Liquid Biopsy in Alzheimer's Disease Patients Reveals Epigenetic Changes in the PRLHR Gene.

In recent years, new DNA methylation variants have been reported in genes biologically relevant to Alzheimer's disease (AD) in human brain tissue. However, this AD-specific epigenetic information remains brain-locked and unreachable during patients' lifetimes. In a previous methylome performed in the hippocampus of 26 AD patients and 12 controls, we found higher methylation levels in AD patients in the promoter region of PRLHR, a gene involved in energy balance regulation. Our aim was to further characterize PRLHR's role in AD and to evaluate if the liquid biopsy technique would provide life access to this brain information in a non-invasive way. First, we extended the methylation mapping of PRLHR and validated previous methylome results via bisulfite cloning sequencing. Next, we observed a positive correlation between PRLHR methylation levels and AD-related neuropathological changes and a decreased expression of PRLHR in AD hippocampus. Then, we managed to replicate the hippocampal methylation differences in plasma cfDNA from an additional cohort of 35 AD patients and 35 controls. The isolation of cfDNA from the plasma of AD patients may constitute a source of potential epigenetic biomarkers to aid AD clinical management.

Association of Blood-Based DNA Methylation Markers With Late-Onset Alzheimer Disease: A Potential Diagnostic Approach.

BACKGROUND AND OBJECTIVES: There is an urgent need to identify novel noninvasive biomarkers for Alzheimer disease (AD) diagnosis. Recent advances in blood-based measurements of phosphorylated tau (pTau) species are promising but still insufficient to address clinical needs. Epigenetics has been shown to be helpful to better understand AD pathogenesis. Epigenetic biomarkers have been successfully implemented in other medical disciplines, such as oncology. The objective of this study was to explore the diagnostic accuracy of a blood-based DNA methylation marker panel as a noninvasive tool to identify patients with late-onset Alzheimer compared with age-matched controls. METHODS: A case-control study was performed. Blood DNA methylation levels at 46 cytosine-guanine sites (21 genes selected after a comprehensive literature search) were measured by bisulfite pyrosequencing in patients with "probable AD dementia" following National Institute on Aging and the Alzheimer's Association guidelines (2011) and age-matched and sex-matched controls recruited at Neurology Department-University Hospital of Navarre, Spain, selected by convenience sampling. Plasma pTau181 levels were determined by Simoa technology. Multivariable logistic regression analysis was performed to explore the optimal model to discriminate patients with AD from controls. Furthermore, we performed a stratified analysis by sex. RESULTS: The final study cohort consisted of 80 patients with AD (age: median [interquartile range] 79 [11] years; 58.8% female) and 100 cognitively healthy controls (age 77 [10] years; 58% female). A panel including DNA methylation levels at NXN, ABCA7, and HOXA3 genes and plasma pTau181 significantly improved (area under the receiver operating characteristic curve 0.93, 95% CI 0.89-0.97) the diagnostic performance of a single pTau181-based model, adjusted for age, sex, and APOE ɛ4 genotype. The sensitivity and specificity of this panel were 83.30% and 90.00%, respectively. After sex-stratified analysis, HOXA3 DNA methylation levels showed consistent association with AD. DISCUSSION: These results highlight the potential translational value of blood-based DNA methylation biomarkers for noninvasive diagnosis of AD. REGISTRATION INFORMATION: Research Ethics Committee of the University Hospital of Navarre (PI17/02218).

circRNA from APP Gene Changes in Alzheimer's Disease Human Brain.

