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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.

Resumen Objetivo La estereoelectroencefalografia (E-EEG) es una tecnica de evaluacion prequirurgica en pacientes con epilepsia focal refractaria de dificil localizacion (EFRDL) que permite explorar con electrodos profundos regiones cerebrales de dificil acceso y la profundidad de la corteza. Esta tecnica, en auge en centros internacionales, apenas se ha desarrollado en Espana. Describimos nuestra experiencia con la E-EEG en la evaluacion de pacientes con EFRDL. Material y metodos En los ultimos 8 anos, 71 pacientes con EFRDL fueron evaluados con E-EEG en nuestro centro. Analizamos prospectivamente los resultados obtenidos en la localizacion, los resultados quirurgicos y las complicaciones asociadas a la tecnica. Resultados La mediana de edad fue de 30 anos (rango 4-59 anos), 27 pacientes eran mujeres (38%). La RM cerebral fue negativa en 45 pacientes (63,4%). Se implantaron 627 electrodos (mediana de 9 electrodos por paciente, rango 1-17), con un 50% de implantaciones multilobares. En 64 (90,1%) pacientes se localizo la zona epileptogena (ZE), siendo extratemporal o temporal plus en el 66% de los casos. En 55 pacientes de los 61 intervenidos el seguimiento fue superior al ano: en el ultimo ano de seguimiento 32/55 pacientes (58,2%) estaban libres de crisis (Engel I) siendo los resultados favorables (Engel I-II) en el 76,4% de las intervenciones. Tres pacientes (4,2%) presentaron una hemorragia cerebral. Conclusion La E-EEG permite localizar la ZE en pacientes en quienes anteriormente no era posible, ofreciendo unos resultados quirurgicos superiores a otras tecnicas invasivas y una tasa de complicaciones relativamente baja.

Patients with antibody deficiency disorders, such as common variable immunodeficiency (CVID), or secondary immunodeficiency (SIDs) to B-cell lymphoproliferative disorder (B-CLPD), are two vulnerable groups of developing severe or chronic form of coronavirus disease caused by SARS-CoV-2 (COVID-19). Data on adaptive immune responses against SARS-CoV-2 is well described in healthy donors, but still limited in patients with antibody deficiency of different cause. Herein, we analyzed Spike-specific IFN-γ and anti-Spike IgG antibody responses at 3 and 6 months after exposure to SARS-CoV-2 derived from vaccination and infection in two cohorts of immunodeficient patients (CVID vs. SID) compared to healthy controls (HC). Baseline cellular responses before vaccine administration were measured in 10 CVID patients. Adequate specific cellular responses was observed in 18 out of 20 (90%) CVID patients, in 14 out of 20 (70%) out of 20 SID patients and in 74 out of 81 (96%) HC. Specific IFN-γ response was significantly higher in HC respect to CVID (1,908.5 mUI/ml versus 1,694.1 mUI/ml; p = 0.005). Pre-vaccine anti-SARS-CoV-2 cellular responses were detectable in 4 out of 10 CVID patients, who had COVID-19 prior to vaccination, noticing an increase in cellular responses after vaccination (p p = 0.040), without significant differences between CVID and HC (p = 0.123) and between CVID and SID (p = 0.683). High proportions of CVID and SID patients showed adequate specific cellular responses to S1 neoantigen, with divergence between cellular and humoral immune responses in CVID and SID patients. Our data might support the relevance of these immunological studies to determine the correlate of protection to severe disease and for deciding the need of additional boosters. Follow-up studies are required to evaluate the duration and variability of the immune response to COVID-19 vaccination or infection.

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.

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 analysed 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. Resumen: Introducción: La utilidad del Inventario Multifásico de Personalidad de Minnesota 2 (MMPI-2) para el diagnóstico de crisis no epilépticas psicógenas (CNEP) es controvertida. Este estudio analiza la validez de las escalas clínicas y, a diferencia de trabajos previos, las escalas de contenido. Métodos: Estudio transversal de 209 pacientes atendidos en la unidad de epilepsia. Se realizó un análisis de regresión logística tomando como prueba de referencia la vídeo-electroencefalografía y como variables predictoras edad, sexo, cociente intelectual y las escalas clínicas (modelo A) o de contenido (modelo B) del MMPI-2. Los modelos se seleccionaron según el índice de Aikake y se compararon con el test de DeLong. Resultados: Se analizó a 37 pacientes con CNEP solas o combinadas con crisis epilépticas y 172 pacientes solo con crisis epilépticas. El modelo A, compuesto por sexo, hipocondría (Hs) y paranoia (Pa), mostró una sensibilidad del 77,1%, una especificidad del 76,8%, un porcentaje de clasificación correcta del 76,8% y un área bajo la curva (AUC) de 0,836 para el diagnóstico de CNEP. El modelo B, compuesto por sexo, preocupación por la salud (HEA) y miedos (FRS), mostró una sensibilidad del 65,7%, una especificidad del 78,0%, un porcentaje de clasificación correcta del 75,9% y un AUC de 0,840. El test de DeLong no detectó diferencias significativas. Conclusiones: El MMPI-2 presenta una validez moderada para el diagnóstico de CNEP en los pacientes remitidos a una unidad de epilepsia. El uso de las escalas de contenido no mejora de forma significativa los resultados obtenidos con las escalas clínicas. Keywords: Multiphasic Personality Inventory Minnesota 2, Basic scales, Content scales, Psychogenic non-epileptic seizures, Seizures, Palabras clave: Inventario Multifásico de Personalidad de Minnesota 2, Escalas básicas, Escalas de contenido, Crisis no epilépticas psicógenas, Crisis epilépticas

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

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.

