Activation of Extracellular Signal-Regulated Kinases (ERK 1/2) in the Locus Coeruleus Contributes to Pain-Related Anxiety in Arthritic Male Rats.

Background: There is increasing evidence suggesting that the Locus Coeruleus plays a role in pain-related anxiety. Indeed, we previously found that prolonged arthritis produces anxiety-like behavior in rats, along with enhanced expression of phosphorylated extracellular signal-regulated kinase 1/2 (a marker of plasticity) in the Locus Coeruleus. However, it is unknown how this effect correlates with the electrophysiological activity of Locus Coeruleus neurons or pain-related anxiety. Methods: Using the complete Freund's adjuvant model of monoarthritis in male Sprague-Dawley rats, we studied the behavioral attributes of pain and anxiety as well as Locus Coeruleus electrophysiology in vivo 1 (MA1W) and 4 weeks (MA4W) after disease induction. Results: The manifestation of anxiety in MA4W was accompanied by dampened tonic Locus Coeruleus activity, which was coupled to an exacerbated evoked Locus Coeruleus response to noxious stimulation of the inflamed and healthy paw. When a mitogen-activating extracellular kinase inhibitor was administered to the contralateral Locus Coeruleus of MA4W, the phosphorylated extracellular signal-regulated kinase 1/2 levels in the Locus Coeruleus were restored and the exaggerated evoked response was blocked, reversing the anxiogenic-like behavior while pain hypersensitivity remained unaltered. Conclusion: As phosphorylated extracellular signal-regulated kinase 1/2 blockade in the Locus Coeruleus relieved anxiety and counteracted altered LC function, we propose that phosphorylated extracellular signal-regulated kinase 1/2 activation in the Locus Coeruleus plays a crucial role in pain-related anxiety.

Corticotropin-Releasing Factor Mediates Pain-Induced Anxiety through the ERK1/2 Signaling Cascade in Locus Coeruleus Neurons.

BACKGROUND: The corticotropin-releasing factor is a stress-related neuropeptide that modulates locus coeruleus activity. As locus coeruleus has been involved in pain and stress-related patologies, we tested whether the pain-induced anxiety is a result of the corticotropin-releasing factor released in the locus coeruleus. METHODS: Complete Freund's adjuvant-induced monoarthritis was used as inflammatory chronic pain model. α-Helical corticotropin-releasing factor receptor antagonist was microinjected into the contralateral locus coeruleus of 4-week-old monoarthritic animals. The nociceptive and anxiety-like behaviors, as well as phosphorylated extracellular signal-regulated kinases 1/2 and corticotropin-releasing factor receptors expression, were quantified in the paraventricular nucleus and locus coeruleus. RESULTS: Monoarthritic rats manifested anxiety and increased phosphorylated extracellular signal-regulated kinases 1/2 levels in the locus coeruleus and paraventricular nucleus, although the expression of corticotropin-releasing factor receptors was unaltered. α-Helical corticotropin-releasing factor antagonist administration reversed both the anxiogenic-like behavior and the phosphorylated extracellular signal-regulated kinases 1/2 levels in the locus coeruleus. CONCLUSIONS: Pain-induced anxiety is mediated by corticotropin-releasing factor neurotransmission in the locus coeruleus through extracellular signal-regulated kinases 1/2 signaling cascade.

Reversal of monoarthritis-induced affective disorders by diclofenac in rats.