Alzheimer's disease (AD) is the most common cause of age-related dementia. Amyloid precursor protein (APP) is the precursor of Aß peptides, and its role in AD has been widely investigated. Recently, it has been reported that a circular RNA (circRNA) originated from APP gene can serve as a template for Aß synthesis, postulating it as an alternative pathway for the Aß biogenesis. Moreover, circRNAs play important roles in brain development and in neurological diseases. Therefore, our aim was to study the expression of a circAPP (hsa_circ_0007556) and its linear cognate in AD human entorhinal cortex, a brain region most vulnerable to AD pathology. First, we confirmed the presence of circAPP (hsa_circ_0007556) in human entorhinal cortex samples using RT-PCR and Sanger sequencing of PCR products. Next, a 0.49-fold decrease in circAPP (hsa_circ_0007556) levels was observed in entorhinal cortex of AD cases compared to controls (p-value < 0.05) by qPCR. In contrast, APP mRNA expression did not show changes in the entorhinal cortex between AD cases and controls (Fold-change = 1.06; p-value = 0.81). A negative correlation was found between Aß deposits and circAPP (hsa_circ_0007556) and APP expression levels (Rho Spearman = -0.56, p-value < 0.001 and Rho Spearman = -0.44, p-values < 0.001, respectively). Finally, by using bioinformatics tools, 17 miRNAs were predicted to bind circAPP (hsa_circ_0007556), and the functional analysis predicted that they were involved in some pathways, such as the Wnt-signaling pathway (p = 3.32 × 10-6). Long-term potentiation (p = 2.86 × 10-5), among others, is known to be altered in AD. To sum up, we show that circAPP (hsa_circ_0007556) is deregulated in the entorhinal cortex of AD patients. These results add to the notion that circAPP (hsa_circ_0007556) could be playing a role in the pathogenesis of AD disease.

Is the Phenotype Designation by PSP-MDS Criteria Stable Throughout the Disease Course and Consistent With Tau Distribution?

INTRODUCTION: The MDS-PSP criteria have shown high sensitivity for the PSP diagnosis, but do not discriminate the phenotype diversity. Our purpose was to search for anatomopathological differences among PSP phenotypes resulting from the application of the MDS-PSP criteria comparing with the previous ones. METHODS: Thirty-four PSP cases from a single brain bank were retrospectively classified according to the criteria used by Respondek et al. in 2014 and the PSP-MDS criteria at 3 years (MDS-3y), 6 years (MDS-6y) and at the last clinical evaluation before death (MDS-last). Semiquantitative measurement of total, cortical and subcortical tau load was compared. For comparative analysis, PSP-Richardson syndrome and PSP postural instability were grouped (PSP-RS/PI) as well as the PSP atypical cortical phenotypes (PSP-Cx). RESULTS: Applying the Respondek's criteria, PSP phenotypes were distributed as follow: 55.9% PSP-RS/PI, 26.5% PSP-Cx, 11.8% PSP-Parkinsonism (PSP-P), and 5.9% PSP-Cerebellum. PSP-RS/PI and PSP-Cx had a higher total tau load than PSP-P; PSP-Cx showed a higher cortical tau load than PSP-RS/PI and PSP-P; and PSP-RS/PI had a higher subcortical tau load than PSP-P. Applying the MDS-3y, MDS-6y and MDS-last criteria; the PSP-RS/PI group increased (67.6, 70.6 and 70.6% respectively) whereas the PSP-Cx group decreased (8.8, and 8.8 and 11.8%). Then, only differences in total and subcortical tau burden between PSP-RS/PI and PSP-P were observed. INTERPRETATION: After the retrospective application of the new MDS-PSP criteria, total and subcortical tau load is higher in PSP-RS/PI than in PSP-P whereas no other differences in tau load between phenotypes were found, as a consequence of the loss of phenotypic diversity.

Gender-Dependent Deregulation of Linear and Circular RNA Variants of HOMER1 in the Entorhinal Cortex of Alzheimer's Disease.

The HOMER1 gene is involved in synaptic plasticity, learning and memory. Recent studies show that circular RNA derived from HOMER1 (circHOMER1) expression is altered in some Alzheimer's disease (AD) brain regions. In addition, HOMER1 messenger (mRNA) levels have been associated with ß-Amyloid (Aß) deposits in brain cortical regions. Our aim was to measure the expression levels of HOMER1 circRNAs and their linear forms in the human AD entorhinal cortex. First, we showed downregulation of HOMER1B/C and HOMER1A mRNA and hsa_circ_0006916 and hsa_circ_0073127 levels in AD female cases compared to controls by RT-qPCR. A positive correlation was observed between HOMER1B/C, HOMER1A mRNA, and hsa_circ_0073128 with HOMER1B/C protein only in females. Global average area of Aß deposits in entorhinal cortex samples was negatively correlated with HOMER1B/C, HOMER1A mRNA, and hsa_circ_0073127 in both genders. Furthermore, no differences in DNA methylation were found in two regions of HOMER1 promoter between AD cases and controls. To sum up, we demonstrate that linear and circular RNA variants of HOMER1 are downregulated in the entorhinal cortex of female patients with AD. These results add to the notion that HOMER1 and its circular forms could be playing a female-specific role in the pathogenesis of AD.

