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Anoctamin 3 (ANO3) belongs to a family of transmembrane proteins that form phospholipid scramblases and ion channels. A large number of ANO3 variants were identified as the cause of craniocervical dystonia, but the underlying pathogenic mechanisms remain obscure. It was suggested that ANO3 variants may dysregulate intracellular Ca2+ signalling, as variants in other Ca2+ regulating proteins like hippocalcin were also identified as a cause of dystonia. In this study, we conducted a comprehensive evaluation of the clinical, radiological, and molecular characteristics of four individuals from four families who carried heterozygous variants in ANO3. The median age at follow-up was 6.6 years (ranging from 3.8 to 8.7 years). Three individuals presented with hypotonia and motor developmental delay. Two patients exhibited generalized progressive dystonia, while one patient presented with paroxysmal dystonia. Additionally, another patient exhibited early dyskinetic encephalopathy. One patient underwent bipallidal deep brain stimulation (DBS) and showed a mild but noteworthy response, while another patient is currently being considered for DBS treatment. Neuroimaging analysis of brain MRI studies did not reveal any specific abnormalities. The molecular spectrum included two novel ANO3 variants (V561L and S116L) and two previously reported ANO3 variants (A599D and S651N). As anoctamins are suggested to affect intracellular Ca2+ signals, we compared Ca2+ signalling and activation of ion channels in cells expressing wild type ANO3 and cells expressing ANO variants. Novel V561L and S116L variants were compared with previously reported A599D and S651N variants and with wtANO3 expressed in fibroblasts isolated from patients or when overexpressed in HEK293 cells. We identified ANO3 as a Ca2+-activated phospholipid scramblase that also conducts ions. Impaired Ca2+ signalling and compromised activation of Ca2+ dependent K+ channels were detected in cells expressing ANO3 variants. In the brain striatal cells of affected patients, impaired activation of KCa3.1 channels due to compromised Ca2+ signals may lead to depolarized membrane voltage and neuronal hyperexcitability and may also lead to reduced cellular viability, as shown in the present study. In conclusion, our study reveals the association between ANO3 variants and paroxysmal dystonia, representing the first reported link between these variants and this specific dystonic phenotype. We demonstrate that ANO3 functions as a Ca2+-activated phospholipid scramblase and ion channel; cells expressing ANO3 variants exhibit impaired Ca2+ signalling and compromised activation of Ca2+-dependent K+ channels. These findings provide a mechanism for the observed clinical manifestations and highlight the importance of ANO3 for neuronal excitability and cellular viability.
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Introduction: Complex cortical dysplasia with other brain malformations-7 (a.k.a. polymicrogyria) caused by mutations in TUBB2B gene is a clinically heterogeneous condition. Case report: We report two siblings with polymicrogyria. Brain MRI showed polymicrogyria, small brainstem, thin corpus callosum and fused basal ganglia. Karyotypes and chromosomal microarray analysis were normal. By whole exome sequencing, there were a de novo variant of c.728C > T (p.P243L) in both siblings and a common single nucleotide polymorphism (SNP) (c.718C > T) in both siblings and the mother. Seminal DNA analysis obtained from father was normal. Conclusion: Maternal germline mosaicism was considered because the sequencing result of the father's sperm was normal, two siblings had the same disease, and both patients and mother had the same SNP.