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.

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.

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 3 T T1-weighted MRI files were analyzed. Regional gray matter and total intracranial volumes were calculated with a shell script (gm_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_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_extractor.

SummaryObjective 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.

Resumen: Introducción: los criterios diagnósticos actuales de la enfermedad de Creutzfeldt-Jakob (ECJ) probable incluyen la combinación de datos clínicos, electroencefalográficos y analíticos. En los últimos años se ha demostrado que la RM craneal con el uso de secuencias FLAIR y difusión (DWI) puede ser una herramienta útil en el diagnóstico de esta enfermedad. Describimos nuestra experiencia en la utilización de la DWI convencional (b: 1000 s/mm2) y DWI con valor b alto (3000 s/mm2) en el diagnóstico de la ECJ probable o definitiva. Pacientes y métodos: realizamos un análisis retrospectivo de los pacientes atendidos en nuestro hospital diagnosticados de ECJ probable o definitiva, desde el año 2002 al 2008. A todos ellos se les realizó una RM craneal con un protocolo que incluyó secuencias potenciadas en T1, T2, FLAIR y dos secuencias DWI, una con valor b convencional (1000 s/mm2) y otra con valor b alto (3000 s/mm2). Resultados: se atendieron a 7 pacientes con diagnóstico de ECJ probable o definitiva. En tres de ellos (43%) la secuencia FLAIR mostró cambios de señal compatibles con ECJ. En todos los pacientes en la secuencia DWI con valor b alto se observaron alteraciones características de la enfermedad, incluyendo dos casos (28%) en los que todas las secuencias realizadas, incluida la DWI convencional, fueron normales. Adicionalmente en los 7 casos (100%) las alteraciones radiológicas fueron más fáciles de identificar y más extensas con valores altos b de DWI. Conclusión: la utilización de un valor b alto (3000 s/mm2) en la secuencia DWI puede aumentar la sensibilidad de la RM craneal en el diagnóstico de la ECJ, permitiendo la detección de casos en los que la DWI convencional es normal. Abstract: 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 (3000 s/mm2) diffusion-weighted imaging (DWI) in patients with probable or definite CJD and compare it with standard b-value (1000 s/mm2) 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 (1000 s/mm2) DWI. In all the patients the changes were more conspicuous and extensive at high b-value DWI (b = 3000 s/mm2). 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. Palabras clave: Enfermedad de Creutzfeldt-Jakob, Rsonancia magnética cerebral, Secuencias potenciadas en difusión, DWI, Valor b, Keywords: Creutzfeldt-Jakob disease, MRI, Magnetic resonance imaging, Diffusion-weighted imaging, DWI, b value

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

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/mm2) diffusion-weighted imaging (DWI) in patients with probable or definite CJD and compare it with standard b-value (1000s/mm2) 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/mm2) DWI. In all the patients the changes were more conspicuous and extensive at high b-value DWI (b=3000s/mm2). 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. Resumen: Introducción: Los criterios diagnósticos actuales de la enfermedad de Creutzfeldt-Jakob (ECJ) probable incluyen la combinación de datos clínicos, electroencefalográficos y analíticos. En los últimos años se ha demostrado que la RM craneal con el uso de secuencias FLAIR y difusión (DWI) puede ser una herramienta útil en el diagnóstico de esta enfermedad. Describimos nuestra experiencia en la utilización de la DWI convencional (b: 1000s/mm2) y DWI con valor b alto (3000s/mm2) en el diagnóstico de la ECJ probable o definitiva. Pacientes y métodos: Realizamos un análisis retrospectivo de los pacientes atendidos en nuestro hospital diagnosticados de ECJ probable o definitiva, desde el año 2002 al 2008. A todos ellos se les realizó una RM craneal con un protocolo que incluyó secuencias potenciadas en T1, T2, FLAIR y dos secuencias DWI, una con valor b convencional (1000s/mm2) y otra con valor b alto (3000s/mm2). Resultados: Se atendieron a 7 pacientes con diagnóstico de ECJ probable o definitiva. En tres de ellos (43%) la secuencia FLAIR mostró cambios de señal compatibles con ECJ. En todos los pacientes en la secuencia DWI con valor b alto se observaron alteraciones características de la enfermedad, incluyendo dos casos (28%) en los que todas las secuencias realizadas, incluida la DWI convencional, fueron normales. Adicionalmente en los 7 casos (100%) las alteraciones radiológicas fueron más fáciles de identificar y más extensas con valores altos b de DWI. Conclusión: La utilización de un valor b alto (3000s/mm2) en la secuencia DWI puede aumentar la sensibilidad de la RM craneal en el diagnóstico de la ECJ, permitiendo la detección de casos en los que la DWI convencional es normal. Keywords: Creutzfeldt-Jakob disease, MRI, Magnetic resonance imaging, Diffusion-weighted imaging, DWI, b value, Palabras clave: Enfermedad de Creutzfeldt-Jakob, Resonancia magnética cerebral, Secuencias potenciadas en difusión, DWI, Valor b

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-Straussler-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.

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.