[Contribution of the Ibero-American Academy of Neuropediatrics to the knowledge of self-limited epilepsy in infants]. / Aporte de la Academia Iberoamericana de Neuropediatría al conocimiento de la epilepsia autolimitada del lactante.

Since the first presentation at the IV Iberoamerican Academy of Neuropediatrics Congress in 1995, our group has studied self-limited infantile epilepsy (SeLIE), both familial and non-familial, corroborating that they belong to the same entity due to their clinical and electroencephalographic characteristics and excellent prognosis. Associations were found with paroxysmal dyskinesias and migraine, as well as with hemiplegic migraine, episodic ataxia and intellectual disability in atypical cases. Mutations in PRRT2 are the main cause of SeLIE, however, other genes, such as SCN2A, KCNQ2-3 and SCN8A, have been recognized. Drugs for focal seizures that act on sodium channels are indicated. In emergencies, during cluster seizures, the use of benzodiazepines is important. In this publication, we review our contribution in SeLIE from our first report to the present and review the existing literature on the subject.

Desde la primera presentación en el IV Congreso de la Academia Iberoamericana de Neurología Pediátrica en 1995, nuestro grupo ha estudiado las epilepsias autolimitadas del lactante (EAL), tanto familiares y no familiares, corroborando que pertenecen a una misma entidad por sus características clínicas, electroencefalográficas y excelente pronóstico. Se encontraron asociaciones con discinesias paroxísticas y migraña, como también con la migraña hemipléjica, la ataxia episódica y la discapacidad intelectual en casos atípicas. Las mutaciones en PRRT2 son la principal causa de EAL. Sin embargo, otros genes, como SCN2A, KCNQ2-3 y SCN8A, han sido reconocidos. Los fármacos para las crisis focales que actúan sobre los canales de sodio son los indicados. En emergencias, durante las convulsiones agrupadas, es importante el uso de benzodiacepinas. En esta publicación, hacemos un recorrido de nuestro aporte en EAL desde nuestra primera contribución hasta la actualidad y además realizamos una revisión de la literatura existente sobre el tema.

Cerebral hemiatrophy and hemiparesis following hemiclonic status epilepticus in Dravet syndrome.

Dravet syndrome is currently considered as an developmental and epileptic encephalopathy and, recently, mandatory, alert, and exclusionary criteria have been proposed. Here, we describe three patients with Dravet syndrome with the typical early presentation including febrile and afebrile alternating hemiclonic seizures due to loss-of-function SCN1A variants. Subsequently, they developed episodes of febrile focal status epilepticus (SE) associated with hemiparesis and cerebral hemiatrophy with posterior focal seizures, as a consequence of Dravet syndrome. This sequence of events has been previously published in patients with Dravet syndrome and does not contradict the recent classification by the International League Against Epilepsy (ILAE). The ILAE guidance identifies "Focal neurological findings" as alert criteria and "MRI showing a causal focal lesion" as exclusionary criteria for making an initial diagnosis of Dravet syndrome at presentation. Our three patients would correspond to a severe phenotype, similar to the well-known presentation of generalized atrophy following prolonged status epilepticus. Common genetic findings in cases of diffuse and unilateral brain involvement may help explain these clinical presentations. Further genotype-phenotype studies may provide additional insights into this electroclinical behavior.

Use of ketogenic dietary therapy for drug-resistant epilepsy in early infancy.

OBJECTIVE: There is growing evidence that ketogenic dietary therapy (KDT) can be safely and efficiently used in young children, but little evidence exists on its use in newborns. Developmental and epileptic encephalopathies starting in the neonatal period or early infancy usually present a poor prognosis. The aim of this study was to evaluate effectiveness, safety, and survival of infants younger than 3 months of age with drug-resistant epilepsy in whom KDT was used. METHODS: A retrospective study was conducted to evaluate neonates and infants younger than 3 months who started KDT for drug-resistant developmental and epileptic encephalopathies at three referral centers. Data were collected on demographic features, time of epilepsy onset, epilepsy syndrome, seizure type, seizure frequency at diet onset, etiology, details regarding diet initiation, type of ketogenic formula, breastfeeding, route of administration, blood ketones, growth, length of NICU stay, and survival. RESULTS: Nineteen infants younger than 12 weeks of life who received KDT with a minimum follow-up of 1 month were included; 13 had early-infantile developmental and epileptic encephalopathy, four epilepsy of infancy with migrating focal seizures, and two focal epilepsy. A >50% response was observed in 73.7% at 1 month on the diet; 37% achieved a > 75% seizure reduction, and 10.5% became seizure free. At 3 months, a >50% decrease in seizure frequency was observed in 72.2%; 15.8% had a >75% reduction; 21% became seizure free. Overall survival was 76% at 1 year on diet. Incidence of acute and late adverse effects was low and most adverse effects were asymptomatic and manageable. SIGNIFICANCE: Our experience suggests that KDT is safe and effective in newborns and very young infants; however, further studies on the management of the diet in this vulnerable age group are necessary.