BACKGROUND: Nonsteroidal anti-inflammatory drugs are effective for arthritic pain, but it is unknown whether they also benefit anxiety and depression that frequently coexist with pain. Using the monoarthritis model, the authors evaluated the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in structures implicated in both sensorial and emotional pain spheres, and it was verified whether analgesia can reverse monoarthritis-mediated affective responses. METHODS: Monoarthritis was induced in male rats by complete Freund's adjuvant injection. Allodynia (ankle-bend test), mechanical hyperalgesia (paw-pinch test), anxiety- and depression-like behaviors (elevated zero maze and forced swimming tests, respectively), and ERK1/2 phosphorylation (Western blot) in the spinal cord, paragigantocellularis nucleus, locus coeruleus, and prefrontal cortex were evaluated at 4, 14, and 28 days postinoculation (n = 6 per group). Changes in these parameters were evaluated after induction of analgesia by topical diclofenac (n = 5 to 6 per group). RESULTS: Despite the pain hypersensitivity and inflammation throughout the testing period, chronic monoarthritis (28 days) also resulted in depressive- (control [mean ± SEM]: 38.3 ± 3.7 vs. monoarthritis: 51.3 ± 2.0; P < 0.05) and anxiogenic-like behaviors (control: 36.8 ± 3.7 vs. monoarthritis: 13.2 ± 2.9; P < 0.001). These changes coincided with increased ERK1/2 activation in the spinal cord, paragigantocellularis, locus coeruleus, and prefrontal cortex (control vs. monoarthritis: 1.0 ± 0.0 vs. 5.1 ± 20.8, P < 0.001; 0.9 ± 0.0 vs. 1.9 ± 0.4, P < 0.05; 1.0 ± 0.3 vs. 2.9 ± 0.6, P < 0.01; and 1.0 ± 0.0 vs. 1.8 ± 0.1, P < 0.05, respectively). Diclofenac decreased the pain threshold of the inflamed paw and reversed the anxio-depressive state, restoring ERK1/2 activation levels in the regions analyzed. CONCLUSION: Chronic monoarthritis induces affective disorders associated with ERK1/2 phosphorylation in paragigantocellularis, locus coeruleus, and prefrontal cortex which are reversed by diclofenac analgesia. (Anesthesiology 2014; 120:1476-90).

Opioid receptors mRNAs expression and opioids agonist-dependent G-protein activation in the rat brain following neuropathy.

Potent opioid-based therapies are often unsuccessful in promoting satisfactory analgesia in neuropathic pain. Moreover, the side effects associated with opioid therapy are still manifested in neuropathy-like diseases, including tolerance, abuse, addiction and hyperalgesia, although the mechanisms underlying these effects remain unclear. Studies in the spinal cord and periphery indicate that neuropathy alters the expression of mu-[MOP], delta-[DOP] or kappa-[KOP] opioid receptors, interfering with their activity. However, there is no consensus as to the supraspinal opioidergic modulation provoked by neuropathy, the structures where the sensory and affective-related pain components are processed. In this study we explored the effect of chronic constriction of the sciatic nerve (CCI) over 7 and 30 days (CCI-7d and CCI-30d, respectively) on MOP, DOP and KOP mRNAs expression, using in situ hybridization, and the efficacy of G-protein stimulation by DAMGO, DPDPE and U-69593 (MOP, DOP and KOP specific agonists, respectively), using [35S]GTPγS binding, within opioid-sensitive brain structures. After CCI-7d, CCI-30d or both, opioid receptor mRNAs expression was altered throughout the brain: MOP - in the paracentral/centrolateral thalamic nuclei, ventral posteromedial thalamic nuclei, superior olivary complex, parabrachial nucleus [PB] and posterodorsal tegmental nucleus; DOP - in the somatosensory cortex [SSC], ventral tegmental area, caudate putamen [CPu], nucleus accumbens [NAcc], raphe magnus [RMg] and PB; and KOP - in the locus coeruleus. Agonist-stimulated [35S]GTPγS binding was altered following CCI: MOP - CPu and RMg; DOP - prefrontal cortex [PFC], SSC, RMg and NAcc; and KOP - PFC and SSC. Thus, this study shows that several opioidergic circuits in the brain are recruited and modified following neuropathy.

Opioid and noradrenergic contributions of tapentadol to the inhibition of locus coeruleus neurons in the streptozotocin rat model of polyneuropathic pain.

Tapentadol is an analgesic that acts as an agonist of µ opioid receptors (MOR) and that inhibits noradrenaline reuptake. Data from healthy rats show that tapentadol inhibits neuronal activity in the locus coeruleus (LC), a nucleus regulated by both the noradrenergic and opioid systems. Thus, we set out to investigate the effect of tapentadol on LC activity in streptozotocin (STZ)-induced diabetic rats, a model of diabetic polyneuropathy, by analyzing single-unit extracellular recordings of LC neurons. Four weeks after inducing diabetes, tapentadol dose-response curves were obtained from animals pre-treated with RX821002 or naloxone (alpha2-adrenoceptors and opioid receptors antagonists, respectively). In STZ rats, the spontaneous activity of LC neurons (0.9 ±â€¯0.1 Hz) was lower than in naïve animals (1.5 ±â€¯0.1 Hz), and tapentadol's inhibitory effect was also weaker. Alpha2-adrenoceptors blockade by RX821002 (100 µg/kg i.v.) in STZ animals significantly increased the spontaneous activity (from 0.8 ±â€¯0.1 to 1.4 ±â€¯0.2 Hz) and it dampened the inhibition of LC neurons produced by tapentadol. However, opioid receptors blockade following naloxone pre-treatment (5 mg/kg i.v.) did not alter the spontaneous firing rate (0.9 ±â€¯0.2 vs 0.9 ±â€¯0.2 Hz) or the inhibitory effect of tapentadol on LC neurons in STZ animals. Thus, diabetic polyneuropathy appears to exert neuroplastic changes in LC neurotransmission, enhancing the sensitivity of alpha2-adrenoceptors and dampening opioid receptors expression. Tapentadol's activity seems to be predominantly mediated through its noradrenergic effects rather than its influence on opioid receptors in the STZ model of diabetic polyneuropathy.