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Malformações do Desenvolvimento Cortical , Mosaicismo , Células Germinativas , Humanos , Malformações do Desenvolvimento Cortical/genética , Mutação , Irmãos , Tubulina (Proteína)/genéticaRESUMO
INTRODUCTION: Neurofibromatosis type 1 (NF1) is accompanied by epileptic seizures in 4-7% of patients. We examined clinical, electrophysiological, and radiological features associated with epilepsy in our NF1 series in order to identify risk factors. METHODS: We reviewed data of 641 pediatric patients with NF1 diagnosis according to National Institutes of Health (NIH) criteria in Hacettepe University records from January 2008-August 2018. Demographic features, NF1-related clinical and imaging characteristics, age at onset of epilepsy, seizure semiology, and frequency, electroencephalogram (EEG) findings, and response to treatment were noted. RESULTS: Twenty-six patients with NF1, 15 male, 11 female, had epilepsy. Age at seizure onset was 6â¯months to 13â¯years. Seizure semiology was focal with impaired awareness (nâ¯=â¯9, 34%), focal aware motor (nâ¯=â¯2, 8%), focal to bilateral tonic-clonic (nâ¯=â¯3, 12%), generalized tonic-clonic (nâ¯=â¯7, 28%), absence (nâ¯=â¯3, 12%), infantile spasms (nâ¯=â¯1), and unclassified type (nâ¯=â¯1). None had a history of status epilepticus. The EEG findings were normal for age in ten patients (38%). Others had focal (nâ¯=â¯8, 30%), generalized (nâ¯=â¯7, 27%), or multifocal (nâ¯=â¯1, 4%) discharges. On brain magnetic resonance imaging (MRI) signal intensity changes typical for NF1 (neurofibromatosis bright objects, NBOs) were the most common finding (80%), followed by normal MRI (20%). There was no relation between the localization of NBOs and discharges on EEG. Seventeen patients (65%) were seizure-free at the time of the study; 11 of them still under medication including four on multiple antiepileptic drugs. The rate of learning problems and NBO were significantly higher in patients with NF1 with epilepsy compared to those without. DISCUSSION: Epilepsy in NF1 is associated with relatively infrequent seizures and good response to treatment. Learning disorders are markedly frequent in this group, irrespective of the severity of epilepsy. The absence of correlation between the localizations of epileptiform discharges and lesions on MRI support the role of cellular or synaptic mechanisms rather than structural causes in the pathogenesis of epilepsy.
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Encéfalo/fisiopatologia , Epilepsia/fisiopatologia , Neurofibromatose 1/complicações , Adolescente , Adulto , Criança , Pré-Escolar , Eletroencefalografia/métodos , Epilepsia/etiologia , Feminino , Humanos , Deficiências da Aprendizagem/etiologia , Imageamento por Ressonância Magnética , Masculino , Estudos Retrospectivos , Fatores de Risco , Convulsões/etiologia , Convulsões/fisiopatologia , Adulto JovemAssuntos
Acidose Láctica , Beriberi , Deficiência de Tiamina , Encefalopatia de Wernicke , Humanos , Deficiência de Tiamina/complicações , Deficiência de Tiamina/diagnóstico , Encefalopatia de Wernicke/diagnóstico , Encefalopatia de Wernicke/etiologia , Encefalopatia de Wernicke/tratamento farmacológico , Acidose Láctica/etiologia , Acidose Láctica/diagnóstico , Beriberi/diagnóstico , Beriberi/complicações , Beriberi/tratamento farmacológico , Beriberi/etiologia , Masculino , Tiamina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , FemininoRESUMO
BACKGROUND: There is no certain validated electroencephalographic (EEG) parameters for outcome prediction in children with self-limited epilepsy with centrotemporal spikes. To assess the effectiveness of antiseizure medication (ASM) for seizure outcome with respect to the spike-wave index (SWI) on serial EEG recordings. METHODS: In this multicenter study, the study cohort consisted of 604 children with self-limited epilepsy with centrotemporal spikes. A data set of epilepsy centers follow-up between 2010 and 2022. The cohort was divided into 4 groups as those receiving 3 different monotherapy (carbamazepine [CBZ]/valproic acid [VPA]/levetiracetam [LEV]) and dual therapy. SWI analysis was performed with the percent of spikes in the 2-minute epoch in the 5th 6th minutes of the nonrapid eye movement sleep EEG record. The study group were also categorized according to seizure burden with seizure frequency (I) >2 seizures and (II) >5 seizures. Seizure outcome was evaluated based on the reduction in seizure frequency over 6-month periods: (1) 50% reduction and (2) seizure-free (complete response). RESULTS: ASM monotherapy was achieved in 74.5% children with VPA, CBZ, and LEV with similar rates of 85.8%, 85.7%, and 77.9%. Dual therapy was need in the 25.5% of children with SeLECT. More dual therapy was administered in children aged below 5 years with a rate of 46.2%. Earlier seizure-free achievement time was seen in children with LEV monotherapy with more complete-response rate (86.7%) compared the VPA and CBZ. CONCLUSIONS: We also determined that the children on dual therapy had more SWI clearance in the subsequent EEG recordings. The ROC curve analyses were performed to predict initial drug selection with using the SWI% might be used for the prediction of ASM type and drug selection in children.
