[Neuropediatrician of the 21st century and the neurosciences]. / El neuropediatra del siglo XXI y las neurociencias.

AIM: To describe the training process of the neuropediatrician in the 21st century in accordance with the clinical and scientific characteristics required by society at a time when there is an explosion of knowledge in neurosciences. DEVELOPMENT: The neuropediatrician of the 21st century, knowing the lack of future professionals, must stimulate neuroscientific vocations, starting in middle school and participating as early as possible in the teaching of medical students. During the fellowship, the neuropediatrician must continue the same encouraging attitude, getting the future colleague ready to face the professional requirements. In addition, he must teach the principles that will allow the future neuropediatrician to excel: critical thinking, evidence based medicine and continuing medical education. The certified professional neuropediatrician must exercise the same principles. Aware of the complexity of maintaining up to date medical knowledge, he/she must identify review courses and seminars. Also, he/she has to get accustomed to frequently use the Internet, the best means of self-education available to the neuropediatrician. The Spanish Pediatric Neurology Society and the Spanish Neurology Society should consider the possibility of reviewing the materials and methods used to train neuropediatricians in the US, with the goal of considering if any of them could be implemented in Spain. CONCLUSION: The neuropediatrician of the 21st century has the responsibility of his/her own continuing medical education, both clinical and neuroscientific. Moreover, he/she has the obligation of sharing this information with other colleagues and use it to stimulate future neuropediatricians and subspecialized neuropediatricians. Finally, he/she has the responsibility of establishing a productive interaction with the government and politicians in order to facilitate attaining the objectives of pediatric neurology.

El neuropediatra del siglo XXI y las neurociencias / Neuropediatrician of the 21st century and the neurosciences

Objetivo. Describir el proceso de formación del neuropediatra del siglo XXI de acuerdo con las características clínicas y científicas que le exige la sociedad en un momento de explosión del conocimiento en las neurociencias. Desarrollo. El neuropediatra del siglo XXI, consciente de la falta de profesionales en el futuro, debe estimular activamente las vocaciones neurocientíficas, comenzando en la escuela primaria y participando tempranamente en la enseñanza de los estudiantes de medicina. Durante la residencia, el neuropediatra debe continuar con la misma actitud estimulante, preparando al futuro colega para afrontar las exigencias de la profesión. Además, debe enseñar los principios que permitirán al futuro neuropediatra mantener un nivel de excelencia: pensamiento crítico, medicina basada en la evidencia y formación médica continua. El neuropediatraprofesional certificado o acreditado debe ejercer también los mismos principios. Consciente de la complejidad de mantener al día los conocimientos, debe identificar cursos y seminarios de revisión. Además, debe acostumbrarse a usar frecuentemente Internet, el mejor medio de actualización a disposición del neuropediatra, tanto clínico como neurocientífico.Las Sociedades Españolas de Neuropediatría y Neurología deberían considerar la posibilidad de revisar los métodos y materiales de formación neuropediátrica usados en Estados Unidos, con objeto de ver si alguno de ellos podría implementarse en España. Conclusión. El neuropediatra del siglo XXI tiene la responsabilidad de su formación continua, tanto clínica como neurocien-tífica. Además, tiene la obligación de compartir dicha formación con colegas y de estimular a través de ella a futuros neuropediatras y subespecia-listas neuropediá-tricos. Finalmente, tiene también la responsabilidad de establecer una interacción productiva con el gobierno y los estamentos políticos para favorecer la consecución de los objetivos de la neuropediatría

Aim. To describe the training process of the neuropediatrician in the 21st century in accordance with the clinical and scientific characteristics required by society at a time when there is an explosion of knowledge in neurosciences.Development. The neuropediatrician of the 21st century, knowing the lack of future professionals, must stimulate neuroscientific vocations, starting in middle school and participating as early as possible in the teaching of medical students. During the fellowship, the neuropediatrician must continue the same encouraging attitude, getting the future colleague ready to face theprofessional requirements. In addition, he must teach the principles that will allow the future neuropediatrician to excel: critical thinking, evidence based medicine and continuing medical education. The certified professional neuropediatrician must exercise the same principles. Aware of the complexity of maintaining up to date medical knowledge, he/she must identify review courses and seminars. Also, he/she has to get accustomed to frequently use the Internet, the best means of self-education available to the neuropediatrician. The Spanish Pediatric Neurology Society and the Spanish Neurology Society shouldconsider the possibility of reviewing the materials and methods used to train neuropediatricians in the US, with the goal of considering if any of them could be implemented in Spain. Conclusion. The neuropediatrician of the 21st century has the responsibility of his/her own continuing medical education, both clinical and neuroscientific. Moreover, he/she has the obligation of sharing this information with other colleagues and use it to stimulate future neuropediatricians and subspecialized neuropediatricians. Finally, he/she has the responsibility of establishing a productive interaction with the government and politicians in order to facilitate attaining the objectives of pediatric neurology

Epilepsy and respiratory chain defects in children with mitochondrial encephalopathies.

