Understanding the role of the blood brain barrier and peripheral inflammation on behavior and pathology on ongoing confined cortical lesions.

BACKGROUND: Inflammation in the Central Nervous System (CNS) is associated with blood brain barrier (BBB) breakdown during the early stages of Multiple Sclerosis (MS), indicating a facilitated entry of waves of inflammatory cells from the circulation to the CNS. In the progressive forms of MS, as the lesion becomes chronic, the inflammation remains trapped within the CNS compartment forming the slow evolving lesion, characterized by low inflammation and microglia activation at the lesions edges. The chronic expression of interleukin 1ß (IL-1ß) in the cortex induces BBB breakdown, demyelination, neurodegeneration, microglial/macrophage activation and impaired cognitive performance. The latter can be improved, as long as the BBB recovers and the lesion presents low inflammation. Here, we study the effects of peripheral inflammation on cortical central lesions after the restoration of the BBB, in order to elucidate the role of the peripheral inflammation on these lesions with intact BBB, as it occurs in the progressive forms of MS. MATERIALS AND METHODS: Cortical lesions and peripheral inflammation were induced by the chronic expression of IL-1ß using an adenovector. We performed histological, immunohistochemistry on brain tissue and behavioural analyses. RESULTS: The effects of the chronic expression of IL-1ß in the cortex resolved within 56 days. However, peripheral and sustained inflammation re-opened the BBB, allowing the reappearance of the neuroinflammatory processes within the cortical lesions, increased demyelination and neurodegeneration, and an increase of the behavioral symptoms, such as cognitive impairment and anxiety-like symptoms. CONCLUSIONS: The early treatment of peripheral inflammatory processes should be considered in order to protect the brain from exacerbation of the ongoing neurodegenerative process.

Usefulness of a new semiological classification for characterizing psychogenic nonepileptic seizures.

BACKGROUND: Nonepileptic events misdiagnosed as epilepsy lead to a risk of iatrogenic morbidity, which increases health costs. Among the patients affected by nonepileptic events, 11-46% are psychogenic nonepileptic seizures (PNESs). OBJECTIVE: To investigate the usefulness of the semiological classification of PNESs among patients diagnosed by means of video electroencephalograms (vEEGs). METHODS: This was a retrospective review of the medical records of patients admitted to the adult vEEG unit between April 2007 and December 2016, who were diagnosed with PNES that was confirmed through vEEG. Analysis on demographic and clinical data and classification of PNESs according to the Magaudda classification were performed. RESULTS: We identified 143 patients, among whom 31.5% had also epilepsy. According to the Magaudda classification, the events were: hypermotor (58%); subjective symptoms (21.7%); akinetic (14.7%) and focal motor (5.6%). Hypermotor predominated in both genders, followed by subjective symptoms in women (23.9%) and akinetic in men (19.2%). The mean number of antiepileptic drugs (AEDs) prescribed per patient was 2.3. Thirty-two patients (22.4%) required at least one hospitalization for PNESs. 48.3% of the patients had psychiatric comorbidities. CONCLUSION: The proposed semiological classification of PNESs is a relevant tool that general neurologists can use to characterize these events in their daily practice. Correct use of this classification, together with vEEG and appropriate clinical suspicion, makes it possible to reach an accurate early diagnosis, thus reducing morbidity and, possibly, the high costs associated with PNESs.

Usefulness of a new semiological classification for characterizing psychogenic nonepileptic seizures / Utilidad de una nueva clasificación semiológica para caracterización de eventos paroxísticos no epilépticos de origen psicógeno

ABSTRACT Background: Nonepileptic events misdiagnosed as epilepsy lead to a risk of iatrogenic morbidity, which increases health costs. Among the patients affected by nonepileptic events, 11-46% are psychogenic nonepileptic seizures (PNESs). Objective: To investigate the usefulness of the semiological classification of PNESs among patients diagnosed by means of video electroencephalograms (vEEGs). Methods: This was a retrospective review of the medical records of patients admitted to the adult vEEG unit between April 2007 and December 2016, who were diagnosed with PNES that was confirmed through vEEG. Analysis on demographic and clinical data and classification of PNESs according to the Magaudda classification were performed. Results: We identified 143 patients, among whom 31.5% had also epilepsy. According to the Magaudda classification, the events were: hypermotor (58%); subjective symptoms (21.7%); akinetic (14.7%) and focal motor (5.6%). Hypermotor predominated in both genders, followed by subjective symptoms in women (23.9%) and akinetic in men (19.2%). The mean number of antiepileptic drugs (AEDs) prescribed per patient was 2.3. Thirty-two patients (22.4%) required at least one hospitalization for PNESs. 48.3% of the patients had psychiatric comorbidities. Conclusion: The proposed semiological classification of PNESs is a relevant tool that general neurologists can use to characterize these events in their daily practice. Correct use of this classification, together with vEEG and appropriate clinical suspicion, makes it possible to reach an accurate early diagnosis, thus reducing morbidity and, possibly, the high costs associated with PNESs