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Epilepsia , Criança , Humanos , Epilepsia/tratamento farmacológico , Levetiracetam/uso terapêutico , Convulsões/tratamento farmacológico , Ácido Valproico , Carbamazepina/uso terapêutico , Eletroencefalografia , Benzodiazepinas , Resposta Patológica Completa , Anticonvulsivantes/uso terapêuticoRESUMO
Background: GNAO1-related disorders (GNAO1-RD) encompass a diverse spectrum of neurodevelopmental and movement disorders arising from variants in the GNAO1 gene. Dyskinetic crises, marked by sudden and intense exacerbations of abnormal involuntary movements, present a significant challenge in GNAO1-RD. Objectives: This study aimed to establish a standardized framework for understanding dyskinetic crises, addressing crucial aspects such as definition, triggers, diagnostic criteria, complications, and management strategies. Methods: A Delphi consensus process was conducted involving international experts in GNAO1-RD. The panel of thirteen experts participated in three voting rounds, discussing 90 statements generated through a literature review and clinical expertise. Results: Consensus was achieved on 31 statements, defining dyskinetic crises as abrupt, paroxysmal episodes involving distinct abnormal movements in multiple body regions, triggered by emotional stress or infections. Dyskinetic crises may lead to functional impairment and complications, emphasizing the need for prompt recognition. While individualized pharmacological recommendations were not provided, benzodiazepines and clonidine were suggested for acute crisis management. Chronic treatment options included tetrabenazine, benzodiazepines, gabapentin, and clonidine. Deep brain stimulation should be considered early in the treatment of refractory or prolonged dyskinetic crisis. Conclusion: This consensus provides a foundation for understanding and managing dyskinetic crises in GNAO1-RD for clinicians, caregivers, and researchers. The study emphasizes the importance of targeted parental and caregiver education, which enables early recognition and intervention, thereby potentially minimizing both short- and long-term complications. Future research should concentrate on differentiating dyskinetic crises from other neurological events and investigating potential risk factors that influence their occurrence and nature. The proposed standardized framework improves clinical management, stakeholder communication, and future GNAO1-RD research.
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OBJECTIVES: This study aimed to evaluate seizure semiology, electroencephalogram (EEG), magnetic resonance imaging (MRI), and genetic findings, as well as treatment choices in Rett syndrome (RTT). METHODS: A retrospective analysis was conducted on one hundred and twenty cases diagnosed with RTT with a genetic mutation. Data were obtained from nine participating centers. RESULTS: In this study, 93.3â¯% of patients were female, with typical RTT found in 70â¯% of cases. Genetic etiology revealed MECP2, FoxG1, and CDKL5 in 93.8â¯%, 2.7â¯%, and 1.8â¯% of cases, respectively. Atypical RTT clinics were observed in 50â¯% of male cases, with the first EEG being normal in atypical RTT cases (p = 0.01). Generalized tonic-clonic and myoclonic epilepsy were the most common seizure semiologies, while absence and focal epilepsy were less prevalent. Valproate, levetiracetam, lamotrigine, and clobazam were the most commonly used antiepileptic drugs, affecting the severity and frequency of seizures (p = 0.015, p=<0.001, p = 0.022, and p=<0.001, respectively). No significant differences were observed in EEG findings. The initiation of anti-seizure medications significantly altered seizure characteristics (Table 4). A ketogenic diet and vagal nerve stimulation (VNS) correlated with a 50â¯% improvement in cognitive function, while steroid treatment showed a 60â¯% improvement. Remarkably, seizures were substantially reduced after VNS application. CONCLUSION: This study underscores the importance of genetic diagnosis in RTT cases with a clinical diagnosis. These preliminary results will be further validated with the inclusion of clinically diagnosed RTT cases in our ongoing study.