OBJECTIVE: The purpose of this study was to determine the relationship between epilepsy and respiratory chain defects in children with mitochondrial encephalopathies (ME). STUDY DESIGN: We conducted a retrospective review of the medical records of children referred for evaluation of an ME. Only patients assigned a definite diagnosis of ME using modified Walker criteria and with a respiratory chain defect were included. Clinical data pertaining to the ME and epilepsy type were collected. Mitochondria were isolated by subcellular fractionation from a vastus lateralis muscle biopsy and studies were performed using polarographic and spectroscopic techniques for the quantitative determination of NADH and cytochrome components of the respiratory chain. RESULTS: A total of 38 children with ME were identified. Seizures were present in 61%. Sixteen of 23 children with epilepsy (70%) had refractory epilepsy associated with a progressive encephalopathy. Children with epilepsy had a significantly higher incidence of complex I defects than children without epilepsy (p<0.01). Complex III and IV defects were significantly higher in patients without epilepsy (p<0.01 and p<0.05, respectively) than in those with epilepsy. CONCLUSIONS: Epilepsy is an important component of ME. The higher incidence of complex I defects in patients with epilepsy suggests a possible relationship between mitochondrial oxidative stress dysfunction and epileptogenic process.

[The effect of neonatal convulsions and antiepileptic drugs on the developing brain: controversial aspects and therapeutic implications]. / Efecto de las convulsiones neonatales y de los fármacos antiepilépticos sobre el cerebro en desarrollo: aspectos controvertidos e implicaciones terapéuticas.

INTRODUCTION: Neonatal seizures are the clinical or subclinical manifestations of epileptic nature during the first 28 days of life. Their pathophysiological basis depends on the anatomic and biochemical characteristics of the developing brain. The question whether neonatal seizures cause brain damage, even today, has not a clear answer. DEVELOPMENT: Data from clinical cases suggest that neonatal seizures may increase the cerebral blood flow and augment the energy requirements of the developing brain. Clinical research studies also suggest that neonatal seizures, even when they are only electrographic, may cause brain lesion independently from their cause. Multiple experimental investigations using mostly rat models of isolated or repeated induced seizures, have demonstrated that neonatal seizures may alter brain metabolic content, maturation of glutamatergic and GABAergic receptors, future cognitive development and epileptogenic risk, neuroneogenesis, intranuclear penetration of calcium, and neuronal apoptotic activation. On the other hand, some experimental studies suggest that phenobarbital, phenytoin and benzodiazepines may have a negative effect on brain development. CONCLUSIONS: In my opinion, the ideal short-term goal of treating neonatal seizures should be stopping not only the clinical but also the subclinical epileptic activity. If prolonged treatment is necessary, one should consider to stop it as soon as the clinical and EEG course allows it. There is a need for future randomized, controlled trials of sufficient statistical power to assess the efficacy and tolerability of classic and new antiepileptic drugs in the treatment of neonatal seizures.

Efecto de las convulsiones neonatales y de los fármacos antiepilépticos sobre el cerebro en desarrollo: aspectos controvertidos e implicaciones terapéuticas / The effect of neonatal convulsions and antiepileptic drugs on the developing brain: controversial aspects and therapeutic implications

Introducción. Las convulsiones neonatales son las manifestaciones clínicas o subclínicas, de naturaleza epiléptica, que suceden durante los primeros 28 días de vida. Su base fisiopatológica se caracteriza por las peculiaridades anatómicas y bioquímicas del cerebro en desarrollo. La pregunta de si las convulsiones causan lesión en el cerebro en desarrollo no tiene una respuesta clara. Desarrollo. Datos de casos clínicos sugieren que las convulsiones neonatales pueden aumentar el flujo sanguíneo cerebral e incrementar las demandas energéticas del cerebro en desarrollo. Investigaciones clínicas sugieren que las convulsiones neonatales, incluso si son sólo electrográficas, pueden producir lesión cerebral independientemente de su causa. Múltiples investigaciones experimentales, con modelos de convulsiones únicas o repetidas, la mayoría en ratas, han demostrado que las convulsiones neonatales pueden alterar el contenido metabólico cerebral, la maduración de los receptores glutamatérgicos y gabérgicos, el desarrollo cognitivo y el riesgo epileptógeno futuro, la neuroneogénesis, la penetración intranuclear de calcio y la activación de la muerte neuronal por apoptosis. Algunos datos experimentales sugieren que el fenobarbital, la fenitoína y las benzodiacepinas pueden tener un efecto nocivo sobre el desarrollo cerebral. Conclusiones. El objetivo ideal del tratamiento a corto plazo con fármacos antiepilépticos (FAE) debe ser el cese o la reducción de las convulsiones clínicas y de las crisis epilépticas. Cuando se necesita un tratamiento prolongado, debe considerarse su suspensión cuanto antes lo permita la evolución clínica y electroencefalográfica. Se necesitan estudios prospectivos, aleatorizados, controlados por placebo, con poder estadístico suficiente, para valorar la eficacia y la tolerabilidad de los FAE en el tratamiento de las convulsiones neonatales (AU)

Introduction. Neonatal seizures are the clinical or subclinical manifestations of epileptic nature during the first 28 days of life. Their pathophysiological basis depends on the anatomic and biochemical characteristics of the developing brain. The question whether neonatal seizures cause brain damage, even today, has not a clear answer. Development. Data from clinical cases suggest that neonatal seizures may increase the cerebral blood flow and augment the energy requirements of the developing brain. Clinical research studies also suggest that neonatal seizures, even when they are only electrographic, may cause brain lesion independently from their cause. Multiple experimental investigations using mostly rat models of isolated or repeated induced seizures, have demonstrated that neonatal seizures may alter brain metabolic content, maturation of glutamatergic and GABAergic receptors, future cognitive development and epileptogenic risk, neuroneogenesis, intranuclear penetration of calcium, and neuronal apoptotic activation. On the other hand, some experimental studies suggest that phenobarbital, phenytoin and benzodiazepines may have a negative effect on brain development. Conclusions. In my opinion, the ideal short-term goal of treating neonatal seizures should be stopping not only the clinical but also the subclinical epileptic activity. If prolonged treatment is necessary, one should consider to stop it as soon as the clinical and EEG course allows it. There is a need for future randomized, controlled trials of sufficient statistical power to assess the efficacy and tolerability of classic and new antiepileptic drugs in the treatment of neonatal seizures (AU)

[The role played by calcium in neuronal injury following neonatal hypoxia or convulsions]. / Función del calcio en la lesión neuronal tras hipoxia o convulsiones neonatales.