[Benefit of surgery in a case of negative motor focal epileptic seizures secondary to parietal cortical dysplasia]. / Beneficio de la cirugía en un caso de crisis epilépticas focales motoras negativas secundarias a displasia cortical parietal.

Focal atonic seizures are recognized rarely as ictal phenomena, they can correspond to both generalized epilepsy and focal epilepsy. The areas of the brain involved in the management of this type of seizure are: the negative motor area and the primary motor and primary somatosensory cortices, although the neurophysiology that generates them is still unclear. We present the case of a patient with focal atonic seizures in the left upper limb, refractory to drug treatment. Neuroimaging was performed, a parietal cortical lesion was diagnosed. A scalp Video EEG and then a Stereo EEG was performed, defining the epileptogenic area and its relationship with eloquent areas. Surgical resection of the lesion was performed, achieving complete seizure control.

Las crisis atónicas focales son poco reconocidas como fenómenos ictales, pueden corresponder tanto a una epilepsia generalizada como a una epilepsia focal. Las áreas del cerebro implicadas en la gestión de este tipo de crisis son: el área motora negativa y las cortezas motora primaria y somatosensitiva primaria, aunque aún la neurofisiología que las genera no está aclarada. Presentamos el caso de un paciente con crisis atónicas focales farmacorresistentes en miembro superior izquierdo. Se realizó resonancia de cerebro con diagnóstico de displasia cortical parietal, se monitoreó con video EEG de scalp y luego a video EEG con electrodos profundos. Se definieron el área epileptógena y su relación con áreas elocuentes, se realizó resección quirúrgica de la lesión, logrando el control completo de las crisis.

Beneficio de la cirugía en un caso de crisis epilépticas focales motoras negativas secundarias a displasia cortical parietal / Benefit of surgery in a case of negative motor focal epileptic seizures secondary to parietal cortical dysplasia

Resumen Las crisis atónicas focales son poco reconocidas como fenómenos ictales, pueden corresponder tanto a una epilepsia generalizada como a una epilepsia focal. Las áreas del cerebro implicadas en la gestión de este tipo de crisis son: el área motora negativa y las cortezas motora primaria y somatosensitiva primaria, aunque aún la neurofisiología que las genera no está aclarada. Presentamos el caso de un paciente con crisis atónicas focales farmacorresistentes en miembro superior iz quierdo. Se realizó resonancia de cerebro con diagnóstico de displasia cortical parietal, se monitoreó con video EEG de scalp y luego a video EEG con electrodos profundos. Se definieron el área epileptógena y su relación con áreas elocuentes, se realizó resección quirúrgica de la lesión, logrando el control completo de las crisis.

Abstract Focal atonic seizures are recognized rarely as ictal phenomena, they can correspond to both generalized epilepsy and focal epilepsy. The areas of the brain in volved in the management of this type of seizure are: the negative motor area and the primary motor and primary somatosensory cortices, although the neurophysiology that generates them is still unclear. We present the case of a patient with focal atonic seizures in the left upper limb, refractory to drug treatment. Neuroimaging was performed, a parietal cortical lesion was diagnosed. A scalp Video EEG and then a Stereo EEG was performed, defining the epileptogenic area and its relationship with eloquent areas. Surgical resection of the lesion was performed, achieving complete seizure control.

Real-World Evidence of Factors Affecting Cannabidiol Exposure in Children with Drug-Resistant Developmental and Epileptic Encephalopathies.

The identification of factors that affect cannabidiol (CBD) systemic exposure may aid in optimizing treatment efficacy and safety in clinical practice. In this study, we aimed to correlate CBD plasma concentrations at a steady state to demographic, clinical, and pharmacological characteristics as well as seizure frequency after the administration of a purified CBD oil solution in a real-world setting of children with drug-resistant developmental and epileptic encephalopathies (DEEs). Patients receiving oral CBD pharmaceutical products at maintenance were enrolled. Venous blood samples were drawn before the CBD morning dose, 12 h apart from the last evening dose (C0 or CBD trough concentration). A linear mixed-effect analysis was implemented to assess the correlation between C0 and clinical, laboratory, pharmacological, and lifestyle factors. Fifteen females and seven males with a median age of 12.8 years (ranging between 4.7 and 17.2) were included. The median CBD dose was 8.8 mg/kg/day (ranging between 2.6 and 22.5), and the CBD C0 median (range) was 48.2 ng/mL (3.5-366.3). The multivariate model showed a 109.6% increase in CBD C0 in patients with concomitant levothyroxine (ß = 0.74 ± 0.1649, p < 0.001), 56.8% with food (ß = 0.45 ± 0.1550, p < 0.01), and 116.0% after intake of a ketogenic diet (ß = 0.77 ± 0.3141, p < 0.05). All patients included were responders without evidence of an association between C0 and response status. In children with DEEs, systemic concentrations of CBD may be significantly increased when co-administered with levothyroxine, food, or a ketogenic diet.