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Anticonvulsivantes , Eletroencefalografia , Imageamento por Ressonância Magnética , Proteína 2 de Ligação a Metil-CpG , Síndrome de Rett , Convulsões , Humanos , Síndrome de Rett/genética , Síndrome de Rett/fisiopatologia , Feminino , Masculino , Estudos Retrospectivos , Eletroencefalografia/métodos , Criança , Imageamento por Ressonância Magnética/métodos , Pré-Escolar , Convulsões/genética , Convulsões/fisiopatologia , Anticonvulsivantes/uso terapêutico , Adolescente , Proteína 2 de Ligação a Metil-CpG/genética , Lactente , Mutação/genética , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição Forkhead/genética , Proteínas Serina-Treonina QuinasesRESUMO
Pediatric neurology is the medical subspecialty responsible for diagnosing and managing diseases and disorders of the nervous system in childhood and adolescence. In many, but not all, regions of the world, the discipline of pediatric neurology is recognized as a specialty or subspecialty of either neurology or pediatrics. Significant knowledge and competencies in this area are necessary to be effective in clinical practice. The need for this is driven by the high burden of disease from neurologic conditions in children and the effect on their families. As the first part of a multistaged project under the auspices of the International Child Neurology Association, in collaboration with key stakeholders, a survey was undertaken to establish which countries have practicing child neurologists. For those countries that have child neurologists, the survey established the number of practitioners and which countries have access to in-country child neurology training. Responses were obtained from 177 countries. Worldwide, there is a median of 0.07 and mean of 0.39 child neurologists per 100,000 population. The greatest deficits in child neurology specialists and access to training were evident in countries which fell under the World Bank rating of low-income country status (range of 0-0.008 child neurologists per 100,000 population). Seventy-three percent of low-income countries lack access to child neurologists: The majority are in the African and South-East Asia regions. For the population of 1.37 billion in the continent of Africa, there were 324 child neurologists, equating to a median of 0.01 per 100,000 population in comparison with a median of 0.59 child neurologists per 100,000 across high-income countries. Ninety-four countries had capacity to support in-country pediatric neurology training. Worldwide, there are inadequate numbers of child neurologists and a great need for increased training capacity.
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Doenças do Sistema Nervoso , Neurologia , Humanos , Criança , Neurologia/educação , Neurologistas , Inquéritos e Questionários , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/epidemiologia , Doenças do Sistema Nervoso/terapia , Educação de Pós-Graduação em MedicinaRESUMO
PURPOSE: Valproic acid (VPA) is frequently used and effective in juvenile myoclonic epilepsy (JME). Recently, levetiracetam (LEV) has been suggested as a monotherapy in JME. This study aimed to evaluate antiseizure medication (ASM) use in patients with JME. METHODS: Treatment choices in a total of 257 patients (age range 8-18 years, 152 girls, 105 boys) with JME diagnosed and treated between 2010 and 2020 were evaluated retrospectively. Seizure remission was defined as complete seizure control for at least 12 months. RESULTS: Across the study period and entire patient group, VPA was most commonly chosen as the initial ASM (50.9%), followed by LEV (44.4%), and lamotrigine (4.7%). VPA was also the most frequent first choice in the subgroup of boys (73.3%), while LEV was the commonest first choice in girls (57.9%). The sex difference regarding the ASM of the first choice was statistically significant (p<0.001). While VPA was the most frequent initial ASM in the first 5 years of the study period (2010-2015,n = 66, 64%), LEV had taken over as the most popular first ASM in the last 5 years (n = 83, 53.9%, p = 0.005). The most frequent reasons for discontinuation were inefficacy for LEV and adverse effects for VPA (p = 0.001). During follow-up, 237 patients (92.2%) were seizure-free for at least 12 months, and 159 (61.9%) were also in electrographic remission. Seizure remission occurred earlier than electroencephalographic remission (p<0.001). CONCLUSION: This study revealed that LEV has become the most frequently chosen initial ASM in the treatment of JME. Although LEV appears to have a better adverse effect profile, VPA seems more likely to be effective in achieving seizure control.