RESUMEN Introducción: Los eventos no epilépticos diagnosticados erróneamente como epilepsia conducen a un riesgo de morbilidad iatrogénica que aumenta los costes en salud. Entre los pacientes afectados por eventos no epilépticos, un 11-46% son de origen psicógeno (PNES). Objetivos: Evaluar la utilidad de la clasificación semiológica de PNES en pacientes diagnosticados por video electroencefalograma (vEEG). Métodos: Revisión retrospectiva de los registros médicos de pacientes ingresados en la unidad de adultos de vEEG entre 04-2007 y 12-2016, que fueron diagnosticados con PNES confirmado por vEEG. Se realizó un análisis de los datos demográficos y clínicos, y la clasificación de los PNES según la clasificación de Magaudda. Resultados: Identificamos 143 pacientes, el 31,5% de los cuales también tenía epilepsia. Según la clasificación de Magaudda, los eventos fueron: hipermotor 58%; síntomas subjetivos 21,7%; akinética 14,7% y motor focal 5,6%. El hipermotor predominó en ambos los sexos, seguido de síntomas subjetivos en las mujeres (23,9%) y akinéticos en los hombres (19,2%). La cantidad media de fármacos antiepilépticos (FAE) recetados por paciente fue 2.3. Un total de 32 pacientes (22.4%) requirieron al menos una hospitalización por PNES. El 48,3% de los pacientes tenía comorbilidad psiquiátrica. Conclusión: La clasificación semiológica de los PNES propuesta es una herramienta relevante que los neurólogos generales pueden usar para caracterizar esos eventos en su práctica diaria. El uso correcto de esta clasificación, vEEG y una sospecha clínica adecuada permite llegar a un diagnóstico preciso y temprano, reduciendo así la morbilidad y, posiblemente, los altos costes asociados con las PNES.

Quality of life in patients with epilepsy or psychogenic nonepileptic seizures and the contribution of psychiatric comorbidities.

Epilepsy is a common neurological disorder, and psychogenic nonepileptic seizures (PNES) is an important differential diagnosis. Psychiatric comorbidities are prevalent among people with epilepsy (PWE). Additionally, lower quality of life (QoL) in people with PNES compared with PWE was reported with higher rates of general psychiatric comorbidity. Although there are previous studies evaluating the QoL in patients with epilepsy, this study is unique and compelling because it represents a study comparing PNES and PWE on QoL, depression, and anxiety in a Spanish-speaking group of Argentine patients. The aim of this study was to analyze self-reported anxiety and depression in PWE and PNES and to establish the impact on QoL. METHODS: This is a cross-sectional study; QoL was measured using the Quality of Life in Epilepsy Inventory (QOLIE-31). To study anxiety and depression, the Hospital Anxiety and Depression Scale (HADS) was administered. Clinical and complementary data were recorded. RESULTS: Psychogenic nonepileptic seizures scored significantly higher in anxiety and depression and with lower levels of QoL compared with PWE. Anxiety and depression had a negative correlation with QoL. CONCLUSION: Nonepileptic seizures have an even greater impact on QoL than epileptic seizures, and this could be influenced by psychiatric comorbidities. These findings corroborate what other studies in English-speaking nations that have found regarding the impact of psychopathology on QoL in those with PNES and further support the importance of assessing for psychiatric comorbidities to tailor treatment.

[Cerebral structural changes in generalized idiopathic epilepsy identified by automated magnetic resonance imaging analysis]. / Cambios estructurales cerebrales en epilepsia generalizada idiopática identificados por análisis de imágenes de resonancia magnética automatizados.

The purpose of this study was to combine two automated methods of magnetic resonance imaging (MRI) structural analysis in order to identify structural changes in patients born in Argentina with idiopathic generalized epilepsy (IGE) compared to a healthy adult control group. Twenty-eight patients with IGE and 26 controls with no significant demographic differences were included. The analysis of the brain structures was conducted with two automated methods of magnetic resonance image analysis: voxelbased morphometry and FSL-integrated registration and segmentation toolbox (FSL-FIRST). FSL showed volume decrease in both thalamus in patients with IGE compared to the control group (left: 8092 mm3 control group vs. 7424 mm3 IGE, p = 0.0015; right: 7951 mm3 control group vs. 7247 mm3 IGE, p = 0.0016). A reduction in the volume of both caudate nuclei was also seen (left: 3612 mm3 control group vs. 3376 mm3 IGE, p = 0.01; right: 3683 mm3 control group vs. 3459 mm3 IGE, p = 0.04). Voxel-based-morphometry showed a volume decrease in both caudate nuclei in patients with IGE compared to the control group. The other cerebral structures analyzed did not show significant differences between the groups. In conclusion, this study shows the reduction in volume in the subcortical, thalamic, and caudate nuclei structures in patients with IGE in comparison to control group. This study conducted in our country delves into the analysis of brain structural changes in patients with EGI compared to healthy subjects.