Deficiencia del transportador de glucosa tipo 1: aspectos clínicos, diagnóstico y terapéutica / Glucose transporter type 1 deficiency syndrome: clinical aspects, diagnosis, and treatment

El síndrome de deficiencia del transportador de glucosa tipo 1 es una enfermedad de causa genética, que involucra el gen SLC2A1. En general, se presenta durante los primeros años de vida con retraso en la adquisición de pautas madurativas, epilepsia farmacorresistente y desórdenes del movimiento. La clínica y la disminución de glucosa en líquido cefalorraquídeo permiten sospechar el diagnóstico, el cual debe ser confirmado mediante el estudio molecular del gen SLC2A1. Debido a que se trata de una enfermedad poco frecuente y de expresión clínica variable, el diagnóstico precoz suele representar un desafío para los equipos de salud. Este es importante, ya que la implementación de la terapia cetogénica logra controlar las manifestaciones clínicas y mejora el pronóstico a largo plazo. Presentamos una revisión sobre el déficit del transportador de glucosa tipo 1, que abarca sus características clínicas, bioquímicas, moleculares y terapéuticas.

Glucose transporter type 1 deficiency with a typical onset is a genetic disorder associated with the SLC2A1 gene. Usually appears during the first years of life with severe developmental delay, drugresistant epilepsy, and movement disorders. Diagnosis is suspected based on clinical manifestations and a low glucose level in cerebrospinal fluid, and should be confirmed by the molecular genetic study of the SLC2A1 gene. As it is a rare disease with variable clinical expression, early diagnosis is often challenging for the healthcare team. Nevertheless, this is important because early implementation of ketogenic therapy will lead to control of the clinical manifestations and a better long-term prognosis. Here we review the glucose transporter type 1 deficiency syndrome focusing on its clinical, biochemical, molecular, and therapeutic characteristics.

Glucose transporter type 1 deficiency syndrome: clinical aspects, diagnosis, and treatment. / Deficiencia del transportador de glucosa tipo 1: aspectos clínicos, diagnóstico y terapéutica.

Glucose transporter type 1 deficiency with a typical onset is a genetic disorder associated with the SLC2A1 gene. Usually appears during the first years of life with severe developmental delay, drugresistant epilepsy, and movement disorders. Diagnosis is suspected based on clinical manifestations and a low glucose level in cerebrospinal fluid,and should be confirmed by the molecular genetic study of the SLC2A1 gene. As it is a rare disease with variable clinical expression, early diagnosis is often challenging for the healthcare team. Nevertheless, this is important because early implementation of ketogenic therapy will lead to control of the clinical manifestations and a better long-term prognosis. Here we review the glucose transporter type 1 deficiency syndrome focusing on its clinical, biochemical, molecular, and therapeutic characteristics.

El síndrome de deficiencia del transportador de glucosa tipo 1 es una enfermedad de causa genética, que involucra el gen SLC2A1. En general, se presenta durante los primeros años de vida con retraso en la adquisición de pautas madurativas, epilepsia farmacorresistente y desórdenes del movimiento. La clínica y la disminución de glucosa en líquido cefalorraquídeo permiten sospechar el diagnóstico, el cual debe ser confirmado mediante el estudio molecular del gen SLC2A1. Debido a que se trata de una enfermedad poco frecuente y de expresión clínica variable, el diagnóstico precoz suele representar un desafío para los equipos de salud. Este es importante, ya que la implementación de la terapia cetogénica logra controlar las manifestaciones clínicas y mejora el pronóstico a largo plazo. Presentamos una revisión sobre el déficit del transportador de glucosa tipo 1, que abarca sus características clínicas, bioquímicas, moleculares y terapéuticas.

Clinical and genetic study of developmental and epileptic encephalopathy in Argentinean pediatric patients.