An Unusual Case of CMV/EBV Ventriculoencephalitis with Evolution to Primary Central Nervous System Lymphoma in HIV-Positive Patient.

Epstein-Barr virus (EBV) is a well-known cause of different types of malignancies particularly Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's lymphomas, and non-Hodgkin's lymphomas including primary central nervous system lymphoma (PCNSL). A higher tendency of malignant transformation associated with EBV has been noticed in immunocompromised patients, such as human immunodeficiency virus (HIV) infected patients. The rapid and effective immune reconstitution is crucial to prevent PCNSL in HIV-positive patients. We present a clinical case of a young patient diagnosed with HIV infection and medicated with antiretroviral therapy (ART) with poor immunological recovery. After two weeks, he developed ventriculoencephalitis, observed in the cranial magnetic resonance imaging (MRI), caused by cytomegalovirus (CMV) and EBV, both with high serum viral load, rapidly evolving to PCNSL. With this unusual clinical case, the authors want to draw attention to the importance of rapid immunological reconstitution in preventing the progression of EBV infection to PCNSL, as well as encouraging the confirmation of the usefulness of early combination of chemotherapy and antiviral therapy, in order to reach a more effective treatment of this herpesvirus infection and associated malignancies.

Diagnóstico ecográfico prenatal en el Centro Municipal de Genética Médica de Marianao, La Habana / Prenatal Ultrasound Diagnosis at the Genetics Center of Marianao Municipality, Havana

Introducción: La ecografía prenatal en el Programa de Prevención de Enfermedades Genéticas permite la detección precoz de malformaciones congénitas y mejora la calidad de vida de la madre y su familia. Objetivo: Conocer la frecuencia de malformaciones congénitas diagnosticadas en el Centro de Genética de Marianao y compararla con las estadísticas nacionales e internacionales. Métodos: Estudio retrospectivo, descriptivo y observacional. Se cuantificaron 203 malformaciones diagnosticadas entre 2007 y 2017 en el Centro de Genética de Marianao. Se consideraron como variables la edad materna, la edad gestacional del diagnóstico, la frecuencia por años y los tipos de malformaciones por sistemas. Resultados: En 13 307 nacimientos se diagnosticaron 203 fetos malformados (1,52 por ciento) a una edad gestacional media de 20,15 semanas. Las malformaciones más frecuentes fueron neurológicas (27,1 por ciento) y cardiovasculares (16,2 por ciento). En las madres adolescentes predominaron las cardiovasculares (27,3 por ciento) y digestivas (16,2 por ciento en las madres añosas, las cromosómicas (57,1 por ciento). Antes de la semana 17 se diagnosticaron malformaciones digestivas (41,7 por ciento) y neurológicas (40 por ciento); entre las 18 y 21 semanas, las esqueléticas (41,2 por ciento); entre las 22 y 26 semanas, cardiovasculares (66,7 por ciento) y cromosómicas (52,4 por ciento) y, después de la semana 27, las renales (9 por ciento. Conclusión: Predominaron las malformaciones neurológicas y cardiovasculares. La edad materna media fue superior en las malformaciones cromosómicas y menor en las digestivas y cardiovasculares. En el primer marcador del programa se diagnosticó la mayoría de las malformaciones digestivas y neurológicas; y en el segundo marcador, las cardiovasculares, cromosómicas y esqueléticas(AU)