El objetivo de este estudio fue combinar dos métodos automatizados de análisis estructural de imágenes de resonancia magnética para identificar cambios estructurales en pacientes nacidos en Argentina con epilepsia generalizada idiopática (EGI) en comparación con un grupo control de adultos sanos. Fueron incluidos 28 pacientes con EGI y 26 controles sin diferencias demográficas significativas. El análisis de las estructuras cerebrales se realizó con dos métodos automatizados de análisis de imágenes de resonancia magnética: la morfometría basada en vóxel y con la herramienta de segmentación y registro integrada FSL (FSL-FIRST). FSL mostró una disminución del volumen en ambos tálamos en EGI en comparación con el grupo control (tálamo izquierdo: 8092 mm3 grupo control vs. 7424 mm3 EGI, p = 0.0015; tálamo derecho: 7951 mm3 grupo control vs. 7247 mm3 EGI, p = 0.0016). Se observó una reducción en el volumen de ambos núcleos caudados (izquierdo: 3612 mm3 grupo control vs. 3376 mm3 EGI, p = 0.01; derecho 3683 mm3 grupo control vs. 3459 mm3 EGI, p = 0.04). La morfometría basada en vóxel mostró una disminución del volumen en ambos núcleos caudados en EGI en comparación con el grupo control. Las otras estructuras cerebrales analizadas no mostraron diferencias significativas entre los grupos. Este estudio muestra la reducción en el volumen en las estructuras subcortical, tálamos y núcleos caudados en pacientes con EGI comparado con un grupo control.

Cambios estructurales cerebrales en epilepsia generalizada idiopática identificados por análisis de imágenes de resonancia magnética automatizados / Cerebral structural changes in generalized idiopathic epilepsy identified by automated magnetic resonance imaging analysis

El objetivo de este estudio fue combinar dos métodos automatizados de análisis estructural de imágenes de resonancia magnética para identificar cambios estructurales en pacientes nacidos en Argentina con epilepsia generalizada idiopática (EGI) en comparación con un grupo control de adultos sanos. Fueron incluidos 28 pacientes con EGI y 26 controles sin diferencias demográficas significativas. El análisis de las estructuras cerebrales se realizó con dos métodos automatizados de análisis de imágenes de resonancia magnética: la morfometría basada en vóxel y con la herramienta de segmentación y registro integrada FSL (FSL-FIRST). FSL mostró una disminución del volumen en ambos tálamos en EGI en comparación con el grupo control (tálamo izquierdo: 8092 mm³ grupo control vs. 7424 mm³ EGI, p = 0.0015; tálamo derecho: 7951 mm³ grupo control vs. 7247 mm³ EGI, p = 0.0016). Se observó una reducción en el volumen de ambos núcleos caudados (izquierdo: 3612 mm³ grupo control vs. 3376 mm³ EGI, p = 0.01; derecho 3683 mm³ grupo control vs. 3459 mm³ EGI, p = 0.04). La morfometría basada en vóxel mostró una disminución del volumen en ambos núcleos caudados en EGI en comparación con el grupo control. Las otras estructuras cerebrales analizadas no mostraron diferencias significativas entre los grupos. Este estudio muestra la reducción en el volumen en las estructuras subcortical, tálamos y núcleos caudados en pacientes con EGI comparado con un grupo control.

The purpose of this study was to combine two automated methods of magnetic resonance imaging (MRI) structural analysis in order to identify structural changes in patients born in Argentina with idiopathic generalized epilepsy (IGE) compared to a healthy adult control group. Twenty-eight patients with IGE and 26 controls with no significant demographic differences were included. The analysis of the brain structures was conducted with two automated methods of magnetic resonance image analysis: voxel-based morphometry and FSL-integrated registration and segmentation toolbox (FSL-FIRST). FSL showed volume decrease in both thalamus in patients with IGE compared to the control group (left: 8092 mm³ control group vs. 7424 mm³ IGE, p = 0.0015; right: 7951 mm³ control group vs. 7247 mm³ IGE, p = 0.0016). A reduction in the volume of both caudate nuclei was also seen (left: 3612 mm³ control group vs. 3376 mm³ IGE, p = 0.01; right: 3683 mm³ control group vs. 3459 mm³ IGE, p = 0.04). Voxel-based-morphometry showed a volume decrease in both caudate nuclei in patients with IGE compared to the control group. The other cerebral structures analyzed did not show significant differences between the groups. In conclusion, this study shows the reduction in volume in the subcortical, thalamic, and caudate nuclei structures in patients with IGE in comparison to control group. This study conducted in our country delves into the analysis of brain structural changes in patients with EGI compared to healthy subjects.