INTRODUCTION: The aim of this study was to extend our knowledge of the genetic background of Argentinean pediatric patients with developmental and epileptic encephalopathy (DEE) applying a next generation sequencing (NGS) panel. METHODS: Thirty one patients with DEE were studied, including these phenotypes: Dravet syndrome (n:7), Dravet like syndrome (n:3), West syndrome (WS) (n:6), WS that evolved to Lennox-Gastaut syndrome (LGS) (n:4), epilepsy of infancy with migrating focal seizures (n:2), continuous spikes and waves during slow sleep evolving to LGS (n:1), LGS (n:1), myoclonic status in non-progressive encephalopathy (n:1), myoclonic atonic epilepsy (n:1), epileptic encephalopathy with multifocal spikes (n:1) and unclassified epileptic encephalopathy (n:4). Fifty-two genes frequently associated with DEE were studied by NGS in genomic DNA from peripheral blood. RESULTS: Relevant variants were detected in 12 cases; 6 novel pathogenic or likely pathogenic variants, 6 previously reported as pathogenic and 1 variant of unknown significance. Single-nucleotide heterozygous variants were identified in the SCN1A (5), GABRG2 (1), STXBP1 (2) genes, a mosaic variant in SCN2A (1) and a homozygous variant in SCN1B (1). Additionally, a heterozygous deletion involving the SCN1A, SCN2A and SCN3A genes (1), and the most frequent triplet repeat expansion in the ARX gene (1) were detected. DISCUSSION: Genetic diagnosis was made in 39% of patients. We emphasize the importance of considering mosaic variants, copy number variants and hereditary forms when designing and interpreting molecular studies, to optimize diagnosis and management of patients. Approximately 42% of the detected variants were novel, expanding the knowledge of the molecular basis of DEEs in Latin-American patients.

Introducción: El objetivo del estudio fue ampliar el conocimiento de las bases moleculares de las encefalopatías epilépticas y del desarrollo (EED) en pacientes pediátricos argentinos aplicando un panel de secuenciación de nueva generación (NGS). Métodos: Se analizaron 31 pacientes con los fenotipos clínicos de síndrome de Dravet (n:7), síndrome símil Dravet (n:3), síndrome de West (SW) (n:6), SW que evoluciona a síndrome de Lennox Gastaut (SLG)(N:4), epilepsia de la infancia con crisis focales migratorias (n:2), actividad de punta onda continua durante el sueño que evolucionan a SLG (n:1), SLG (n:1), encefalopatía no progresiva con estatus mioclónico (n:1), epilepsia mioclónica atónica (n:1), encefalopatía epiléptica con espigas multifocales (n:1) y encefalopatía epiléptica indeterminada (n:4). Se estudiaron los 52 genes más frecuentemente asociados a EED a través de NGS, en ADN extraído de sangre periférica. Resultados: Se identificaron variantes relevantes en 12 casos, de las cuales 5 fueron nuevas y 6 previamente reportadas como patogénicas o posiblemente patogénicas, mientras que una variante fue clasificada como de significado incierto. Variantes heterocigotas, de nucleótido único, se identificaron en los genes SCN1A (5), GABRG2 (1), STXBP1 (2), una variante en mosaico en SCN2A (1) y otra homocigota en SCN1B (1). Además, se detectó una deleción que involucra a los genes SCN1A, SCN2A y SCN3A (1) y la expansión de repeticiones de tripletes más frecuente en el gen ARX (1). Discusión: Se alcanzó el diagnóstico molecular en el 39% de los pacientes. Remarcamos la importancia de considerar variantes en mosaico, variantes en el número de copias y formas heredadas al momento de diseñar e interpretar los estudios moleculares, de tal forma de optimizar el diagnóstico y seguimiento de los pacientes con EED. Cabe destacar, que el 42% de las variantes detectadas fueron nuevas, ampliando nuestro conocimiento sobre las bases moleculares de las EED en población latino americana.

Clinical and genetic study of developmental and epileptic encephalopathy in argentinean pediatric patients / Estudio clínico y genético de encefalopatía epiléptica y del desarrollo en pacientes pediátricos argentinos