Early epigenetic changes of Alzheimer's disease in the human hippocampus.

The discovery of new biomarkers would be very valuable to improve the detection of early Alzheimer's disease (AD). DNA methylation marks may serve as epigenetic biomarkers of early AD. Here we identified epigenetic marks that are present in the human hippocampus from the earliest stages of AD. A previous methylome dataset of the human AD hippocampus was used to select a set of eight differentially methylated positions (DMPs) since early AD stages. Next, bisulphite pyrosequencing was performed in an expanded homogeneous cohort of 18 pure controls and 35 hippocampal samples with neuropathological changes of pure AD. Correlation between DNA methylation levels in DMPs and phospho-tau protein burden assessed by immunohistochemistry in the hippocampus was also determined. We found four DMPs showing higher levels of DNA methylation at early AD stages compared to controls, involving ELOVL2, GIT1/TP53I13 and the histone gene locus at chromosome 6. DNA methylation levels assessed by bisulphite pyrosequencing correlated with phospho-tau protein burden for ELOVL2 and HIST1H3E/HIST1H3 F genes. In this discovery study, a set of four epigenetic marks of early AD stages have been identified in the human hippocampus. It would be worth studying in-depth the specific pathways related to these epigenetic marks. These early alterations in DNA methylation in the AD hippocampus could be regarded as candidate biomarkers to be explored in future translational studies. ABBREVIATIONS: AD: Alzheimer's disease; DMPs: Differentially methylated positions; CSF: Cerebrospinal fluid; ßA42: ß-amyloid 42; PET: positron emission tomography; 5mC: 5-methyl cytosine; CpG: cytosine-guanine dinucleotides; ANK1: ankyrin-1; BIN1: amphiphysin II; p-tau: hyperphosphorylated tau; CERAD: Consortium to Establish A Registry for Alzheimer's Disease; SD: standard deviation; ANOVA: one-way analysis of variance; VLCFAs: very long-chain fatty acids; DHA: docosahexaenoic acid; mTOR: mechanistic target of rapamycin.

Microglia-Related Gene Triggering Receptor Expressed in Myeloid Cells 2 (TREM2) Is Upregulated in the Substantia Nigra of Progressive Supranuclear Palsy.

BACKGROUND: The role of the microglia-related gene triggering receptor expressed in myeloid cells 2 (TREM2) in primary tauopathies, such as progressive supranuclear palsy (PSP), still remains unclear. OBJECTIVES: The objective of this study was to profile overall and transcript-specific TREM2 expression levels in the substantia nigra (SN) of PSP patients and controls. METHODS: SN samples from neuropathologically confirmed PSP cases (n = 24) and controls (n = 14) were used to measure TREM2 and TREM2-modulating gene Membrane-spanning 4-domains subfamily A member 4A (MS4A4A) mRNA levels by real-time quantitative polymerase chain reaction. Correlation with hyperphosphorylated tau protein burden was assessed. RESULTS: Overall TREM2 and each of the 3 TREM2 transcripts mRNA levels were significantly increased in the SN of PSP cases versus controls. TREM2 mRNA levels positively correlated with hyperphosphorylated tau burden in SN, specifically in neurons. The MS4A4A gene was also upregulated in PSP patients versus controls. CONCLUSIONS: These results add evidence to the involvement of microglia in the disease process of PSP. These findings support the idea that different tauopathies may share common patterns of deregulation in innate immune molecular pathways. © 2020 International Parkinson and Movement Disorder Society.

DNA methylation signature of human hippocampus in Alzheimer's disease is linked to neurogenesis.