AIM: Calcium plays a complex and pivotal role both in neuronal development and function, and in hypoxia/ ischemia-induced cell death. In this paper, we review current concepts of calcium function emphasizing the neonatal period. DEVELOPMENT: Calcium enters the neuron through glutamate receptors (NMDA and AMPA) located on the neuronal membrane. After hypoxia or seizures, there is a conformational change of the receptors, with increased flow of calcium into the cytoplasm. Cytoplasmatic calcium triggers activation of several free-radical generation pathways, including the nitric oxide pathway, with a deleterious effect upon the neuron. Calcium then enters the neuronal nucleus, through specific receptors on the nuclear membrane. In our experience, hypoxia and neonatal seizures create nuclear membrane dysfunction, increasing the nitric-oxide-dependent flow of calcium into the nucleus. Nuclear calcium increase is critical for genetic transcription, pro-apoptotic gene activation and a cascade of biochemical and molecular events that lead to an increase of caspases and apoptotic neuronal death. CONCLUSIONS: Calcium has a crucial role in neuronal damage after neonatal hypoxia or seizures. A better knowledge of the pathogenic mechanisms that lead to neuronal damage after neonatal hypoxia or seizures will assist in future development of efficacious neuroprotective therapies.

[Cerebrovascular disorders in preterm neonates]. / Accidentes vasculares encefálicos en neonatos pretérmino.

AIM: To review the etiology, pathogenesis, clinical manifestations, diagnosis and treatment of cerebrovascular disorders (CVD) in preterm neonates. DEVELOPMENT: The germinal matrix-intraventricular hemorrhage (GM-IVH) is the most frequent intracranial hemorrhage. The pathogenesis includes intravascular, vascular and extravascular factors. The neuropathologic lesion is the hemorrhage within the subependymal GM. There are four degrees of severity. Clinical manifestations include three syndromes: catastrophic, saltatory and silent. Treatment is prophylactic. Periventricular hemorrhagic infarct is of venous origin, might be associated to GM-IVH and is difficult to differentiate from periventricular leukomalacia (PVL). Cerebellar hemorrhage frequency increases with decreasing gestational age. It may be asymptomatic or manifest with a non-specific neurologic picture. PVL is the most important ischemic lesion. Its pathogenesis includes anatomic, physiologic, maturational, biochemical, infectious and immunologic factors. The neuropathologic lesion is focal necrosis in the terminal distribution of the long penetrating arteries. Treatment is prophylactic. Other ischemic lesions are ischemic arterial infarct, cerebellar infarct, telencephalic leukoencephalopathy and pontosubicular necrosis. CVD diagnostic tests include cerebral ultrasound, computed tomography, magnetic resonance imaging and spectroscopy and electroencephalogram. Mortality of some CVD is high and some others are associated with a high risk of cerebral palsy and cognitive deficits. CONCLUSION: CVD are common in preterm neonates and represent an important cause of neurologic disease in the child.

Función del calcio en la lesión neuronal tras hipoxia o convulsiones neonatales / The role played by calcium in neuronal injury following neonatal hypoxia or convulsions

Objetivo. El calcio posee una función importante en eldesarrollo y función neuronales, así como también en los mecanismosde lesión neuronal tras hipoxia o convulsiones. En este trabajose revisarán los conceptos actuales de dicha función, con énfasisen el período neonatal. Desarrollo. El calcio entra en las neuronaspor medio de receptores de glutamato (NMDA y AMPA) localizados en la membrana celular. Tras hipoxia o convulsiones, hay uncambio en la conformación de estos receptores por el que aumentala entrada de calcio al citoplasma de la neurona. El calcio citoplasmáticoactiva varias vías de generación de radicales libres,incluida la del óxido nítrico, con efecto tóxico para la neurona.Posteriormente, el calcio penetra en el núcleo neuronal a través dereceptores específicos en la membrana nuclear. En nuestra experiencia,la hipoxia y las convulsiones neonatales producen una disfunciónde la membrana nuclear que incrementa el flujo del calcioal interior del núcleo, el cual es dependiente del óxido nítrico. Elaumento intranuclear del calcio es crítico para la transcripcióngenética, pues activa genes proapoptóticos y una cascada de fenómenosbioquímicos y moleculares que culminan con el aumento delas caspasas y muerte neuronal por apoptosis. Conclusiones. Elcalcio tiene un papel central en el daño neuronal secundario ahipoxia y convulsiones durante el período neonatal. Un mejorconocimiento de los mecanismos patogénicos que producen lesiónneuronal tras hipoxia o convulsiones neonatales puede favoreceren el futuro el desarrollo de terapias neuroprotectoras eficaces