Abstract Introduction: The aim of this study was to extend our knowledge of the genetic background of Argentinean pediatric patients with developmental and epileptic encephalopathy (DEE) applying a next generation sequencing (NGS) panel. Methods: Thirty one patients with DEE were studied, including these phenotypes: Dravet syndrome (n:7), Dravet like syndrome (n:3), West syndrome (WS) (n:6), WS that evolved to Lennox-Gastaut syndrome (LGS) (n:4), epilepsy of infancy with migrating focal seizures (n:2), continuous spikes and waves during slow sleep evolving to LGS (n:1), LGS (n:1), myoclonic status in non-progressive encephalopathy (n:1), myoclonic atonic epilepsy (n:1), epileptic encephalopathy with multifocal spikes (n:1) and unclassified epileptic encephalopathy (n:4). Fifty-two genes frequently associated with DEE were studied by NGS in genomic DNA from peripheral blood. Results: Relevant variants were detected in 12 cases; 6 novel pathogenic or likely pathogenic variants, 6 previously reported as pathogenic and 1 variant of unknown sig nificance. Single-nucleotide heterozygous variants were identified in the SCN1A (5), GABRG2 (1), STXBP1 (2) genes, a mosaic variant in SCN2A (1) and a homozygous variant in SCN1B (1). Additionally, a heterozygous deletion involving the SCN1A, SCN2A and SCN3A genes (1), and the most frequent triplet repeat expansion in the ARX gene (1) were detected. Discussion: Genetic diagnosis was made in 39% of patients. We emphasize the importance of considering mosaic variants, copy number variants and hereditary forms when designing and interpreting molecular studies, to optimize diagnosis and management of patients. Approximately 42% of the de tected variants were novel, expanding the knowledge of the molecular basis of DEEs in Latin-American patients.

Resumen Introducción: El objetivo del estudio fue ampliar el conocimiento de las bases moleculares de las encefalopatías epilépticas y del desarrollo (EED) en pacientes pediátricos argentinos aplicando un panel de secuenciación de nueva generación (NGS). Métodos: Se analizaron 31 pacientes con los fenotipos clínicos de síndrome de Dra vet (n:7), síndrome símil Dravet (n:3), síndrome de West (SW) (n:6), SW que evoluciona a síndrome de Lennox Gastaut (SLG)(N:4), epilepsia de la infancia con crisis focales migratorias (n:2), actividad de punta onda continua durante el sueño que evolucionan a SLG (n:1), SLG (n:1), encefalopatía no progresiva con estatus mioclónico (n:1), epilepsia mioclónica atónica (n:1), encefalopatía epiléptica con espigas multifocales (n:1) y encefalopatía epiléptica indeterminada (n:4). Se estudiaron los 52 genes más frecuentemente asociados a EED a través de NGS, en ADN extraído de sangre periférica. Resultados: Se identificaron variantes relevantes en 12 casos, de las cuales 5 fueron nuevas y 6 previamente reportadas como patogénicas o posiblemente patogénicas, mien tras que una variante fue clasificada como de significado incierto. Variantes heterocigotas, de nucleótido único, se identificaron en los genes SCN1A (5), GABRG2 (1), STXBP1 (2), una variante en mosaico en SCN2A (1) y otra homocigota en SCN1B (1). Además, se detectó una deleción que involucra a los genes SCN1A, SCN2A y SCN3A (1) y la expansión de repeticiones de tripletes más frecuente en el gen ARX (1). Discusión: Se alcanzó el diagnóstico molecular en el 39% de los pacientes. Remarcamos la importancia de considerar variantes en mosaico, variantes en el número de copias y formas heredadas al momento de diseñar e interpretar los estudios moleculares, de tal forma de optimizar el diagnóstico y seguimiento de los pacientes con EED. Cabe destacar, que el 42% de las variantes detectadas fueron nuevas, ampliando nuestro conocimiento sobre las bases mole culares de las EED en población latino americana.

Manejo práctico de las epilepsias farmacorresistentes en pediatría / Management of drug-resistant epilepsies in children

Resumen La prevalencia de las verdaderas epilepsias farmacorresistentes (EFR) en la población general es el 20% aproximadamente. El grupo de trabajo perteneciente a la International League Against Epi lepsy definió a las EFR como la falla en el control de las crisis al tratamiento con dos fármacos bien tolerados y adecuadamente seleccionados, en monoterapia o en combinación. Las EFR pueden dividirse en dos grandes categorías: las pseudo resistentes a los fármacos (RF) y las verdaderamente RF. Las epilepsias pseudo RF co rresponden a aquellas que son incorrectamente tratadas debido a errores por parte del paciente, por deficiencias sanitarias y por error u omisión del médico. Los errores por parte del paciente son el cumplimiento irregular de la toma de los fármacos anticonvulsivos (FACs) como la distribución horaria inadecuada y una vida desordena da. Las deficiencias sanitarias corresponden por ejemplo a una mala calidad en algunos fármacos en pacientes que dejan de recibir medicamentos originales y pasan a ingerir drogas genéricas. En relación a una omisión o error de los médicos, es importante destacar que un grupo importante de pacientes remitidos a la consulta como portadores de EFR, pueden presentar trastornos paroxísticos no epilépticos incluidas crisis funcionales, errores en el reconocimiento del tipo de crisis y síndromes epilépticos como la etiología y un manejo inadecuado de los FACs y otros tratamientos. Consideramos imprescindible el estudio sistemático de los pacientes con EFR a través de un equipo multidisciplinario, por lo cual creemos que un número considerable de pacientes se beneficiarán si se realiza un diagnóstico correcto temprano y un tratamiento integral adecuado.

