Inmunoglobulina G intravenosa como tratamiento adyuvante en epilepsia infantil farmacorresistente / Intravenous immunoglobulin G as adjuvant treatment in drug-resistant childhood epilepsy

INTRODUCCIÓN: La epilepsia es la enfermedad neurológica más común en la infancia; dependiendo de la definición de epilepsia farmacorresistente la incidencia varía del 10 a 23% en la población pediátrica. El objetivo de este estudio fue contabilizar la disminución en la frecuencia y/o duración mensual de crisis epilépticas en pacientes pediátricos con epilepsia farmacorresistente tratados con antiepilépticos, antes y después de la adición de inmunoglobulina G intravenosa (IgG iv). MÉTODOS: Estudio analítico, observacional retrospectivo de casos-controles. Se estudiaron pacientes pediátricos con epilepsia farmacorresistente atendidos en el Centro Médico Nacional 20 de Noviembre de la Ciudad de México durante el período 2003-2013 y que recibieron tratamiento con IgG IV. RESULTADOS: Ciento sesenta y siete pacientes (19,5%) presentaron epilepsia farmacorresistente y 44 (5,1%) iniciaron tratamiento adyuvante con IgG IV. La edad media de los pacientes al inicio del tratamiento fue de 6,12 años (± 5,14); 28 (73,6%) tuvieron una etiología estructural adquirida, 5 (13,1%) genética, uno (2,6%) inmune y 4 (10,5%) desconocida. A los 2 meses de la aplicación de inmunoglobulina la duración de las crisis se redujo al 66,66% y la frecuencia de las crisis alcanzó una reducción del 64% a los 4 meses de iniciado el tratamiento(p < 0,001). CONCLUSIONES: La IgG IV puede ser una terapia eficaz para la disminución en la frecuencia y duración de las convulsiones en pacientes pediátricos con epilepsia farmacorresistente, como lo demuestran los resultados de este estudio

BACKGROUND: Epilepsy is the most common neurological disease in childhood; depending on the definition of drug-resistant epilepsy, incidence varies from 10% to 23% in the paediatric population. The objective of this study was to account for the decrease in the frequency and/or monthly duration of epileptic seizures in paediatric patients with drug-resistant epilepsy treated with antiepileptic drugs, before and after adding intravenous immunoglobulin G (iIV IgG). METHODS: This is an analytic, observational, retrospective case-control study. We studied paediatric patients with drug-resistant epilepsy who were treated with IV IgG at the Centro Médico Nacional 20 de Noviembre, in Mexico City, from 2003 to 2013. RESULTS: One hundred and sixty seven patients (19.5%) had drug-resistant epilepsy and 44 (5.1%) started adjuvant treatment with IV IgG. The mean age of patients at the beginning of treatment was 6.12 years ± 5.14); aetiology was structural acquired in 28 patients (73.6%), genetic in 5 (13.1%), immune in 1 (2.6%), and unknown in 4 (10.5%). At 2 months from starting IV IgG, seizure duration had reduced to 66.66%; the frequency of seizures was reduced by 64% at 4 months after starting treatment (P < .001). CONCLUSIONS: According to the results of this study, intravenous immunoglobulin may be an effective therapy for reducing the frequency and duration of seizures in paediatric patients with drug-resistant epilepsy

Intravenous immunoglobulin G as adjuvant treatment in drug-resistant childhood epilepsy. / Inmunoglobulina G intravenosa como tratamiento adyuvante en epilepsia infantil farmacorresistente.

