLE patients with an initial MRI study reported as normal (23.3%) than in those with MRI-visible lesions (1.4%; p = 0.0002). Stereo-electroencephalography was performed in four patients, confirming the localization of the epileptogenic zone at the temporal pole with late participation of the hippocampus. Long-term seizure control was achieved in four of five operated patients., Significance: STPE can be a hidden cause of TLE in a subgroup of patients with an initial report of "normal" MRI. Early identification of this lesion may help to select patients for presurgical evaluation and tailored resection., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

Objective: To (1) determine the value of the recently proposed criteria of neuromyelitis optica (NMO) spectrum disorder (NMOSD) that unify patients with NMO and those with limited forms (NMO/LF) with aquaporin-4 immunoglobulin G (AQP4-IgG) antibodies; and (2) investigate the clinical significance of the serologic status in patients with NMO., Methods: This was a retrospective, multicenter study of 181 patients fulfilling the 2006 NMO criteria (n = 127) or NMO/LF criteria with AQP4-IgG (n = 54). AQP4-IgG and myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) antibodies were tested using cell-based assays., Results: Patients were mainly white (86%) and female (ratio 6.5:1) with median age at onset 39 years (range 10-77). Compared to patients with NMO and AQP4-IgG (n = 94), those with NMO/LF presented more often with longitudinally extensive transverse myelitis (LETM) (p < 0.001), and had lower relapse rates (p = 0.015), but similar disability outcomes. Nonwhite ethnicity and optic neuritis presentation doubled the risk for developing NMO compared with white race (p = 0.008) or LETM presentation (p = 0.008). Nonwhite race (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.4-13.6) and older age at onset were associated with worse outcome (for every 10-year increase, HR 1.7, 95% CI 1.3-2.2). Patients with NMO and MOG-IgG (n = 9) had lower female:male ratio (0.8:1) and better disability outcome than AQP4-IgG-seropositive or double-seronegative patients (p < 0.001)., Conclusions: In patients with AQP4-IgG, the similar outcomes regardless of the clinical phenotype support the unified term NMOSD; nonwhite ethnicity and older age at onset are associated with worse outcome. Double-seronegative and AQP4-IgG-seropositive NMO have a similar clinical outcome. The better prognosis of patients with MOG-IgG and NMO suggests that phenotypic and serologic classification is useful.

Introduction: The use of the Multiphasic Personality Inventory Minnesota 2 (MMPI-2) for the diagnosis of psychogenic non-epileptic seizures (PNES) is controversial. This study examines the validity of the clinical scales and, unlike previous works, the content scales., Methods: Cross-sectional study of 209 patients treated in the epilepsy unit. We performed a logistic regression analysis, taking video-electroencephalography as the reference test, and as predictor variables age, sex, IQ and clinical (model A) or content scales (model B) of the MMPI-2. The models were selected according to the Aikake index and compared using the DeLong test., Results: We analyzed 37 patients with PNES alone, or combined with seizures, and 172 patients with seizures only. The model consisting of sex, Hs (hypochondriasis) and Pa (paranoia) showed a sensitivity of 77.1%, a specificity of 76.8%, a percentage of correct classification of 76.8%, and an area under the curve (AUC) of 0.836 for diagnosing CNEP. Model B, consisting of sex, HEA (health concerns) and FRS (fears), showed a sensitivity of 65.7%, a specificity of 78.0%, a percentage of correct classification of 75.9% and an AUC of 0.840. DeLong's test did not detect significant differences., Conclusions: The MMPI-2 has a moderate validity for the diagnosis of PNES in patients referred to an epilepsy unit. Using content scales does not significantly improve results from the clinical scales., (Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: The validity of neuropsychological tests for the differential diagnosis of degenerative dementias may depend on the clinical context. We constructed a series of logistic models taking into account this factor., Methods: We retrospectively analyzed the demographic and neuropsychological data of 301 patients with probable Alzheimer's disease (AD), frontotemporal degeneration (FTLD), or dementia with Lewy bodies (DLB). Nine models were constructed taking into account the diagnostic question (eg, AD vs DLB) and subpopulation (incident vs prevalent)., Results: The AD versus DLB model for all patients, including memory recovery and phonological fluency, was highly accurate (area under the curve = 0.919, sensitivity = 90%, and specificity = 80%). The results were comparable in incident and prevalent cases. The FTLD versus AD and DLB versus FTLD models were both inaccurate., Conclusion: The models constructed from basic neuropsychological variables allowed an accurate differential diagnosis of AD versus DLB but not of FTLD versus AD or DLB., (© The Author(s) 2014.)