Aim. Calcium plays a complex and pivotal role both in neuronal development and function, and in hypoxia/ischemia-induced cell death. In this paper, we review current concepts of calcium function emphasizing the neonatal period.Development. Calcium enters the neuron through glutamate receptors (NMDA and AMPA) located on the neuronal membrane.After hypoxia or seizures, there is a conformational change of the receptors, with increased flow of calcium into the cytoplasm.Cytoplasmatic calcium triggers activation of several free-radical generation pathways, including the nitric oxide pathway,with a deleterious effect upon the neuron. Calcium then enters the neuronal nucleus, through specific receptors on the nuclearmembrane. In our experience, hypoxia and neonatal seizures create nuclear membrane dysfunction, increasing the nitricoxide-dependent flow of calcium into the nucleus. Nuclear calcium increase is critical for genetic transcription, pro-apoptoticgene activation and a cascade of biochemical and molecular events that lead to an increase of caspases and apoptoticneuronal death. Conclusions. Calcium has a crucial role in neuronal damage after neonatal hypoxia or seizures. A betterknowledge of the pathogenic mechanisms that lead to neuronal damage after neonatal hypoxia or seizures will assist in futuredevelopment of efficacious neuroprotective therapies

Accidentes vasculares encefálicos en neonatos pretérmino / Cerebrovascular disorders in preterm neonates

Objetivo. Revisar los aspectos etiopatogénicos, clínicos,diagnósticos y terapéuticos de los accidentes vasculares encefálicos(AVE) en neonatos pretérmino. Desarrollo. La hemorragia dela matriz germinal-hemorragia intraventricular (HMG-HIV) es lahemorragia intracraneal más frecuente. La patogenia incluye factoresintravasculares, vasculares y extravasculares. La lesión neuropatológicaes la hemorragia en la matriz germinal subependimaria.Hay cuatro grados de gravedad. La clínica se caracteriza portres síndromes: de deterioro catastrófico, saltatorio y silencioso. Eltratamiento es preventivo. El infarto hemorrágico periventricular es de origen venoso, se puede asociar a HMG-HIV y es difícil diferenciarlode la leucomalacia periventricular (LPV). La hemorragiacerebelosa aumenta a medida que disminuye la edad gestacional.Puede ser asintomática o presentar un cuadro neurológicoinespecífico. Otras hemorragias son la del plexo coroideo, talámicay subaracnoidea. La LPV es la lesión isquémica más importante.En su patogenia participan factores anatómicos, fisiológicos,madurativos, bioquímicos, infecciosos, e inmunológicos. La lesiónneuropatológica es la necrosis focal en la distribución terminal delas arterias penetrantes largas. El tratamiento es preventivo. Otraslesiones isquémicas son el infarto arterial isquémico, el infartocerebeloso, la leucoencefalopatía telencefálica y la necrosis de laprotuberancia y del subículo. Las pruebas diagnósticas de los AVEincluyen la ecografía, la tomografia axial computarizada, la resonanciamagnética, la espectroscopia de resonancia magnética y elelectroencefalograma. La mortalidad de algunos AVE es alta yotros plantean un alto riesgo de parálisis cerebral y déficit cognoscitivos.Conclusión. Los AVE en el neonato pretérmino son frecuentesy representan una causa importante de patología neurológicaen el niño

Aim. To review the etiology, pathogenesis, clinical manifestations, diagnosis and treatment of cerebrovasculardisorders (CVD) in preterm neonates. Development. The germinal matrix-intraventricular hemorrhage (GM-IVH) is the mostfrequent intracranial hemorrhage. The pathogenesis includes intravascular, vascular and extravascular factors. The neuropathologiclesion is the hemorrhage within the subependymal GM. There are four degrees of severity. Clinical manifestationsinclude three syndromes: catastrophic, saltatory and silent. Treatment is prophylactic. Periventricular hemorrhagic infarct is ofvenous origin, might be associated to GM-IVH and is difficult to differentiate from periventricular leukomalacia (PVL). Cerebellarhemorrhage frequency increases with decreasing gestational age. It may be asymptomatic or manifest with a non-specificneurologic picture. PVL is the most important ischemic lesion. Its pathogenesis includes anatomic, physiologic, maturational,biochemical, infectious and immunologic factors. The neuropathologic lesion is focal necrosis in the terminal distribution of thelong penetrating arteries. Treatment is prophylactic. Other ischemic lesions are ischemic arterial infarct, cerebellar infarct,telencephalic leukoencephalopathy and pontosubicular necrosis. CVD diagnostic tests include cerebral ultrasound, computedtomography, magnetic resonance imaging and spectroscopy and electroencephalogram. Mortality of some CVD is high and someothers are associated with a high risk of cerebral palsy and cognitive deficits. Conclusion. CVD are common in preterm neonatesand represent an important cause of neurologic disease in the child

[Fetal neurological evaluation]. / Evaluación neurológica del feto.

AIM: To review recent advances in the procedures and techniques that have made possible to evaluate the anatomy and function of the central nervous system (CNS) in the fetus. DEVELOPMENT: The neurological evaluation of the fetus can be performed at different levels: clinical, anatomical and functional. At a clinical level the analysis of body, ocular or respiratory fetal movements, as well as fetal heart rate, defines 4 behavioural states: 1F and 2F correspond to the quiet and active sleep, respectively. States 3F and 4F occur during wakefulness in the newborn, but there is no scientific evidence that the fetus is awake. Behavioral states probably play an important role in the process of CNS maturation and development. Anatomic evaluation of the CNS to rule out brain malformations can be performed with ultrasound since week 7-8 of gestational age and with magnetic resonance imaging (MRI) since week 18-20. Both techniques are also useful in the diagnosis of acquired fetal neurological diseases. Both modalities are concordant in the majority of cases, but in others each of them provides additional, different information. Computed tomography should only be used in selected cases that involve bone structures. Functional evaluation of fetal CNS can be performed with proton MR spectroscopy, which determines the cerebral content of inositol, choline, creatine and N-acetylaspartate. Other techniques to functionally study the fetal brain are functional MRI (fMRI), near infrared spectroscopy, and magnetoencephalography. CONCLUSIONS: Fetal neurology is a discipline that will continue to develop fast in the immediate future. Technological advances will facilitate the possibility of a more rapid and reliable diagnosis of anatomic or functional abnormalities of the fetal CNS.