Introduction: Prenatal ultrasound in the Genetic Disease Prevention Program allows early detection of congenital malformations and improves the quality of life of the mother and her family. Objective: To know the frequency of congenital malformations diagnosed at the Genetics Center of Marianao Municipality, Havana, Cuba, and to compare it with national and international statistics. Methods: Retrospective, descriptive and observational study. A total of 203 malformations diagnosed between 2007 and 2017 at the Genetics Center of Marianao were quantified. Maternal age, gestational age at diagnosis, frequency by years and types of malformations by systems were considered as variables. Results: In 13,307 births, 203 malformed fetuses were diagnosed (1.52 percent), at a mean gestational age of 20.15 weeks. The most frequent malformations were neurological (27.1 percent) and cardiovascular (16.2 percent). Cardiovascular (27.3 percent) and digestive (16.2 percent) malformations predominated in adolescent mothers, while chromosomal malformations predominated in older mothers (57.1 percent). Before the seventeenth week, digestive (41.7 percent) and neurological (40 percent) alformations were diagnosed; between the eighteenth and twenty-first weeks, skeletal (41.2 percent) malformations were diagnosed; between the twenty-second and twenty-sixth weeks, cardiovascular (66.7 percent) and chromosomal (52.4 percent) malformations were diagnosed; and after the twenty-seventh week, renal (9 percent) malformations were diagnosed. Conclusion: Neurological and cardiovascular malformations prevailed. The mean maternal age was higher in chromosomal malformations, and lower in digestive and cardiovascular malformations. Most of the digestive and neurological malformations were diagnosed in the first marker of the Program, while cardiovascular, chromosomal and skeletal malformations were diagnosed in the second marker(AU)

Noradrenergic Locus Coeruleus pathways in pain modulation.

The noradrenergic system is crucial for several activities in the body, including the modulation of pain. As the major producer of noradrenaline (NA) in the central nervous system (CNS), the Locus Coeruleus (LC) is a nucleus that has been studied in several pain conditions, mostly due to its strategic location. Indeed, apart from a well-known descending LC-spinal pathway that is important for pain control, an ascending pathway passing through this nucleus may be responsible for the noradrenergic inputs to higher centers of the pain processing, such as the limbic system and frontal cortices. Thus, the noradrenergic system appears to modulate different components of the pain experience and accordingly, its manipulation has distinct behavioral outcomes. The main goal of this review is to bring together the data available regarding the noradrenergic system in relation to pain, particularly focusing on the ascending and descending LC projections in different conditions. How such findings influence our understanding of these conditions is also discussed.

Conocimientos sobre salud sexual y reproductiva en adolescentes epilépticos / Knowledge about Sexual and Reproductive Health in Epileptic Adolescents

Introducción: La adolescencia por sí sola implica conductas sexuales de riesgos con repercusiones reproductivas que son más graves en el paciente epiléptico. Objetivo: Identificar la percepción de riesgo sexual y reproductivo vinculado con la enfermedad y tratamiento en adolescentes epilépticos. Métodos: Estudio descriptivo transversal en 93 adolescentes epilépticos atendidos en el Hospital Juan Manuel Márquez (2016). Se midieron variables demográficas, de la enfermedad y de salud sexual y reproductiva, con empleo de prueba de hipótesis (significativo p < 0.05). Resultados: Hubo 58,1 por ciento con epilepsia focal (n = 54), aproximadamente 17 por ciento tuvo crisis epiléptica en el último año. Sobre salud sexual reproductiva, la información se obtuvo en la escuela o de amigos (86 por ciento) y de las madres (57 por ciento), independientemente del sexo (p = 0,09), asimismo refirieron conocimientos de, condón (100 por ciento), riegos del embarazo en la adolescencia (8,1 por ciento) y sobre VIH/sida (100 por ciento). El conocimiento de los efectos de la epilepsia y los medicamentos en la fertilidad, embarazo y heredabilidad fueron solo 2,2 por ciento. Conclusiones: Los adolescentes epilépticos estudiados solo conocían acerca del condón y sobre el VIH/sida, con información muy insuficiente sobre los efectos de la epilepsia y de los fármacos antiepilépticos en relación a la fertilidad, el embarazo y la heredabilidad de la enfermedad, así como la opción que brinda el ácido fólico para la profilaxis de malformaciones congénitas(AU)