Florbetapir (18F) for brain amyloid positron emission tomography (PET) imaging has been recently approved in Europe to estimate β-amyloid neuritic plaque density in the brain when the subject is still alive. Such density is one of the key issues for the definitive diagnosis of Alzheimer's disease (AD) at autopsy. This capability of florbetapir (18F) is regarded as a significant improvement in the diagnostic procedures for adult patients with cognitive impairment who are being evaluated for AD and other causes of cognitive impairment. The current paper highlights the specific characteristics of the European marketing authorization of florbetapir (18F)., (Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Studies of patients with temporal lobe epilepsy provide few descriptions of seizures that arise in the temporopolar and the anterior temporobasal brain region. Based on connectivity, it might be assumed that the semiology of these seizures is similar to that of medial temporal lobe epilepsy. However, accumulating evidence suggests that the anterior temporobasal cortex may play an important role in the language system, which could account for particular features of seizures arising here. We studied the electroclinical features of seizures in patients with circumscribed temporopolar and temporobasal lesions in order to identify specific features that might differentiate them from seizures that originate in other temporal areas. Among 172 patients with temporal lobe seizures registered in our epilepsy unit in the last 15 years, 15 (8.7%) patients had seizures caused by temporopolar or anterior temporobasal lesions (11 left-sided lesions). The main finding in our study is that patients with left-sided lesions had aphasia during their seizures as the most prominent feature. In addition, while all patients showed normal to high intellectual functioning in standard neuropsychological testing, semantic impairment was found in a subset of 9 patients with left-sided lesions. This case series demonstrates that aphasic seizures without impairment of consciousness can result from small, circumscribed left anterior temporobasal and temporopolar lesions. Thus, the presence of speech manifestation during seizures should prompt detailed assessment of the structural integrity of the basal surface of the temporal lobe in addition to the evaluation of primary language areas., (© 2013.)

Background: current diagnostic criteria of probable Creutzfeldt-Jakob disease (CJD) include a combination of clinical, EEG and analytic data. Recent data indicate that brain MRI including fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI) sequences can be a valid and reliable tool for the diagnosis of CJD. We describe our experience with high b-value (3000s/mm(2)) diffusion-weighted imaging (DWI) in patients with probable or definite CJD and compare it with standard b-value (1000s/mm(2)) DWI., Methods: we performed a retrospective analysis of patients admitted to our Hospital Service between 2002 and 2008 with a final diagnosis of probable or definite CJD. Patients were examined using either a 1.5 Tesla or a 3 Tesla MRI. The MRI protocol included T1-weigthed spin-echo sequences, T2-weighted fast spin-echo, FLAIR and DWI sequences with high b-value and standard b-value., Results: during the study period there were 7 patients with probable or definite CJD. Only 3 patients (43%) showed changes on FLAIR sequence consistent with CJD. All the cases were detected with high b-value DWI, including 2 cases (28%) that would have been missed using standard b-value (1000s/mm(2)) DWI. In all the patients the changes were more conspicuous and extensive at high b-value DWI (b=3000s/mm(2))., Conclusion: our data indicate that high b-value DWI may improve the sensitivity of brain MRI for the diagnosis of CJD, allowing the detection of some cases that would have been overlooked by conventional sequences., (Copyright © 2010 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.)

We describe the clinical phenotype of nine kindred with presenile Alzheimer's disease (AD) caused by different presenilin 1 (PS1) point mutations, and compare them with reported families with mutations in the same codons. Mutations were in exon 4 (Phe105Val), exon 5 (Pro117Arg, Glu120Gly), exon 6 (His163Arg), exon 7 (Leu226Phe), exon 8 (Val261Leu, Val272Ala, Leu282Arg), and exon 12 (Ile439Ser). Three of these amino acid changes (Phe105Val, Glu120Gly, and Ile439Ser) had not been previously reported. Distinct clinical features, including age of onset, symptoms and signs associated with the cortical-type dementia and aggressiveness of the disease, characterized the different mutations and were quite homogeneous across family members. Age of onset fell within a consistent range: some mutations caused the disease in the thirties (P117R, L226F, V272A), other in the forties (E120G, H163R, V261L, L282R), and other in the fifties (F105V, I439S). Associated features also segregated with specific mutations: early epileptic activity (E120G), spastic paraparesis (V261L), subcortical dementia and parkinsonism (V272A), early language impairment, frontal signs, and myoclonus (L226F), and late myoclonus and seizures (H163R, L282R). Neurological deterioration was particularly aggressive in PS1 mutations with earlier age of onset such as P117R, L226F, and E120G. With few exceptions, a similar clinical phenotype was found in families reported to have either the same mutation or different amino acid changes in the same codons. This series points to a strong influence of the specific genetic defect in the development of the clinical phenotype.