Evaluación neurológica del feto / Fetal neurological evaluation

Objetivo. Revisar los avances recientes en los procedimientos y técnicas que han permitido estudiar el estado anatómico y funcional del sistema nervioso central (SNC) en el feto. Desarrollo. La evaluación neurológica del feto puede hacerse desde el punto de vista clínico, anatómico o funcional. Clínicamente, la valoración fetal de los movimientos corporales, oculares y respiratorios, así como del latido cardíaco, permite definir cuatro estados de conducta fetal: 1F y 2F corresponden a los estados de sueño tranquilo y activo. Los estados 3F y 4F se dan en situación de vigilia en el recién nacido, pero no hay evidencia científica de que el feto tenga la capacidad de estar despierto. Los estados de conducta probablemente ejercen una función importante en la maduración y desarrollo del SNC. La evaluación anatómica del SNC para diagnosticar si éste presenta malformaciones puede hacerse con ecografía desde la semana 7-8 de gestación, y con resonancia magnética (RM) desde la semana 18-20. Ambas técnicas son muy útiles también en el diagnóstico de patología neurológica fetal adquirida. Ambas modalidades son concordantes en la mayoría de los casos, pero en otros cada una de ellas proporciona información adicional, diferente. La tomografía axial computarizada sólo debe utilizarse en casos muy específicos que afecten a estructuras óseas. La evaluación funcional del feto puede hacerse con espectroscopia de resonancia magnética, la cual analiza el contenido cerebral de inositol, colina, creatina y N-acetilaspartato. Otras técnicas para el estudio funcional del cerebro fetal son la RM funcional, la espectroscopia de rayo de luz casi infrarrojo y la magnetoencefalografía. Conclusiones. La neurología fetal es una disciplina que continuará su rápida evolución en el futuro inmediato. Los avances tecnológicos favorecerán diagnósticos más rápidos y certeros de alteraciones anatómicas y funcionales del SNC fetal (AU)

Aim. To review recent advances in the procedures and techniques that have made possible to evaluate the anatomy and function of the central nervous system (CNS) in the fetus. Development. The neurological evaluation of the fetus can be performed at different levels: clinical, anatomical and functional. At a clinical level the analysis of body, ocular or respiratory fetal movements, as well as fetal heart rate, defines 4 behavioural states: 1F and 2F correspond to the quiet and active sleep, respectively. States 3F and 4F occur during wakefulness in the newborn, but there is no scientific evidence that the fetus is awake. Behavioral states probably play an important role in the process of CNS maturation and development. Anatomic evaluation of the CNS to rule out brain malformations can be performed with ultrasound since week 7-8 of gestational age and with magnetic resonance imaging (MRI) since week 18-20. Both techniques are also useful in the diagnosis of acquired fetal neurological diseases. Both modalities are concordant in the majority of cases, but in others each of them provides additional, different information. Computed tomography should only be used in selected cases that involve bone structures. Functional evaluation of fetal CNS can be performed with proton MR spectroscopy, which determines the cerebral content of inositol, choline, creatine and N-acetylaspartate. Other techniques to functionally study the fetal brain are functional MRI (fMRI), near infrared spectroscopy, and magnetoencephalography. Conclusions. Fetal neurology is a discipline that will continue to develop fast in the immediate future. Technological advances will facilitate the possibility of a more rapid and reliable diagnosis of anatomic or functional abnormalities of the fetal CNS (AU)

Relapse of herpes encephalitis after acyclovir therapy: report of two new cases and review of the literature.

Relapse of herpes simplex virus (HSV) encephalitis following acyclovir therapy has been reported infrequently in children beyond the neonatal period. The pathogenic mechanism of the recurrence is not fully understood. We report two new cases that support a mechanism of latent HSV infection with reactivation of the disease. Our patients were 2 years (#1) and 8 months (#2) old at initial infection. Both presented with fever, lethargy, focal seizures, and focal motor abnormalities. Serum HSV antibodies (Abs) were negative. The patients were treated with acyclovir for 14 and 21 days, respectively. They were readmitted at 1 month, and 4 days after discharge, respectively, with recurrent lethargy, seizures, and choreo-athetoid movements. Serum and CSF HSV Abs were significantly increased. CSF PCR was positive. In patient # 2 acyclovir-sensitive HSV was isolated from a brain biopsy. Both patients were re-treated with acyclovir, but progressed to a neurovegetative state. In our cases, latent HSV infection and reactivation is the most likely explanation for recurrent encephalitis. The immuno-pathogenic mechanisms of the infection recurrence are discussed. Based on the reported cases in the literature, patients younger than 2 years of age and with lower total dose of acyclovir treatments have a higher risk of recurrence.

Hypoxia-induced caspase-3 activation and DNA fragmentation in cortical neurons of newborn piglets: role of nitric oxide.