Abstract The prevalence of true drug-resistant epilepsy (DRE) in the general population is about 20%. The International League Against Epilepsy (ILAE) working group defined DRE as the failure of seizure control by adequate trials of two well-tolerated and appropriately selected drugs, either in monotherapy or in combination. DREs can be divided into two broad cat egories: pseudo drug-resistant (DR) and true DR. Pseudo DRE correspond to those that are incorrectly treated due to patient error, healthcare deficiencies, or physician error or omission. Errors on the part of the patient are irregular compliance with the intake of antiseizure medications (ASMs) such as inadequate time distribution of the ASMs and an unhealthy lifestyle. Healthcare deficiencies are related, for example, to the poor quality of some drugs in patients who stop receiving original drugs and switch to generic drugs. Regarding omissions or errors by physicians, it is important to note that a significant group of patients referred to the clinic as having DRE may have non-epileptic paroxysmal disorders, including functional seizures, errors in the recognition of the type of seizures and epileptic syndromes as well as etiology, and inadequate management of the ASMs and other treatments We consider it essential to systematically study patients with DRE in a multidisciplinary team and we believe that a considerable number of patients will benefit from an early correct diagnosis and adequate comprehensive treatment.

[Management of drug resistant epilepsies in children]. / Manejo práctico de las epilepsias farmacorresistentes en pediatría.

The prevalence of true drug-resistant epilepsy (DRE) in the general population is about 20%. The International League Against Epilepsy (ILAE) working group defined DRE as the failure of seizure control by adequate trials of two well-tolerated and appropriately selected drugs, either in monotherapy or in combination. DREs can be divided into two broad categories: pseudo drug-resistant (DR) and true DR. Pseudo DRE correspond to those that are incorrectly treated due to patient error, healthcare deficiencies, or physician error or omission. Errors on the part of the patient are irregular compliance with the intake of antiseizure medications (ASMs) such as inadequate time distribution of the ASMs and an unhealthy lifestyle. Healthcare deficiencies are related, for example, to the poor quality of some drugs in patients who stop receiving original drugs and switch to generic drugs. Regarding omissions or errors by physicians, it is important to note that a significant group of patients referred to the clinic as having DRE may have non-epileptic paroxysmal disorders, including functional seizures, errors in the recognition of the type of seizures and epileptic syndromes as well as etiology, and inadequate management of the ASMs and other treatments We consider it essential to systematically study patients with DRE in a multidisciplinary team and we believe that a considerable number of patients will benefit from an early correct diagnosis and adequate comprehensive treatment.

La prevalencia de las verdaderas epilepsias farmacorresistentes (EFR) en la población general es el 20% aproximadamente. El grupo de trabajo perteneciente a la International League Against Epilepsy definió a las EFR como la falla en el control de las crisis al tratamiento con dos fármacos bien tolerados y adecuadamente seleccionados, en monoterapia o en combinación. Las EFR pueden dividirse en dos grandes categorías: las pseudo resistentes a los fármacos (RF) y las verdaderamente RF. Las epilepsias pseudo RF corresponden a aquellas que son incorrectamente tratadas debido a errores por parte del paciente, por deficiencias sanitarias y por error u omisión del médico. Los errores por parte del paciente son el cumplimiento irregular de la toma de los fármacos anticonvulsivos (FACs) como la distribución horaria inadecuada y una vida desordenada. Las deficiencias sanitarias corresponden por ejemplo a una mala calidad en algunos fármacos en pacientes que dejan de recibir medicamentos originales y pasan a ingerir drogas genéricas. En relación a una omisión o error de los médicos, es importante destacar que un grupo importante de pacientes remitidos a la consulta como portadores de EFR, pueden presentar trastornos paroxísticos no epilépticos incluidas crisis funcionales, errores en el reconocimiento del tipo de crisis y síndromes epilépticos como la etiología y un manejo inadecuado de los FACs y otros tratamientos. Consideramos imprescindible el estudio sistemático de los pacientes con EFR a través de un equipo multidisciplinario, por lo cual creemos que un número considerable de pacientes se beneficiarán si se realiza un diagnóstico correcto temprano y un tratamiento integral adecuado.

Panayiotopoulos syndrome: Unusual clinical manifestations.