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Anticonvulsivantes/uso terapêutico , Levetiracetam/uso terapêutico , Epilepsia Mioclônica Juvenil/tratamento farmacológico , Ácido Valproico/uso terapêutico , Adolescente , Criança , Feminino , Humanos , Lamotrigina/uso terapêutico , Masculino , Estudos Retrospectivos , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Fatores Sexuais , Resultado do Tratamento , TurquiaRESUMO
OBJECTIVE: To evaluate the effectiveness and tolerability of clobazam therapy in the pediatric population in terms of seizure semiology, epileptic syndromes, and etiological subgroups. METHODS: A retrospective cohort study was conducted consisting of 1710 epileptic children from eight centers in seven geographic regions of Turkey. The initial efficacy of clobazam therapy was evaluated after three months of treatment. The long-term effectiveness of the drug, overall seizure outcomes, and overall therapeutic outcomes were evaluated during 12 months of therapy. RESULTS: Analysis of initial efficacy after the first three months of clobazam therapy showed that 320 (18.7 %) patients were seizure-free, 683 (39.9 %) had > 50 % seizure reductions, and 297 (17.4 %) had < 50 % seizure reductions. A positive response (seizure-free and >50 % seizure reduction) was determined for focal-onset (62.3 %) seizures, epileptic spasms (61.5 %), and generalized onset seisures (57.4). The highest positive response rate among the epileptic syndromes was for self-limited epilepsy with centrotemporal spikes (SeLECTS). The highest negative response rate was for developmental and/or epileptic encephalopathies (DEEs). Magnetic resonance imaging (MRI) revealed a structural etiological diagnosis in 25.8 % of the cohort. A higher positive response rate was observed at MRI in patients with sequelae lesions than in those with congenital lesions. The seizure recurrence rate was higher in the patient group with epilepsy with genetic and metabolic causes, in individuals with more than one seizure type, and in those using three or more antiseizure drugs. CONCLUSIONS: This cohort study provides additional evidence that clobazam is an effective and well-tolerable drug with a high seizure-free rate (18.7 %), a significant seizure reduction rate (57.3 %), and with excellent overall therapeutic outcomes with a low seizure relapse rate and considerable reversible benefits in the pediatric population.
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Epilepsia , Espasmos Infantis , Anticonvulsivantes/efeitos adversos , Criança , Clobazam/uso terapêutico , Estudos de Coortes , Epilepsia/diagnóstico , Humanos , Estudos Retrospectivos , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Espasmos Infantis/diagnóstico , Resultado do TratamentoRESUMO
INTRODUCTION: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by café-au-lait spots, neurofibromas, skinfold freckles, Lisch nodules, bone deformities, learning disabilities, and predisposition to neoplasms. It is caused by various mutations of the NF1 gene. Recently a 3-bp in-frame deletion in exon 17, c.2970-2972 delAAT mutation, has been associated with a milder phenotype of NF1 manifesting with pigmentary skin changes only. MATERIALS AND METHODS: We therefore analyzed 35 NF1 patients without neurofibromas, learning problems, or bone lesions (19 familial, 16 sporadic, age 7-44 years) for exon 17 mutations by DNA sequencing. RESULTS: We did not find the c.2970-2972 delAAT mutation in this group but identified two base changes in exon 17 (c.2989A>G and c.2894T>A), whether these two novel mutations are related to a mild phenotype remains to be confirmed in further studies. Our results suggest the reported phenotypic associations may not be valid for all populations.