BACKGROUND: Drawing the epigenome landscape of Alzheimer's disease (AD) still remains a challenge. To characterize the epigenetic molecular basis of the human hippocampus in AD, we profiled genome-wide DNA methylation levels in hippocampal samples from a cohort of pure AD patients and controls by using the Illumina 450K methylation arrays. RESULTS: Up to 118 AD-related differentially methylated positions (DMPs) were identified in the AD hippocampus, and extended mapping of specific regions was obtained by bisulfite cloning sequencing. AD-related DMPs were significantly correlated with phosphorylated tau burden. Functional analysis highlighted that AD-related DMPs were enriched in poised promoters that were not generally maintained in committed neural progenitor cells, as shown by ChiP-qPCR experiments. Interestingly, AD-related DMPs preferentially involved neurodevelopmental and neurogenesis-related genes. Finally, InterPro ontology analysis revealed enrichment in homeobox-containing transcription factors in the set of AD-related DMPs. CONCLUSIONS: These results suggest that altered DNA methylation in the AD hippocampus occurs at specific regulatory regions crucial for neural differentiation supporting the notion that adult hippocampal neurogenesis may play a role in AD through epigenetic mechanisms.

Hippocampal LMNA Gene Expression is Increased in Late-Stage Alzheimer's Disease.

Lamins are fibrillary proteins that are crucial in maintaining nuclear shape and function. Recently, B-type lamin dysfunction has been linked to tauopathies. However, the role of A-type lamin in neurodegeneration is still obscure. Here, we examined A-type and B-type lamin expression levels by RT-qPCR in Alzheimer's disease (AD) patients and controls in the hippocampus, the core of tau pathology in the brain. LMNA, LMNB1, and LMNB2 genes showed moderate mRNA levels in the human hippocampus with highest expression for the LMNA gene. Moreover, LMNA mRNA levels were increased at the late stage of AD (1.8-fold increase; p-value < 0.05). In addition, a moderate positive correlation was found between age and LMNA mRNA levels (Pearson's r = 0.581, p-value = 0.018) within the control hippocampal samples that was not present in the hippocampal samples affected by AD. A-type and B-type lamin genes are expressed in the human hippocampus at the transcript level. LMNA mRNA levels are up-regulated in the hippocampal tissue in late stages of AD. The effect of age on increasing LMNA expression levels in control samples seems to be disrupted by the development of AD pathology.

PLD3 epigenetic changes in the hippocampus of Alzheimer's disease.

BACKGROUND: Whole-exome sequencing has revealed a rare missense variant in PLD3 gene (rs145999145) to be associated with late onset Alzheimer's disease (AD). Nevertheless, the association remains controversial and little is known about the role of PLD3 in AD. Interestingly, PLD3 encodes a phospholipase that may be involved in amyloid precursor protein (APP) processing. Our aim was to gain insight into the epigenetic mechanisms regulating PLD3 gene expression in the human hippocampus affected by AD. RESULTS: We assessed PLD3 mRNA expression by qPCR and protein levels by Western blot in frozen hippocampal samples from a cohort of neuropathologically confirmed pure AD cases and controls. Next, we profiled DNA methylation at cytosine-phosphate-guanine dinucleotide (CpG) site resolution by pyrosequencing and further validated results by bisulfite cloning sequencing in two promoter regions of the PLD3 gene. A 1.67-fold decrease in PLD3 mRNA levels (p value < 0.001) was observed in the hippocampus of AD cases compared to controls, and a slight decrease was also found by Western blot at protein level. Moreover, PLD3 mRNA levels inversely correlated with the average area of ß-amyloid burden (tau-b = - 0,331; p value < 0.01) in the hippocampus. A differentially methylated region was identified within the alternative promoter of PLD3 gene showing higher DNA methylation levels in the AD hippocampus compared to controls (21.7 ± 4.7% vs. 18.3 ± 4.8%; p value < 0.05). CONCLUSIONS: PLD3 gene is downregulated in the human hippocampus in AD cases compared to controls. Altered epigenetic mechanisms, such as differential DNA methylation within an alternative promoter of PLD3 gene, may be involved in the pathological processes of AD. Moreover, PLD3 mRNA expression inversely correlates with hippocampal ß-amyloid burden, which adds evidence to the hypothesis that PLD3 protein may contribute to AD development by modifying APP processing.