BACKGROUND: Epilepsy is the most common neurological disease in childhood; depending on the definition of drug-resistant epilepsy, incidence varies from 10% to 23% in the paediatric population. The objective of this study was to account for the decrease in the frequency and/or monthly duration of epileptic seizures in paediatric patients with drug-resistant epilepsy treated with antiepileptic drugs, before and after adding intravenous immunoglobulin G (iIV IgG). METHODS: This is an analytic, observational, retrospective case-control study. We studied paediatric patients with drug-resistant epilepsy who were treated with IV IgG at the Centro Médico Nacional 20 de Noviembre, in Mexico City, from 2003 to 2013. RESULTS: One hundred and sixty seven patients (19.5%) had drug-resistant epilepsy and 44 (5.1%) started adjuvant treatment with IV IgG. The mean age of patients at the beginning of treatment was 6.12 years±5.14); aetiology was structural acquired in 28 patients (73.6%), genetic in 5 (13.1%), immune in 1 (2.6%), and unknown in 4 (10.5%). At 2 months from starting IV IgG, seizure duration had reduced to 66.66%; the frequency of seizures was reduced by 64% at 4 months after starting treatment (P<.001). CONCLUSIONS: According to the results of this study, intravenous immunoglobulin may be an effective therapy for reducing the frequency and duration of seizures in paediatric patients with drug-resistant epilepsy.

The yin/yang of inflammatory status: Blood-brain barrier regulation during sleep.

Sleep loss induces a low-grade inflammatory status characterized by a subtle but sustained increase of pro-inflammatory mediators, which are key regulators of blood-brain barrier function. To investigate the influence of inflammatory status on blood-brain barrier dysfunction induced by sleep restriction we performed an experiment using two strains of mice with different immunological backgrounds, C57BL/6 mice that have a predominant pro-inflammatory response and BALB/c mice that have a predominant anti-inflammatory response. Mice were sleep-restricted during 10 days using the flowerpot technique during 20 h per day with 4 h of daily sleep opportunity. The systemic inflammatory status, blood-brain barrier permeability, and the hippocampal expression of neuroinflammatory markers were characterized at the 10th day. Serum levels of TNF and IFN-γ increased in sleep-restricted C57BL/6 but not in BALB/c mice; no changes in other cytokines were found. Sleep restriction increased blood-brain barrier permeability in C57BL/6 strain but not in BALB/c. The hippocampus of sleep-restricted C57BL/6 mice exhibited an increase in the expression of the neuroinflammatory markers Iba-1, A2A adenosine receptor, and MMP-9; meanwhile in sleep-restricted BALB/c mice the expression of this markers was lesser than the control group. These data suggest that cytokines may be playing a key role in modulating blood-brain barrier function during sleep restriction, and probably the effects are related to Iba-1, MMP-9 and A2A adenosine receptor overexpression.

Chronic sleep restriction disrupts interendothelial junctions in the hippocampus and increases blood-brain barrier permeability.

Chronic sleep loss in the rat increases blood-brain barrier permeability to Evans blue and FITC-dextrans in almost the whole brain and sleep recovery during short periods restores normal blood-brain barrier permeability. Sleep loss increases vesicle density in hippocampal endothelial cells and decreases tight junction protein expression. However, at the ultrastructural level the effect of chronic sleep loss on interendothelial junctions is unknown. In this study we characterised the ultrastructure of interendothelial junctions in the hippocampus, the expression of tight junction proteins, and quantified blood-brain barrier permeability to fluorescein-sodium after chronic sleep restriction. Male Wistar rats were sleep restricted using the modified multiple platform method during 10 days, with a daily schedule of 20-h sleep deprivation plus 4-h sleep recovery at their home-cages. At the 10th day hippocampal samples were obtained immediately at the end of the 20-h sleep deprivation period, and after 40 and 120 min of sleep recovery. Samples were processed for transmission electron microscopy and western blot. Chronic sleep restriction increased blood-brain barrier permeability to fluorescein-sodium, and decreased interendothelial junction complexity by increasing the frequency of less mature end-to-end and simply overlap junctions, even after sleep recovery, as compared to intact controls. Chronic sleep loss also induced the formation of clefts between narrow zones of adjacent endothelial cell membranes in the hippocampus. The expression of claudin-5 and actin decreased after chronic sleep loss as compared to intact animals. Therefore, it seems that chronic sleep loss disrupts interendothelial junctions that leads to blood-brain barrier hyperpermeability in the hippocampus.