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Éxons/genética , Mutação/genética , Neurofibromatose 1/genética , Neurofibromina 1/genética , Adolescente , Adulto , Manchas Café com Leite/complicações , Manchas Café com Leite/genética , Criança , Análise Mutacional de DNA , Saúde da Família , Feminino , Humanos , Masculino , Neurofibromatose 1/complicações , Turquia , Adulto JovemRESUMO
Diffuse alveolar damage (DAD) is one of the pathological hallmarks of acute respiratory distress syndrome (ARDS). We aimed to compare pathological findings of DAD with clinical ARDS criteria. We re-evaluated 20 patients whose clinical autopsy revealed DAD. Total 11/20 patients with DAD (55%) met the 1994 American-European Consensus Conference and 7/17 (41%) met the 2012 Berlin clinical criteria. DAD showed only moderate correlation with current clinical ARDS definition. Oxygenation index (OI), seems to be the most valuable tool in predicting pulmonary damage severity, though OI is not listed in either of the previous definitions. We support the recommended use of OI by 2015 consensus conference.
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BACKGROUND: Given the high prevalence of potentially traumatic events (PTEs), pediatric providers are in a novel position in early identification and referral of the children with PTEs. Yet paucity of culturally adapted instruments to screen PTEs and related symptoms in preschool-aged children limits pediatric providers. This multicenter study aimed to screen the traumatic life events of preschool-aged children admitted to pediatric outpatient clinics at four different cities of Turkey and to determine the socio-demographic risk factors associated with PTEs. Moreover, it was also intended to develop the cultural adaptation of the Child and Adolescent Trauma Screen (CATS) Caregiver-report 3-6 Years version to Turkish and to analyze its reliability. METHODS: Participants of this multicenter study were collected from four different hospitals in three different regions (Central Anatolia, Black Sea, and Southeastern Anatolia regions) of Turkey. All parents of children at the age of 3-6 years who were admitted to the hospital for a clinical visit (sick-child or well-child visits) were invited to the study. In total, 188 preschool-aged children were included in the study. Socio-demographic characteristics of the child and the family were questioned and parents were asked to fill out the Turkish version of the CATS Caregiver-report. RESULTS: Internal consistency (Cronbach`s alpha) of the Turkish version of the CATS Caregiver-report 3-6 Years was found as 0.86. This study revealed that half of the participating children had experienced at least one PTE and more than one fourth experienced more than one event. Strikingly, no association between sociodemographic risk factors and PTE exposure was identified suggesting that PTE exposure is indeed widespread in our study population. CONCLUSION: The findings of this study manifest the importance of routine screening of PTEs and related symptoms in children.
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Cuidadores , Família , Adolescente , Criança , Pré-Escolar , Humanos , Pais , Prevalência , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
INTRODUCTION: Sleep disorders have been described in patients with autoimmune limbic encephalitis (LE). The changes in sleep structure were also reported. Recently sleep spindle abnormalities such as asynchronous or prolonged spindles were observed children with LE. METHODS: We studied the sleep and number of sleep spindles in the continuous electroencephalography-polysomnography (EEG-PSG) recordings of 6 patients with autoimmune epilepsy and/or LE. The longest NREM 2 period was selected. We evaluated the spindle density (spindles per minute), and compared that to the spindle densities of epilepsy patients with bilateral hippocampal sclerosis and healthy controls. RESULTS: We have demonstrated that patients with autoimmune epilepsy and/or LE had reduced slow wave sleep with decreased number of sleep spindles. The mean number of spindles in 60 seconds was 5.86±5.03 in patients with autoimmune epilepsy and/or LE. But spindle density was higher in two control groups (10.6±1.65 and 9.95±0.79). CONCLUSIONS: The sleep abnormalities in LE can result from the disruption of thalamo-limbic circuits, and lead to changes in spindle wave activity. Although density of spindles decreased with acute lesions in thalamo-limbic circuits, the relations with structural lesions or chronicity of disease are not clear. That may be related to functional disruption of neural circuitry.