TREM2 upregulation correlates with 5-hydroxymethycytosine enrichment in Alzheimer's disease hippocampus.

BACKGROUND: Recent genome-wide association studies revealed TREM2 rs75932628-T variant to be associated with Alzheimer's disease (AD) and other neurodegenerative diseases. However, the role that TREM2 plays in sporadic AD is largely unknown. Our aim was to assess messenger RNA (mRNA) expression levels and DNA methylation profiling of TREM2 in human hippocampus in AD brain. We measured TREM2 mRNA levels in the hippocampus in a cohort of neuropathologically confirmed controls and pure AD cases showing no other protein deposits than ß-amyloid and phosphorylated tau. We also examined DNA methylation levels in the TREM2 transcription start site (TSS)-associated region by bisulfite cloning sequencing and further extended the study by measuring 5-hydroxymethycytosine (5hmC) enrichment at different regions of TREM2 by 5hmC DNA immunoprecipitation combined with real-time qPCR. RESULTS: A 3.4-fold increase in TREM2 mRNA levels was observed in the hippocampus of AD cases compared to controls (p = 1.1E-05). Interestingly, TREM2 methylation was higher in AD cases compared to controls (76.2 % ± 15.5 versus 57.9 % ± 17.1; p = 0.0016). Moreover, TREM2 mRNA levels in the AD hippocampus correlated with enrichment in 5hmC at the TREM2 gene body (r = 0.771; p = 0.005). CONCLUSIONS: TREM2 mRNA levels are increased in the human hippocampus in AD cases compared to controls. DNA methylation, and particularly 5hmC, may be involved in regulating TREM2 mRNA expression in the AD brain. Further studies are guaranteed to investigate in depth the role of 5hmC in AD and other neurodegenerative disorders.

CRTC1 gene is differentially methylated in the human hippocampus in Alzheimer's disease.

BACKGROUND: CRTC1 (CREB regulated transcription coactivator 1) gene plays a role in synaptic plasticity, learning and long-term memory formation in the hippocampus. Recently, CRTC1 has been shown to be downregulated in Alzheimer's disease (AD). Nevertheless, the mechanisms underlying CRTC1 dysregulation in AD remain unclear. METHODS: To understand better the epigenetic mechanisms regulating CRTC1 expression that may be altered in AD, we profiled DNA methylation at CpG site resolution by bisulfite cloning sequencing in two promoter regions (referred to as Prom1 and Prom2) of the CRTC1 gene in human hippocampus from controls and AD cases. Next, we correlated DNA methylation levels with AD-related pathology, i.e., ß-amyloid and phosphorylated-tau (p-tau) burden and also measured CRTC1 mRNA levels by RT-qPCR. RESULTS: Methylation levels were lower in AD cases as compared to controls within both promoter regions (Prom1: 0.95% vs. 5%, p-value < 0.01 and Prom2: 2.80% vs. 17.80%, p-value < 0.001). Interestingly, CRTC1 methylation levels inversely correlated with AD-related neuropathological changes, particularly with p-tau deposition (rSpearman = -0.903, p < 0.001). Moreover, a 1.54-fold decrease in CRTC1 mRNA levels was observed in hippocampus of AD cases compared to controls (p < 0.05) supporting the notion that CRTC1 is downregulated in the AD hippocampus. CONCLUSIONS: DNA methylation levels within two distinct promoter regions of the CRTC1 gene were decreased in human hippocampus affected by AD compared with controls and methylation within Prom1 showed a strong inverse correlation with p-tau deposition. Further studies are guaranteed to elucidate the precise role that CRTC1 methylation plays in AD pathophysiology.

Midbrain catecholaminergic neurons co-express α-synuclein and tau in progressive supranuclear palsy.