Introduction: Adolescence alone involves risky sexual behaviors with reproductive repercussions which are more serious in the epileptic patient. Objective: To identify the perception of sexual and reproductive risk related to their disease and treatment in epileptic adolescents. Methods: Cross-sectional and descriptive study carried out in 2016 with 93 epileptic adolescents treated at Juan Manuel Márquez Hospital. Demographic, disease-related, as well as sexual and reproductive health variables were measured, using a hypothesis test (significant P<0.05). Results: 58.1 percent had focal epilepsy (n=54). Approximately 17 percent had epileptic seizures within the last year. Regarding sexual reproductive health, they obtained information at school or from friends (86 percent) and from mothers (57 percent), regardless of sex (P=0.09). They also reported knowledge about the condom (100 percent), risks of pregnancy in adolescence (8.1 percent) and HIV/AIDS (100 percent). Knowledge about the effects of epilepsy and drugs on fertility, pregnancy and heritability accounted only for 2.2 percent. Conclusions: The epileptic adolescents studied only knew about the condom and HIV/AIDS, with very insufficient information about the effects of epilepsy and antiepileptic drugs in relation to fertility, pregnancy and heritability of the disease, as well as the option provided by folic acid for the prophylaxis of congenital malformations(AU)

ERK1/2: Function, signaling and implication in pain and pain-related anxio-depressive disorders.

Despite the increasing knowledge regarding pain modulation, the understanding of the mechanisms behind a complex and pathologic chronic pain condition is still insufficient. These knowledge gaps might result in ineffective therapeutic approaches to relieve painful sensations. As a result, severe untreated chronic pain frequently triggers the onset of new disorders such as depression and/or anxiety, and therefore, both the diagnosis and treatment of patients suffering from chronic pain become seriously compromised, prompting a self-perpetuating cycle of symptomatology. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) are molecules strongly implicated in the somatic component of pain at the spinal cord level and have been emerging as mediators of the emotional-affective component as well. Although these molecules might represent good biomarkers, their use as pharmacological targets is still open to discussion as paradoxical information has been obtained. Here we review the current scientific literature regarding ERK1/2 signaling in the modulation of pain, depression and anxiety, including the emotional-affective spheres of the pain experience.

The function of alpha-2-adrenoceptors in the rat locus coeruleus is preserved in the chronic constriction injury model of neuropathic pain.

RATIONALE: Peripheral neuropathic pain is a chronic condition that may produce plastic changes in several brain regions. The noradrenergic locus coeruleus (LC) is a crucial component of ascending and descending pain pathways, both of which are frequently compromised after nerve injury. OBJECTIVES: The objective of the study was to examine whether chronic constriction injury (CCI), a model of neuropathic pain, alters noradrenergic activity in the rat LC. METHODS: Activity in the LC was assessed by electrophysiology and microdialysis, while protein expression was monitored in western blots and by immunohistochemistry. RESULTS: The pain threshold had dropped in injured rats 7 days after inducing neuropathy. While alpha-2-adrenoceptors mediate activity in the LC and in its terminal areas, no alterations in either spontaneous neuronal activity or extracellular noradrenaline levels were observed following CCI. Moreover, alpha-2-adrenoceptor activity in the LC of CCI rats remained unchanged after systemic administration of UK14,304, RX821002 or desipramine. Accordingly, extracellular noradrenaline levels in the LC were similar in CCI and control animals following local administration of clonidine or RX821002. In addition, there were no changes in the expression of the alpha-2-adrenoceptors, Gαi/z subunits or the regulators of G-protein signaling. However, pERK1/2 (phosphorylated extracellular signal-regulated kinases 1/2) expression augmented in the spinal cord, paragigantocellularis nucleus (PGi) and dorsal raphe nucleus (DRN) following CCI. CONCLUSIONS: Neuropathic pain is not accompanied by modifications in tonic LC activity after the onset of pain. This may indicate that the signals from the PGi and DRN, the excitatory and inhibitory afferents of the LC, cancel one another out.

Neurotrophins role in depression neurobiology: a review of basic and clinical evidence.