Introduction: The performance of the 14-3-3 protein test has been shown to be adequate for sporadic Creutzfeldt-Jakob disease (sCJD) diagnosis in selected populations, but its routine validity has been questioned., Methods: One thousand and sixty-eight patients with clinically suspected sCJD were analyzed in a Spanish reference center. In order to explore the influence of the clinical context on the performance of the immunoassay, the patients were classified at sample reception according to the World Health Organization (WHO) diagnostic criteria excluding the 14-3-3 test results. The yield of the immunoassay was evaluated in each subgroup with criteria of probable, possible sCJD or non-sCJD., Results: In the set of patients with suspicion of sCJD the inclusion of the 14-3-3 test produces a significant increase in the diagnosis certainty (positive likelihood ratio: 10.1) compared to the WHO's criteria, excluding the 14-3-3 test. For patients classified at sample reception as probable sCJD (n=166), possible sCJD (n=129) and non-sCJD (n=773), the positive predictive values for the test were 98.4%, 97.5% and 31%, and the negative predictive values were 22.2%, 73.4% and 100%, respectively., Conclusions: The predictive values of the assay vary according to the previous diagnostic certainty. Therefore, in order to interpret correctly the test, it is necessary to evaluate the degree of initial clinical suspicion of the patient at the moment of the cerebrospinal fluid (CSF) extraction. This study offers up-to-date information, referenced to the Spanish population, and in useful format, and it is intended to serve as a guideline for 14-3-3 test results interpretation to the clinicians in our community.

Background: The 14-3-3 test appears to be a valuable aid for the clinical diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) in selected populations. However, its usefulness in routine practice has been challenged. In this study, the influence of the clinical context on the performance of the 14-3-3 test for the diagnosis of sCJD is investigated through the analysis of a large prospective clinical series., Methods: Six hundred seventy-two Spanish patients with clinically suspected sCJD were analyzed. Clinical classification at sample reception according to the World Health Organization's (WHO) criteria (excluding the 14-3-3 test result) was used to explore the influence of the clinical context on the pre-test probabilities, and positive (PPV) and negative (NPV) predictive values of the 14-3-3 test., Results: Predictive values of the test varied greatly according to the initial clinical classification: PPV of 98.8%, 96.5% and 45.0%, and NPV of 26.1%, 66.6% and 100% for probable sCJDi (n = 115), possible sCJDi (n = 73) and non-sCJDi (n = 484) cases, respectively. According to multivariate and Bayesian analyses, these values represent an improvement of diagnostic certainty compared to clinical data alone., Conclusion: In three different contexts of sCJD suspicion, the 14-3-3 assay provides useful information complementary to clinical and electroencephalographic (EEG) data. The test is most useful supporting a clinical impression, whilst it may show deceptive when it is not in agreement with clinical data.

Objective: To analyse clinical and therapeutic aspects of epilepsy secondary to ulegyria in adults., Patients: Out of 1,020 consecutive patients studied at a tertiary care epilepsy centre, eight cases of ulegyria were identified. All patients had comprehensive clinical evaluation, neuropsychological testing, interictal EEG, and brain magnetic resonance imaging (MRI). In addition, five patients had video-EEG monitoring. Ulegyria was confirmed by histological analysis in two patients who had successful epilepsy surgery., Results: All patients had a history of perinatal asphyxia. In four of them there was psychomotor developmental delay. Mean age at onset of seizures was 5.8 years (range first week to 21 years). Brain MRI demonstrated predominant involvement of occipito-parietal cortical and subcortical areas. This posterior distribution of lesions was also supported by the presence of auras with occipital and parietal semiology in six patients, and signs of visuospatial dysfunction in five. Four patients had medically refractory epilepsy and two of them had significant improvement with surgical treatment., Conclusions: In this group of adult epileptic patients with ulegyria brain MRI, ictal semiology, and neurological examination are consistent with occipital lobe epilepsy. Most patients have severe epilepsy, but in some of them epilepsy can be controlled with antiepileptic drugs, while in others surgical treatment can be effective. Brain MRI criteria of ulegyria are well established, and in two cases it was possible to confirm their diagnosis with histological analysis.