PURPOSE: We retrospectively analyzed the electroclinical features, treatment, and outcome of patients with Panayiotopoulos syndrome (PS) who presented with unusual clinical manifestations. METHOD: A retrospective, descriptive, multicenter study was conducted evaluating 44 patients with PS who had seizures with an unusual semiology. Data from patients with PS seen at eight Argentine centers between April 2000 and April 2019 were collected. RESULTS: Twelve patients (29.2%) had ictal syncope or syncope-like epileptic seizures. Three children (7.3%) had recurrent episodes of vomiting. Four patients (9.7%) presented with urinary incontinence associated with autonomic signs and consciousness impairment. One child had hiccups with autonomic manifestations followed by eye deviation. One boy had episodes of laughter with autonomic symptoms followed by loss of consciousness. Six patients (14.6%) had hyperthermia without acute febrile illness with autonomic symptoms as the first manifestation. Six others (14.6%) had focal motor seizures characterized by eye and head deviation in four and eyelid blinking in two. Four patients (9.7%) had ictal headache as the initial manifestation followed by nausea and vomiting. Two children (4.8%) had their first seizure while asleep associated with cardiorespiratory arrest. Two children (4.8%) had oral automatisms, such as sucking and chewing. In two children (4.8%) coughing was the initial manifestation followed by emetic symptoms. One patient (2.3%) had vertigo with a sensation of fear, with eye deviation and unresponsiveness. One child started with continuous spikes and waves during slow sleep, behavior disturbances, and emetic symptoms. CONCLUSION: In this study, evidence of the existence of unusual clinical cases of PS with typical EEG patterns was found. Outcome was excellent.

Long-term effectiveness and adverse effects of ketogenic diet therapy in infants with drug-resistant epilepsy treated at a single center in Argentina.

INTRODUCTION: Ketogenic diet therapy (KDT) is a metabolic treatment with proven effectiveness for the treatment of drug-resistant epilepsy in children. Although previously not used in infants under 2 years of age, recent studies have shown KDT to be highly effective and well tolerated in infants with epilepsy, especially those with epileptic encephalopathies. Here, we describe the effectiveness and tolerability of the diet in infants up to 2 years of age. MATERIAL AND METHODS: A prospective study was conducted in a cohort of infants younger than 2 years of age with drug-resistant epilepsy who received the classic ketogenic diet using a specific protocol at a single center in Argentina. RESULTS: 56 infants with treatment-refractory epilepsy were evaluated. The etiology was genetic in 21.4%, structural in 28.6%, unknown in 44.7%, and metabolic in 5.4%. At 3 months, a > 50% decrease in seizure frequency was observed in 35 patients (62.4%), of whom 11 (19.6%) became seizure free. At 6 months, 34 patients (60.7%) had a decrease in seizure frequency of > 50%, of whom 10 (17.8%) were seizure free. At the one-year follow-up, 27 patients (48.2%) had a > 50% decrease in seizure frequency, of whom six (10.7%) were seizure free. At two years, 14 patients (25%) had a > 50% seizure control, of whom four (7.1%) were seizure free. The most common early adverse effects were hypoglycemia and vomiting, while after 1 month and beyond metabolic acidosis, vomiting, and constipation more commonly found. A trend towards a higher rate of acute adverse events in infants younger than 1 year was observed. CONCLUSIONS: CKD showed to be a useful option in infants with treatment-resistant epilepsy. Adverse effects were common, but not a reason to discontinue the diet. Further studies are necessary to evaluate in which epilepsy syndromes and etiologies KDT is most effective.

More than one self-limited epilepsy of childhood in the same patient: A multicenter study.