Hypoxia results in generation of nitric oxide (NO) free radicals, activation of caspase-3, and genomic DNA fragmentation. The present study tests the hypothesis that hypoxia-induced caspase-3 activation and DNA fragmentation are nitric oxide mediated. Studies were conducted in newborn piglets, divided into normoxic (n = 5), hypoxic (n = 5), and hypoxic-7-NINA (n = 6). Hypoxic-7-NINA group received the neuronal nitric oxide synthase inhibitor, 7-Nitroindazole (7-NINA). Caspase-3 activity was determined spectrofluorometrically using enzyme-specific substrates. Sections from the neocortex were stained with an antiserum recognizing active caspase-3. Purified DNA was separated by gel electrophoresis. Administration of 7-NINA resulted in decreased immunoreactivity of caspase-3 (mean LI: 20.2%) as compared to the untreated hypoxia group (mean LI: 57.5%) (P < 0.05). 7-NINA attenuated caspase-3 enzymatic activity as well in comparison to the untreated hypoxia group (P < 0.05). Furthermore, multiple low molecular weight bands corresponding to DNA fragments were present in the hypoxic but not in the normoxic or hypoxic-7-NINA groups. Inhibition of nNOS abates the hypoxia-induced increase in active caspase-3 immunoreactivity, as well as enzymatic activity in cortical neurons, and DNA fragmentation in brain homogenates. We conclude that the coordinate increase of capase-3 activity and fragmentation of nuclear DNA in the hypoxic newborn piglet brain are NO mediated.

[Cerebral palsy: new pathogenetic concepts]. / Parálisis cerebral: nuevos conceptos etiopatogénicos.

OBJECTIVE: To review the current knowledge pertaining to the new pathogenetic aspects of cerebral palsy (CP). DEVELOPMENT: CP is a group of static, heterogeneous clinical syndromes, characterized by abnormal postural mechanisms and motor activities. Its prevalence in industrialized countries is 2 2.5/1000 newborns. CP should be differentiated from certain genetic or metabolic conditions with which it can be mistaken. Some cases of CP have a genetic basis and they are inherited following a mendelian pattern or are determined by specific isolated genes. Recently, the elevation of certain coagulation factors (i.e., Leiden factor V mutation) and cytokines (i.e. interleukins, a tumor necrosis factor) and interferons have been related to CP pathogenesis. Hypocapnia with PaCO2< 35 mmHg represents a risk for periventricular leukomalacia (PVL) in premature infants. PVL pathogenesis is complex and includes a series of mechanisms that interact among them: fetal/maternal infection, immuneinflammatory reaction, prematurity, intraventricular hemorrhage/iron, ischemia/reperfusion, free radical production, maturational sensitivity of oligodendrocytes, and glutamate effect. Neuroradiological and neuropathological data have demonstrated a cortical anatomical substrate for the intellectual deficits associated with PVL in premature infants. CONCLUSIONS: Current knowledge about CP pathogenesis opens the possibility of early diagnosis and development of new treatments, both therapeutic and preventive.

[Acquired immunodeficiency syndrome by vertical transmission: neurological disorders]. / Sindrome de inmunodeficiencia adquirida por transmision vertical: alteraciones neurologicas.

INTRODUCTION: Forty million people are currently infected by HIV; of these, 50% are women and children. Vertical transmission occurs in 90% of the cases reported in the literature and was also observed by the authors of the present study at Hospital de Clínicas de Porto Alegre, Brazil, in the follow up of 340 HIV positive children since 1985. Transmission can occur during pregnancy (intrauterine) or during labor and delivery (intrapartum). In addition, HIV has been identified in the breast milk of infected mothers, which represents a contraindication for breastfeeding in these cases. Laboratory diagnosis is carried out using the following tests: ELISA, Western blot, and indirect immunofluorescence. DEVELOPMENT: Neurological manifestations in children may be divided into primary neurological diseases and secondary complications. Primary neurological diseases include both static encephalopathy, of slow evolution, and progressive encephalopathy, which affects neuropsychomotor development. The follow up of 340 children with AIDS showed encephalopathy in 32.5% of cases and delayed neuropsychomotor development in 42.5%. Opportunistic infections occurred in 33.8% of cases (one infant presented meningoencephalitis caused by Trypanosoma cruzi). One child presented lymphomas, 2.6% had cerebrovascular accidents, and 5% had peripheral neuropathies. Currently, 54 children of those followed since birth have over 10 years of age, and of these, 31 (57%) present neurological symptoms 40% with encephalopathy and 30% with neurological complications; the remaining children present educational, behavioral, and developmental difficulties. CONCLUSIONS: Several factors have influenced the natural history of AIDS in childhood, such as early diagnosis, drug regimen used, social, economic, and nutritional conditions, as well as health practices aimed at this population.

Síndrome de inmunodeficiencia adquirida por transmisión vertical: alteraciones neurológicas / Acquired immunodeficiency syndrome by vertical transmission: neurological disorders