[Progressive myoclonic epilepsy secondary to Lafora's body disease]. / Epilepsia mioclónica progresiva secundaria a enfermedad por cuerpos de Lafora.

Lafora's disease is infrequent. However, it is one of the most common causes of progressive myoclonus epilepsy. We present the case of a 19-year-old woman, without comorbidities and normal development that started at 8 years with seizures and that from 15 years, had progressive cognitive deterioration. She was admitted to our institution with a diagnosis of super refractory status epilepticus. The diagnosis of Lafora's disease was made through pathological anatomy, later a genetic test was performed that reported a pathogenic variant of the EPM2A gene, confirming the diagnosis. We present a cause of progressive myoclonic epilepsy, with an ominous prognosis and a treatment oriented to palliative measures, so it is important to analyze the differential diagnoses with other entities, in order to establish a prognosis, offer better quality of life, adequate medical care and provide genetic counseling to family members.

Epilepsia mioclónica progresiva secundaria a enfermedad por cuerpos de Lafora / Progressive myoclonic epilepsy secondary to Lafora's body disease

La enfermedad de Lafora es infrecuente; sin embargo, es una de las causas más comunes de epilepsia mioclónica progresiva. Presentamos el caso de una mujer de 19 años sin comorbilidades y pautas madurativas normales, que inició a los 8 años con convulsiones y que a partir de los 15 años agregó deterioro cognitivo progresivo. Fue internada en nuestra institución con diagnóstico de estatus epiléptico super refractario. Se diagnosticó enfermedad de Lafora, confirmada por la anatomía patológica, y posteriormente se realizó un test genético que informó una variante patogénica del gen EPM2A, que confirmó el diagnóstico. Presentamos una causa de epilepsia mioclónica progresiva, con un pronóstico ominoso y un tratamiento orientado a medidas paliativas, por lo que es importante analizar los diagnósticos diferenciales con otras entidades, a fin de establecer un pronóstico, ofrecer mejor calidad de vida, asistencia médica adecuada y brindar asesoría genética a los familiares.

Lafora's disease is infrequent. However, it is one of the most common causes of progressive myoclonus epilepsy. We present the case of a 19-year-old woman, without comorbidities and normal development that started at 8 years with seizures and that from 15 years, had progressive cognitive deterioration. She was admitted to our institution with a diagnosis of super refractory status epilepticus. The diagnosis of Lafora's disease was made through pathological anatomy, later a genetic test was performed that reported a pathogenic variant of the EPM2A gene, confirming the diagnosis. We present a cause of progressive myoclonic epilepsy, with an ominous prognosis and a treatment oriented to palliative measures, so it is important to analyze the differential diagnoses with other entities, in order to establish a prognosis, offer better quality of life, adequate medical care and provide genetic counseling to family members.

A new focal model resembling features of cortical pathology of the progressive forms of multiple sclerosis: Influence of innate immunity.

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of unknown aetiology that causes neurological disabilities in young adults. MS displays different clinical patterns, including recurrent episodes with remission periods ("relapsing-remitting MS" (RRMS)), which can progress over several years to a secondary progressive form (SPMS). However, 10% of patients display persistent progression at the onset of disease ("primary progressive MS" (PPMS)). Currently, no specific therapeutic agents are available for the progressive forms, mainly because the underlying pathogenic mechanisms are not clear and because no animal models have been specifically developed for these forms. The development of MS animal models is required to clarify the pathological mechanisms and to test novel therapeutic agents. In the present work, we overexpressed interleukin 1 beta (IL-1ß) in the cortex to develop an animal model reflecting the main pathological hallmarks of MS. The treated animals presented with neuroinflammation, demyelination, glial activation, and neurodegeneration along with cognitive symptoms and MRI images consistent with MS pathology. We also demonstrated the presence of meningeal inflammation close to cortical lesions, with characteristics similar to those described in MS patients. Systemic pro-inflammatory stimulation caused a flare-up of the cortical lesions and behavioural symptoms, including impairment of working memory and the appearance of anxiety-like symptoms. Our work demonstrated induced cortical lesions, reflecting the main histopathological hallmarks and cognitive impairments characterizing the cortical pathology described in MS patients with progressive forms of the disease.