OBJECTIVE: We describe the evolution of the electroclinical picture of patients with different types of self-limited epilepsy of childhood (SLEC) occurring at the same or at different times with or without atypical evolutions as well as patients with SLEC associated with childhood absence epilepsy (CAE). MATERIAL AND METHODS: A multicenter, retrospective, descriptive study was conducted evaluating patients with SLEC who had focal seizures of different types of SLEC including atypical evolutions as well as SLEC associated with absence epilepsy seen at eight Argentinian centers between April 2000 and April 2019. Of 7705 patients with SLEC, aged between 2 and 14 years (mean, 7.5 years), of whom 2013 were female and 5692 male (ratio, 1:2.8), 5068 patients had SLECTS, 2260 patients had self-limited childhood occipital epilepsy Panayiotopoulos type (SLE-P), 356 had self-limited childhood occipital epilepsy Gastaut type (SLE-G), and 21 had self-limited epilepsy with affective seizures (SLEAS). Electroclinical features typical of more than one SLEC syndrome were recognized in 998 (13 %) children. RESULTS: We recognized three well-defined groups of patients. The most frequent association was SLE-P and SLECTS, the paradigmatic type, but associations of SLE-P and SLE-G, SLECTS and SLE-G, and SLEAS and SLE-P or SLECTS were also recognized. The second-most-common association was SLEC and an atypical evolution. In this group, the most frequent combination was SLECTS with its atypical evolution, opercular status epilepticus, epileptic encephalopathy with continuous spike-and-waves during slow sleep, or Landau-Kleffner syndrome. SLE-P and SLE-G associated with an atypical evolution were also identified. The third, less-frequent group had SLECTS, SLE-P, or SLE-G associated with CAE. These cases support the concept that the different types of SLEC are part of a self-limited childhood seizure susceptibility syndrome. CONCLUSION: Our study demonstrated that 13 % of our patients with SLEC have with different types of SLEC occurring at the same or at different times with or without atypical evolutions - i.e. CSWSS - as well as patients with SLEC associated with CAE, supporting the concept of the self-limited childhood seizure susceptibility syndrome.

Clinical and molecular characterization of mitochondrial DNA disorders in a group of Argentinian pediatric patients.

OBJECTIVE: To describe the clinical and molecular features of a group of Argentinian pediatric patients with mitochondrial DNA (mtDNA) disorders, and to evaluate the results of the implementation of a classical approach for the molecular diagnosis of mitochondrial diseases. METHODS: Clinical data from 27 patients with confirmed mtDNA pathogenic variants were obtained from a database of 89 patients with suspected mitochondrial disease, registered from 2014 to 2020. Clinical data, biochemical analysis, neuroimaging findings, muscle biopsy and molecular studies were analyzed. RESULTS: Patients were 18 females and 9 males, with ages at onset ranging from 1 week to 14 years (median = 4 years). The clinical phenotypes were: mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome (n = 11), Leigh syndrome (n = 5), Kearns-Sayre syndrome (n = 3), Chronic Progressive External Ophthalmoplegia (n = 2), Leber hereditary optic neuropathy (n = 2), myoclonic epilepsy associated with ragged-red fibers (n = 1) and reversible infantile myopathy with cytochrome-C oxidase deficiency (n = 3). Most of the patients harbored pathogenic single nucleotide variants, mainly involving mt-tRNA genes, such as MT-TL1, MT-TE and MT-TK. Other point variants were found in complex I subunits, like MT-ND6, MT-ND4, MT-ND5; or in MT-ATP6. The m.13513G > A variant in MT-ND5 and the m.9185 T > C variant in MT-ATP6 were apparently de novo. The rest of the patients presented large scale-rearrangements, either the "common" deletion or a larger deletion. CONCLUSIONS: This study highlights the clinical and genetic heterogeneity of pediatric mtDNA disorders. All the cases presented with classical phenotypes, being MELAS the most frequent. Applying classical molecular methods, it was possible to achieve a genetic diagnosis in 30% of the cases, suggesting that this is an effective first approach, especially for those centers from low-middle income countries, leaving NGS studies for those patients with inconclusive results.

Self-limited epilepsy of childhood with affective seizures: A well-defined epileptic syndrome?

OBJECTIVE: Here we present cases of focal epilepsy with affective symptoms analyzing seizure characteristics, EEG pattern, treatment, and outcome. METHODS: A multicenter, descriptive, retrospective study was conducted evaluating 18 patients with self-limited epilepsy who presented with seizures with affective symptoms seen between April 2000 and April 2018 at eight Argentinian centers. RESULTS: Eighteen patients had focal seizures with affective symptoms; all of them had affective symptoms characterized by sudden fright or terror and screaming. Seizures started with manifestations of sudden fright or terror manifested by a facial expression of fear; consciousness was mildly impaired in 15/18 patients. Eleven of the patients also had autonomic manifestations, such as pallor, sweating, and abdominal pain. In addition, four of these 11 patients had ictus emeticus and one also presented with unilateral deviation of the eyes and head. Speech arrest, salivation, glottal noises, and chewing or swallowing movements were observed in 2/18 patients at the onset of the affective seizures. Two others also had mild asymmetric dystonic seizures involving both hands and arms. Three patients had tonic deviation of the mouth involving the lips and tongue as well pharyngeal and laryngeal muscles, resulting in anarthria and drooling. Two patients had brief hemifacial focal clonic seizures. CONCLUSION: Affective manifestations associated or not with motor and/or autonomic manifestations and associated with typical EEG features of the idiopathic focal epilepsies of childhood is a particular presentation of self-limited focal epilepsy in childhood.