Introducción. Actualmente, 40 millones de personas están infectadas por VIH; de éstas, un 50 por ciento son mujeres y niños. La forma de transmisión vertical es la que se ha encontrado en el 90 por ciento de los casos informados por otros autores y la que hemos observado nosotros, en el Hospital de Clínicas de Porto Alegre (HCPA), al seguir los casos de 340 niños VIH+ desde 1985. La contaminación puede suceder en varios momentos, tanto intrauterina como intraparto. El virus ya se identificó en la leche materna, lo que contraindica amamantar cuando la madre es VIH+. El diagnóstico de laboratorio se hizo con los tests ELISA, Western-blot e inmunofluorescencia indirecta. Desarrollo. Las manifestaciones neurológicas del niño pueden dividirse en enfermedad neurológica primaria y complicaciones secundarias. En la enfermedad neurológica primaria tenemos que considerar la encefalopatía estática, de evolución menos agresiva, y la encefalopatía progresiva, que conduce a la pérdida de adquisiciones del desarrollo neuropsicomotor. Al seguir a 340 pacientes con sida se observó encefalopatía en un 32,5 por ciento de los casos, y en un 42,5 por ciento, retraso del desarrollo neuropsicomotor. En el 33,8 por ciento de los casos aparecieron algunas infecciones oportunistas, y un lactante presentó meningoencefalitis por Tripanosoma cruzi. Un niño tuvo linfoma. En un 2,6 por ciento de los casos ocurrió AVCI y en un 5 por ciento neuropatía periférica. Actualmente, 54 niños seguidos desde el nacimiento tienen más de 10 años de edad. De éstos, 31 (57 por ciento) presentan síntomas neurológicos: el 40 por ciento, encefalopatía; el 30 por ciento, complicaciones neurológicas; el resto, dificultades escolares, de comportamiento y de desarrollo. Conclusiones. Muchos factores han influido en la historia natural del sida durante la infancia, como el diagnóstico precoz, el esquema terapéutico utilizado y las condiciones sociales, económicas y nutricionales, así como las políticas de salud que contemplan estos casos (AU)

Introduction. Forty million people are currently infected by HIV; of these, 50% are women and children. Vertical transmission occurs in 90% of the cases reported in the literature and was also observed by the authors of the present study at Hospital de Clínicas de Porto Alegre, Brazil, in the follow-up of 340 HIV-positive children since 1985. Transmission can occur during pregnancy (intrauterine) or during labor and delivery (intrapartum). In addition, HIV has been identified in the breast milk of infected mothers, which represents a contraindication for breastfeeding in these cases. Laboratory diagnosis is carried out using the following tests: ELISA, Western-blot, and indirect immunofluorescence. Development. Neurological manifestations in children may be divided into primary neurological diseases and secondary complications. Primary neurological diseases include both static encephalopathy, of slow evolution, and progressive encephalopathy, which affects neuropsychomotor development. The follow-up of 340 children with AIDS showed encephalopathy in 32.5% of cases and delayed neuropsychomotor development in 42.5%. Opportunistic infections occurred in 33.8% of cases (one infant presented meningoencephalitis caused by Trypanosoma cruzi). One child presented lymphomas, 2.6% had cerebrovascular accidents, and 5% had peripheral neuropathies. Currently, 54 children of those followed since birth have over 10 years of age, and of these, 31 (57%) present neurological symptoms -40% with encephalopathy and 30% with neurological complications; the remaining children present educational, behavioral, and developmental difficulties. Conclusions. Several factors have influenced the natural history of AIDS in childhood, such as early diagnosis, drug regimen used, social, economic, and nutritional conditions, as well as health practices aimed at this population (AU)

Parálisis cerebral: nuevos conceptos etiopatogénicos / Cerebral palsy: new pathogenetic concepts

Objetivo. Revisar los conocimientos sobre nuevos aspectos etiopatogénicos de la parálisis cerebral (PC). Desarrollo. La PC es un conjunto de síndromes clínicos heterogéneos estáticos, caracterizados por mecanismos posturales y actividades motoras anormales. Su prevalencia en países industrializados es 2-2,5/1.000 recién nacidos. Hay que diferenciar la PC de algunos síndromes genéticos y metabólicos con los que puede confundirse. Determinados casos de PC tienen una base genética, de herencia mendeliana o de determinación por un gen específico. Recientemente, se ha relacionado la elevación de determinados factores de la coagulación (p. ej., mutación Leiden del factor V) y de citocinas (p. ej., interleucinas, factor de necrosis tumoral a) e interferones con la patogenia de la PC. La hipocapnia, con una PaCO2 menor de 35 mmHg, supone un riesgo de leucomalacia periventricular (LPV) en prematuros. La patogenia de la LPV es compleja e incluye diversos mecanismos que interaccionan entre sí: infección materno/fetal, reacción inmunoinflamatoria, prematuridad, hemorragia intraventricular/hierro, isquemia/reperfusión, producción de radicales libres, sensibilidad madurativa de los oligodendrocitos y acción del glutamato. Datos neurorradiológicos y neuropatológicos han demostrado un sustrato anatómico cortical de los déficit intelectuales asociados con LPV en recién nacidos prematuros. Conclusiones. Los conocimientos actuales sobre la patogenia de la PC abren la posibilidad al diagnóstico precoz y al desarrollo de nuevos tratamientos curativos y preventivos (AU)

Objective. To review the current knowledge pertaining to the new pathogenetic aspects of cerebral palsy (CP). Development. CP is a group of static, heterogeneous clinical syndromes, characterized by abnormal postural mechanisms and motor activities. Its prevalence in industrialized countries is 2-2.5/1000 newborns. CP should be differentiated from certain genetic or metabolic conditions with which it can be mistaken. Some cases of CP have a genetic basis and they are inherited following a mendelian pattern or are determined by specific isolated genes. Recently, the elevation of certain coagulation factors (i.e., Leiden factor V mutation) and cytokines (i.e. interleukins, a tumor necrosis factor) and interferons have been related to CP pathogenesis. Hypocapnia with PaCO2< 35 mmHg represents a risk for periventricular leukomalacia (PVL) in premature infants. PVL pathogenesis is complex and includes a series of mechanisms that interact among them: fetal/maternal infection, immuneinflammatory reaction, prematurity, intraventricular hemorrhage/iron, ischemia/reperfusion, free radical production, maturational sensitivity of oligodendrocytes, and glutamate effect. Neuroradiological and neuropathological data have demonstrated a cortical anatomical substrate for the intellectual deficits associated with PVL in premature infants. Conclusions. Current knowledge about CP pathogenesis opens the possibility of early diagnosis and development of new treatments, both therapeutic and preventive (AU)

[Prevention of epilepsy]. / Prevención de la epilepsia.