OBJECTIVE: To analyze the frequency and distribution of α-synuclein deposits in progressive supranuclear palsy (PSP). METHODS: The brains of 25 cases of pathologically confirmed PSP were evaluated with immunohistochemistry for α-synuclein and tau. Multiple immunofluorescent stains were applied to analyze the expression of tau and α-synuclein aggregates in catecholaminergic neurons. Patients' clinical symptoms were retrospectively recorded. RESULTS: Deposits α-synuclein in the form of typical Lewy bodies (LBs) were only found in two PSP cases (8%) that fulfilled the clinical subtype of PSP known as Richardson's syndrome (RS). LBs were present in the locus ceruleus (LC), substantia nigra pars compacta (SNc), basal forebrain, amygdala and cingulated cortex in a distribution mimicking that of Parkinson's disease (PD). Triple-immunolabeling revealed co-expression of α-synuclein and tau proteins in some tyrosine hydroxilase (TH)-positive neurons of the LC and SNc. CONCLUSIONS: There is no apparent clinical correlation between the presence of LBs in PSP. Tau protein co-aggregate with α-synuclein in catecholaminergic neurons of PSP brains suggesting a synergistic interaction between the two proteins. This is in keeping with the current view of neurodegenerative disorders as "misfolded protein diseases".

Estado epiléptico eléctrico durante el sueño: estudio retrospectivo multicéntrico de 29 casos / Electrical status epilepticus during sleep: a retrospective multi-centre study of 29 cases

Introducción. El estado epiléptico eléctrico durante el sueño (ESES) es un síndrome epiléptico caracterizado por la presencia de descargas epilépticas tipo punta-onda lenta de manera muy persistente durante el sueño no REM. En la actualidad, el manejo de esta patología es heterogéneo y no hay estudios controlados con los tratamientos utilizados, ni se ha comprobado si éstos mejoran la evolución cognitiva de los pacientes. Pacientes y métodos. Se revisan los pacientes diagnosticados de ESES durante 15 años en cuatro centros hospitalarios, se recoge la presentación clínica, el manejo terapéutico y la evolución clínica, y se compara con la bibliografía. Resultados. Se seleccionaron 29 pacientes con ESES, 20 de ellos idiopático y 26 de ellos generalizado. Los fármacos con los que se consiguió mayor control de la actividad eléctrica fueron los corticoides/hormona adrenocorticotropa (ACTH), el clobazam y el levetiracetam. La mediana de duración del ESES en los casos primarios fue de seis meses, y en los secundarios, el doble. El 45% de los pacientes mantuvo un cociente intelectual normal y un 40% presentó en la evolución discapacidad cognitiva de diferente grado. Conclusiones. El pronóstico neuropsicológico evolutivo suele ser desfavorable y la evolución cognitiva parece estar en relación con la duración del ESES y el área donde esté concentrada la actividad epiléptica, lo que sugiere que el mal pronóstico, si se trata precozmente, se puede evitar. Los antiepilépticos más frecuentemente utilizados son el ácido valproico, la etosuximida y el levetiracetam, y en nuestra muestra también se utilizaron con frecuencia el clobazam y la lamotrigina. Los fármacos más eficaces para el control del ESES fueron los corticoides/ACTH, el clobazam y el levetiracetam (AU)

Introduction. Electrical status epilepticus during sleep (ESES) is an epileptic syndrome characterised by the presence of very persistent slow spike-wave-type epileptic discharges during non-REM sleep. The management of this pathology, today, is heterogeneous and no controlled studies have been conducted with the treatments employed; similarly, whether or not they improve patients’ cognitive development or not has still to be determined. atients and methods. A review was carried out of the patients diagnosed with ESES at four hospitals over a period of 15 years; data concerning their clinical presentation, therapeutic management and clinical course were collected and compared with the literature. Results. Altogether 29 patients with ESES were detected, 20 of them idiopathic and 26 generalised. The drugs with which the greatest control of the electrical activity was achieved were corticoids/adrenocorticotropic hormone (ACTH), clobazam and levetiracetam. In the primary cases ESES lasted an average of six months and the duration was twice that time in the secondary cases. Findings showed that the intelligence quotient remained normal in 45% of patients and 40% presented differing degrees of cognitive disability in the course of the pathology. Conclusions. The developmental neuropsychological prognosis is usually unfavourable and the cognitive development seems to be related with the duration of ESES and the area where the epileptic activity is concentrated, which suggests that the poor prognosis can be avoided if treatment is established at an early stage. The antiepileptic drugs that are most commonly used are valproic acid, ethosuximide and levetiracetam, and in our milieu clobazam and lamotrigine were commonly employed. The most effective drugs for controlling ESES were corticoids/ACTH, clobazam and levetiracetam (AU)