Blood-Brain Barrier Disruption Induced by Chronic Sleep Loss: Low-Grade Inflammation May Be the Link.

Sleep is a vital phenomenon related to immunomodulation at the central and peripheral level. Sleep deficient in duration and/or quality is a common problem in the modern society and is considered a risk factor to develop neurodegenerative diseases. Sleep loss in rodents induces blood-brain barrier disruption and the underlying mechanism is still unknown. Several reports indicate that sleep loss induces a systemic low-grade inflammation characterized by the release of several molecules, such as cytokines, chemokines, and acute-phase proteins; all of them may promote changes in cellular components of the blood-brain barrier, particularly on brain endothelial cells. In the present review we discuss the role of inflammatory mediators that increase during sleep loss and their association with general disturbances in peripheral endothelium and epithelium and how those inflammatory mediators may alter the blood-brain barrier. Finally, this manuscript proposes a hypothetical mechanism by which sleep loss may induce blood-brain barrier disruption, emphasizing the regulatory effect of inflammatory molecules on tight junction proteins.

Effect of low-frequency repetitive transcranial magnetic stimulation on sleep pattern and quality of life in patients with focal epilepsy.

OBJECTIVE: In this study we analyzed the effects of transcranial magnetic stimulation (TMS) on sleep and on the self-perceived quality of life in epileptic patients. METHODS: A total of 24 male patients diagnosed with focal epilepsy were included in the study. Pharmacological treatment with levetiracetam was standardized at 2 g daily. Before TMS onset, all-night polysomnographic recording (PSG) was performed, and the Quality of Life in Epilepsy Inventory (QOLIE-31) was administered. Thereafter, patients underwent low-frequency repetitive TMS (1000 pulses/1 Hz) daily for 10 days. After the end of the treatment, a second polysomnographic study was performed, and the QOLIE-31 questionnaire was administered again. RESULTS: TMS induced a significant increase in sleep efficiency and in total sleep time, along with a decrease in sleep latency and the number of awakenings. In addition, the number of interictal discharges during sleep decreased significantly. Concerning the QOLIE-31 scale values, the patients showed great improvement in the self-perceived quality of life. CONCLUSION: The present results indicate that TMS may mediate therapeutic effects in the treatment of patients with focal epilepsy, and that TMS treatment is accompanied by improvement of sleep patterns as well as improvement in self-perceived quality of life. However, a study that includes a control group undergoing sham stimulation is needed to confirm these findings.

Steroid hormones and sleep regulation.

In the search of the sleep substance, many studies have been addressed for different hormones, responsible for sleep-wake cycle regulation. In this article we mentioned the participation of steroid hormones, besides its role regulating sexual behavior, they influence importantly in the sleep process. One of the clearest relationships are that estrogen and progesterone have, that causing changes in sleep patterns associated with the hormonal cycles of women throughout life, from puberty to menopause and specific periods such as pregnancy and the menstrual cycle, including being responsible for some sleep disorders such as hypersomnia and insomnia. Another studied hormone is cortisol, a hormone released in stressful situations, when an individual must react to an extraordinary demand that threatens their survival, but also known as the hormone of awakening because the release peak occurs in the morning, although this may be altered in some sleep disorders like insomnia and mood disorders. Furthermore neurosteroids such as pregnanolone, allopregnanolone and pregnenolone are involved in the generation of slow wave sleep, the effect has been demonstrated in experimental animal studies. Thus we see that the sleep and the endocrine system saved a bidirectional relationship in which depends on each other to regulate different physiological processes including sleep.

Anti-CD43 and anti-galectin-1 autoantibodies in patients with systemic lupus erythematosus.