OBJECTIVE: To review the preventive and prophylactic aspects of epilepsy. DEVELOPMENT: The description of the prevention of the causes of epilepsy includes the measures to prevent epilepsy and epileptic seizures. The concept of antiepileptogenesis is discussed according to the available information about the role that both the classic and new antiepileptic drugs (AEDs) play in this process. Neuroprotection is discussed in the context of the mechanisms of action of the AEDs and of the mechanisms of neuronal lesion produced by the causes of epilepsy or by the seizures themselves. Among the new therapeutic modalities the current knowledge about the vagus nerve stimulator and the surgical treatment is summarized. The potential future therapeutic modalities include alternative medicine, pharmacologic treatment of the epileptogenic focus, genetic treatment and vaccination. CONCLUSIONS: The first step in preventing epilepsy is to avoid the causes or the risk factors. Some classic AEDs have demonstrated to be effective in the prophylaxis of provoked seizures (acute, symptomatic) but not of unprovoked seizures (epileptic). The best knowledge of the pathogenesis and the molecular and biological basis of epileptogenesis secondary to lesional causes, suggest that antioxidant and neuroprotective agents, including the new AEDs, may prevent epilepsy. There is a need to design studies with the goal of demonstrating their antiepileptogenic and/or neuroprotective activity at different ages in life. New and future therapeutic modalities may offer additional preventive options.

Prevención de la epilepsia / Prevention of epilepsy

Objetivo. Revisar los aspectos preventivos y profilácticos de la epilepsia. Desarrollo. La descripción de la prevención de las causas de la epilepsia incluye las medidas para prevenir la epilepsia y las convulsions epilépticas. El concepto de antiepileptogénesis se discute de acuerdo con la información disponible sobre el papel que los fármacos antiepilépticos, clásicos y nuevos, tienen en este proceso. La neuroprotección se describe en el contexto de los mecanismos de acción de los fármacos antiepilépticos, así como de los mecanismos de lesión neuronal producida por las causas de la epilepsia o por las convulsiones mismas. Dentro de las nuevas modalidades terapéuticas de la epilepsia se comentan los conocimientos recientes del estimulador del nervio vago y del tratamiento quirúrgico. En las posibles modalidades terapéuticas futuras se incluyen terapias alternativas, tratamiento farmacológico dirigido al foco epiléptico, tratamiento genético y vacunación. Conclusiones. El primer paso en la prevención de la epilepsia es evitar las causas o factores de riesgo. Algunos fármacos anticonvulsivantes clásicos han demostrado su eficacia en la profilaxis de convulsiones provocadas (agudas sintomáticas), pero no de convulsiones no provocadas (epilépticas). El mejor conocimiento de la patogenia y las bases biomoleculares de la epileptogénesis secundaria a varias causas lesionales, sugiere que fármacos antioxidantes y neuroprotectores, junto a los nuevos anticonvulsivantes, pueden prevenir el desarrollo de la epilepsia. Se necesita diseñar estudios con el objetivo de demostrar su actividad antiepileptógena y/o neuroprotectora a distintas edades de la vida. Nuevas y futuras modalidades terapéuticas pueden ofrecer posibilidades preventivas adicionales (AU)

Presence of oligoclonal T cells in cerebrospinal fluid of a child with multiphasic disseminated encephalomyelitis following hepatitis A virus infection.

We have investigated the clonality of beta-chain T-cell receptor (TCR) transcripts from the cerebrospinal fluid (CSF) and peripheral blood from a 7-year old child who developed a multiphasic disseminated encephalomyelitis following an infection with hepatitis A virus. We amplified beta-chain TCR transcripts by nonpalindromic adaptor (NPA)-PCR-Vbeta-specific PCR. TCR transcripts from only five Vbeta families (Vbeta13, Vbeta3, Vbeta17, Vbeta8, and Vbeta20) were detected in CSF. The amplified products were combined, cloned, and sequenced. Sequence analysis revealed in the CSF substantial proportions of identical beta-chain of TCR transcripts, demonstrating oligoclonal populations of T cells. Seventeen of 35 (48%) transcripts were 100% identical, demonstrating a major Vbeta13.3 Dbeta2.1 Jbeta1.3 clonal expansion. Six of 35 (17%) transcripts were also 100% identical, revealing a second Vbeta13 clonal expansion (Vbeta13.1 Dbeta2.1 Jbeta1.2). Clonal expansions were also found within the Vbeta3 family (transcript Vbeta3.1 Dbeta2.1 Jbeta1.5 accounted for 5 of 35 transcripts [14%]) and within the Vbeta20 family (transcript Vbeta20.1 Dbeta1.1 Jbeta2.4 accounted for 3 of 35 transcripts [8%]). These results demonstrate the presence of T-cell oligoclonal expansions in the CSF of this patient following infection with hepatitis A virus. Analysis of the CDR3 motifs revealed that two of the clonally expanded T-cell clones exhibited substantial homology to myelin basic protein-reactive T-cell clones. In contrast, all Vbeta TCR families were expressed in peripheral blood lymphocytes. Oligoclonal expansions of T cells were not detected in the peripheral blood of this patient. It remains to be determined whether these clonally expanded T cells are specific for hepatitis A viral antigen(s) or host central nervous system antigen(s) and whether molecular mimicry between hepatitis A viral protein and a host protein is responsible for demyelinating disease in this patient.