Depression is a neuropsychiatric disorder affecting a huge percentage of the active population especially in developed countries. Research has devoted much of its attention to this problematic and many drugs have been developed and are currently prescribed to treat this pathology. Yet, many patients are refractory to the available therapeutic drugs, which mainly act by increasing the levels of the monoamines serotonin and noradrenaline in the synaptic cleft. Even in the cases antidepressants are effective, it is usually observed a delay of a few weeks between the onset of treatment and remission of the clinical symptoms. Additionally, many of these patients who show remission with antidepressant therapy present a relapse of depression upon treatment cessation. Thus research has focused on other possible molecular targets, besides monoamines, underlying depression. Both basic and clinical evidence indicates that depression is associated with several structural and neurochemical changes where the levels of neurotrophins, particularly of brain-derived neurotrophic factor (BDNF), are altered. Antidepressants, as well as other therapeutic strategies, seem to restore these levels. Neuronal atrophy, mostly detected in limbic structures that regulate mood and cognition, like the hippocampus, is observed in depressed patients and in animal behavioural paradigms for depression. Moreover, chronic antidepressant treatment enhances adult hippocampal neurogenesis, supporting the notion that this event underlies antidepressants effects. Here we review some of the preclinical and clinical studies, aimed at disclosing the role of neurotrophins in the pathophysiological mechanisms of depression and the mode of action of antidepressants, which favour the neurotrophic/neurogenic hypothesis.

Factores biológicos asociados al retardo primario del lenguaje en niños menores de cinco años / Biological factors associated to delayed primary language development in the under five years-old children

Introducción: el retardo primario del lenguaje está presente entre 6 y 10 por ciento de niños menores de 6 años, y constituye un frecuente motivo de consulta pediátrica, sobre el que se puede actuar, una vez conocidos los factores de riesgo. Objetivos: identificar factores biológicos o personales asociados al retardo primario del lenguaje, en niños entre 18 meses y 5 años de edad. Metodos: estudio analítico caso-control, en niños entre 18 meses y 5 años, atendidos en la Consulta de Neuropediatría del Hospital Pediátrico Juan Manuel Márquez, por retardo del lenguaje, entre enero de 2010 y julio de 2011, en relación con un grupo control de niños sanos. Resultados: el retardo primario del lenguaje es más frecuente en varones a razón de 1:4,6, que son diagnosticados a una edad media de 3,05 (+0,95) años, con antecedentes familiares de retardo de lenguaje (p= 0,001) y enfermedades neuropsiquiátricas (p= 0,012). Presentaron más antecedentes de malformaciones, traumas y distermia al nacer (p= 0,007), y también mayor retardo en el desarrollo de la lateralidad (p= 0,025). Conclusiones: se consideran factores de riesgo para el retardo primario del lenguaje, el género masculino, los antecedentes familiares de trastornos del lenguaje y enfermedades neuropsiquiátricas, la lateralidad demorada y los eventos posnatales patológicos

Introduction: delayed primary language development is present in 6 to 10 percent of children aged less than 6 years and is a common cause of pediatric consultation, a problem that can be managed once the risk factors are known. Objectives: to identify the biological or personal factors associated to the delayed primary language development in children aged 18 months to 5 years. Methods: analytical case-control study performed in children aged 18 months to 5 years, who were attended to in the neuropediatric service of Juan Manuel Marquez pediatric hospital because of delayed language development, in the period of January 2010 through July 2011, with respect to a control group of healthy children. Results: delayed primary language development was more frequent in boys at a ratio of 1:4.6, who were diagnosed at average age of 3.05 (0.95 percent ) years and had family history of language impairments (p= 0.001) and neuropsychiatric diseases (p= 0.012). They also presented antecedents of malformations, traumas and dystermia at birth (p= 0.007) and more retardation in the development of laterality (p= 0.025). Conclusions: risk factors for the delayed primary language development were considered as masculine gender, family history of language disorders and neuropsychiatric diseases, delayed laterality and postnatal pathological events

Epilepsia de difícil control en Pediatría: nuevas drogas antiepilépticas / Intractable epilepsy in pediatrics: new antiepileptic drugs

Se realizó una revisión actualizada de la epilepsia resistente a drogas en los niños. Se precisaron los factores clínicos y electroencefalográficos de refractariedad. Se revisaron por orden cronológico los fármacos antiepilépticos de uso habitual y se describieron las características farmacológicas, mecanismos de acción, indicaciones y reacciones adversas fundamentales de las nuevas drogas antiepilépticas, que aparecieron en el mercado a partir de 1995 y que recientemente se comienzan a utilizar en nuestro país. Son estas, entre otras, la vigabatrina, gabapentina, topiramato y lamotrigina. Se concluyó que por sus características y experiencias internacionales, éstas representan una opción terapéutica de mucha utilidad en los niños con epilepsia refractaria