OBJECTIVES: Systemic lupus erythematosus (SLE) is characterized by the production of multiple autoantibodies and also by T-cell dysfunction. CD43 is expressed by most immune cells, is involved in lymphocyte adhesion and activation, and interacts with galectin-1 (Gal-1). The aim of this work was to evaluate the plasma levels of autoantibodies against CD43 and Gal-1 as well as the levels of soluble Gal-1 in SLE Mexican mestizo patients, with the aim of establishing a correlation between these parameters and the clinical profile. METHODS: Serum levels of immunoglobulin (Ig)G autoantibodies against CD43 and Gal-1 and levels of soluble Gal-1 were measured by enzyme-linked immunosorbent assay (ELISA) in 55 patients with SLE and 71 healthy controls. RESULTS: We found significantly enhanced titres of anti-CD43 and anti-Gal-1 antibodies in sera from SLE patients compared to controls. In addition, the serum levels of Gal-1 were significantly higher in SLE patients than in healthy individuals. However, we could detect no correlation of these parameters with disease activity [using the Mexican Systemic Lupus Erythematosus Disease Activity Index (MEX-SLEDAI)], age, or a variety of different clinical or laboratory features. Similarly, no significant correlation with immunosuppressive or glucocorticoid therapy was observed. By contrast, a significant association was found between anti-CD43 titres and time of disease evolution, complement levels, and the presence of anti-Gal-1 antibodies. CONCLUSIONS: As CD43 and Gal-1 participate in modulating the immune system, we suggest that the presence of autoantibodies against these molecules may contribute to the immune deregulation observed in SLE.

Polysomnographic features in infants with early diagnosis of congenital hypothyroidism.

Thyroid hormones play a major role in the maturation process of the brain. Currently, congenital hypothyroidism is detected by mass screening. The impact of this early hormonal deficiency on the organization of the sleep pattern is not known. In this study, the polysomnographic features in children diagnosed with congenital hypothyroidism were analyzed. Children were detected by mass population screening and the hormonal replacement therapy starts immediately. Children's age ranged between 1.5 and 18 months of age. The duration of hormonal treatment before sleep recordings varied between 8 days and 17 months. Children were polysomnographically recorded in the morning, for at least 2h, obtaining more than one sleep cycle. Results showed a high prevalence of females (5/1) in the group studied. A high proportion of infants (43%) displayed central apnea in different degrees (mild, moderate and severe) as well as hypopnea (83%), mainly in subjects around 4 and 8 months of age. The proportion of infants displaying central apnea decreases as age increases. In addition, indeterminate (light) sleep increase and quiet (slow wave) sleep decrease significantly regardless of age and treatment. The percentage of REM sleep correlated positively with the age of the child at the beginning of the treatment, and negatively with their age at the time of the study. These data indicate that congenital hypothyroidism facilitates the presence of central sleep apnea. The decrease of these respiratory alterations correlates with the increase of the hormonal replacement therapy. It seems that sleep respiratory alterations in congenital hypothyroidism are linked to brain maturation processes in which thyroid hormones play a major role.

The H1 histamine receptor blocker, chlorpheniramine, completely prevents the increase in REM sleep induced by immobilization stress in rats.

Chlorpheniramine is a selective antagonist of the H1 histaminergic receptor subtype and its effects in humans include somnolence. Chlorpheniramine affects sleep in rats, mainly by decreasing REM sleep. On the other hand, stress by immobilization induces an important increase in the percentage of REM sleep. In this study we analyzed the effects of blocking histaminergic receptors on REM sleep induced by immobilization stress. Adult male Wistar rats were chronically implanted for sleep recording. Immobilization stress was induced by placing the rat in a small cylinder for 2 h. Experimental conditions were: A. Control; B. Stress; C. Stress plus vehicle and D. Stress plus chlorpheniramine. Independent experiments were done both in the dark, as well as the light period. Results showed that the increase in REM sleep observed after immobilization stress was completely abolished by chlorpheniramine, both in the dark and in the light phase. Furthermore, the decrease in REM sleep was significant even when compared to the non-stressed control rats. REM sleep latency was also significantly longer during both light phases. The present results suggest that REM sleep is quite sensitive to histaminergic blockage. It is possible that chlorpheniramine is also blocking the cholinergic mechanisms generating REM sleep.