[Electrical status epilepticus during sleep: a retrospective multi-centre study of 29 cases]. / Estado epiléptico eléctrico durante el sueño: estudio retrospectivo multicéntrico de 29 casos.

INTRODUCTION: Electrical status epilepticus during sleep (ESES) is an epileptic syndrome characterised by the presence of very persistent slow spike-wave-type epileptic discharges during non-REM sleep. The management of this pathology, today, is heterogeneous and no controlled studies have been conducted with the treatments employed; similarly, whether or not they improve patients' cognitive development or not has still to be determined. PATIENTS AND METHODS: A review was carried out of the patients diagnosed with ESES at four hospitals over a period of 15 years; data concerning their clinical presentation, therapeutic management and clinical course were collected and compared with the literature. RESULTS: Altogether 29 patients with ESES were detected, 20 of them idiopathic and 26 generalised. The drugs with which the greatest control of the electrical activity was achieved were corticoids/adrenocorticotropic hormone (ACTH), clobazam and levetiracetam. In the primary cases ESES lasted an average of six months and the duration was twice that time in the secondary cases. Findings showed that the intelligence quotient remained normal in 45% of patients and 40% presented differing degrees of cognitive disability in the course of the pathology. CONCLUSIONS: The developmental neuropsychological prognosis is usually unfavourable and the cognitive development seems to be related with the duration of ESES and the area where the epileptic activity is concentrated, which suggests that the poor prognosis can be avoided if treatment is established at an early stage. The antiepileptic drugs that are most commonly used are valproic acid, ethosuximide and levetiracetam, and in our milieu clobazam and lamotrigine were commonly employed. The most effective drugs for controlling ESES were corticoids/ACTH, clobazam and levetiracetam.

TITLE: Estado epileptico electrico durante el sueño: estudio retrospectivo multicentrico de 29 casos.Introduccion. El estado epileptico electrico durante el sueño (ESES) es un sindrome epileptico caracterizado por la presencia de descargas epilepticas tipo punta-onda lenta de manera muy persistente durante el sueño no REM. En la actualidad, el manejo de esta patologia es heterogeneo y no hay estudios controlados con los tratamientos utilizados, ni se ha comprobado si estos mejoran la evolucion cognitiva de los pacientes. Pacientes y metodos. Se revisan los pacientes diagnosticados de ESES durante 15 años en cuatro centros hospitalarios, se recoge la presentacion clinica, el manejo terapeutico y la evolucion clinica, y se compara con la bibliografia. Resultados. Se seleccionaron 29 pacientes con ESES, 20 de ellos idiopatico y 26 de ellos generalizado. Los farmacos con los que se consiguio mayor control de la actividad electrica fueron los corticoides/hormona adrenocorticotropa (ACTH), el clobazam y el levetiracetam. La mediana de duracion del ESES en los casos primarios fue de seis meses, y en los secundarios, el doble. El 45% de los pacientes mantuvo un cociente intelectual normal y un 40% presento en la evolucion discapacidad cognitiva de diferente grado. Conclusiones. El pronostico neuropsicologico evolutivo suele ser desfavorable y la evolucion cognitiva parece estar en relacion con la duracion del ESES y el area donde este concentrada la actividad epileptica, lo que sugiere que el mal pronostico, si se trata precozmente, se puede evitar. Los antiepilepticos mas frecuentemente utilizados son el acido valproico, la etosuximida y el levetiracetam, y en nuestra muestra tambien se utilizaron con frecuencia el clobazam y la lamotrigina. Los farmacos mas eficaces para el control del ESES fueron los corticoides/ACTH, el clobazam y el levetiracetam.