In order to have more specific tools available to approach amyloidogenesis in Alzheimer's disease (AD), we have produced several polyclonal and monoclonal antibodies that recognize specific sequences of the amyloid beta (Abeta) peptide. Here we present results that demonstrate that our monoclonal antibody EM5 recognizes an internal sequence (residues 11-16) of the Abeta peptide. This strategic localization of the epitope allowed us to employ this antibody, together with two previously reported polyclonal antibodies (EM2 and EM3, specific for AbetaX-40 and AbetaX-42, respectively), in an immunohistochemical study aimed at exploring the differential distribution of longer (AbetaX-40/42) and shorter (Abeta17-X) peptides along the various types of amyloid deposits of AD. This antibody panel was used in six AD brains, on sections from associative neocortex, striatum and cerebellar cortex. Single and double immunostaining revealed specific staining of vascular amyloid deposits and neuritic plaques by EM5 antibody, with high co-localization of EM2. Our results suggest that EM5 antibody recognizes pathogenic forms of Abeta deposits (amyloid angiopathy and neuritic plaques) and reveals the existence of a subset of plaques with a profile similar to vascular deposits. Additionally, our results show that diffuse plaques in AD brains may contain Abeta17-X peptides as its principal component. EM5 may be a useful tool in research both on human and transgenic mice tissue that may aid in the study of molecular heterogeneity of plaques in AD.

We report a SUNCT patient who showed both a precipitation and worsening of symptomatic periods after treatment with L-type calcium channel blockers. This pharmacological response may provide us with important clues for understanding the pathophysiology of SUNCT, and hopefully to find a remedy for the victims of this syndrome. This observation could also support a verapamil trial in SUNCT patients as a precipitating of attacks.

Amyloid beta protein deposition in cortical and leptomeningeal vessels, causing the most common type of cerebral amyloid angiopathy, is found in sporadic and familial Alzheimer's disease (AD) and is the principal feature in the hereditary cerebral hemorrhage with amyloidosis, Dutch type. The presence of the Apolipopriotein E (APOE)-epsilon4 allele has been implicated as a risk factor for AD and the development of cerebral amyloid angiopathy in AD. We report clinical, pathological and biochemical studies on two APOE-epsilon4 homozygous subjects, who had senile dementia and whose main neuropathological feature was a severe and diffuse amyloid angiopathy associated with perivascular tau neurofibrillary pathology. Amyloid beta protein and ApoE immunoreactivity were observed in leptomeningeal vessels as well as in medium-sized and small vessels and capillaries in the parenchyma of the neocortex, hippocampus, thalamus, cerebellum, midbrain, pons, and medulla. The predominant peptide form of amyloid beta protein was that terminating at residue Val40, as determined by immunohistochemistry, amino acid sequence and mass spectrometry analysis. A crown of tau-immunopositive cell processes was consistently present around blood vessels. DNA sequence analysis of the Amyloid Precursor Protein gene and Presenilin-1 (PS-1) gene revealed no mutations. In these APOE-epsilon4 homozygous patients, the pathological process differed from that typically seen in AD in that they showed a heavy burden of perivascular tau-immunopositive cell processes associated with severe amyloid beta protein angiopathy, neurofibrillary tangles, some cortical Lewy bodies and an absence of neuritic plaques. These cases emphasize the concept that tau deposits may be pathogenetically related to amyloid beta protein deposition.

We have investigated the proteolytic cleavage of the cellular (PrPC) and pathological (PrPSc) isoforms of the human prion protein (PrP) in normal and prion-affected brains and in tonsils and platelets from neurologically intact individuals. The various PrP species were resolved after deglycosylation according to their electrophoretic mobility, immunoreactivity, Sarkosyl solubility, and, as a novel approach, resistance to endogenous proteases. First, our data show that PrPC proteolysis in brain originates amino-truncated peptides of 21 to 22 and 18 (C1) kd that are similar in different regions and are not modified by the PrP codon 129 genotype, a polymorphism that affects the expression of prion disorders. Second, this proteolytic cleavage of PrPC in brain is blocked by inhibitors of metalloproteases. Third, differences in PrPC proteolysis, and probably in Asn glycosylation and glycosylphosphatidylinositol anchor composition, exist between neural and non-neural tissues. Fourth, protease-resistant PrPSc cores in sporadic Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker F198S disease brains all have an intact C1 cleavage site (Met111-His112), which precludes disruption of a domain associated with toxicity and fibrillogenesis. Fifth, the profile of endogenous proteolytic PrPSc peptides is characteristic of each disorder studied, thus permitting the molecular classification of these prion diseases without the use of proteinase K and even a recognition of PrPSc heterogeneity within type 2 CJD patients having different codon 129 genotype and neuropathological phenotype. This does not exclude the role of additional factors in phenotypic expression; in particular, differences in glycosylation that may be especially relevant in the new variant CJD. Proteolytic processing of PrP may play an important role in the neurotropism and phenotypic expression of prion diseases, but it does not appear to participate in disease susceptibility.