Infantile epileptic encephalopathy with hypsarrhythmia (infantile spasms/west syndrome) and immunity

West syndrome is a severe epilepsy, occurring in infancy, that comprises epileptic seizures known as spasms, in clusters, and a unique EEG pattern, hypsarrhythmia, with psychomotor regression. Maturation of the brain is a crucial component. The onset is within the first year of life, before 12 months of age. Patients are classified as cryptogenic (10 to 20%), when there are no known or diagnosed previous cerebral insults, and symptomatic (80 to 90%), when associated with pre-existing cerebral damages. The time interval from a brain insult to infantile spasms onset ranged from 6 weeks to 11 months. West syndrome has a time-limited natural evolutive course, usually disappearing by 3 or 4 years of age. In 62% of patients, there are transitions to another age-related epileptic encephalopathies, the Lennox-Gastaut Syndrome and severe epilepsy with multiple independent foci. Spontaneous remission and remission after viral infections may occur. Therapy with ACTH and corticosteroids are the most effective. Reports about intravenous immunoglobulins action deserve attention. There is also immune dysfunction, characterized mainly by anergy, impaired cell-mediated immunity, presence of immature thymocytes in peripheral blood, functional impairment of T lymphocytes induced by plasma inhibitory factors, and altered levels of immunoglobulins. Changes in B lymphocytes frequencies and increased levels of activated B cells have been reported. Sensitized lymphocytes to brain extract were also described. Infectious diseases are frequent and may, sometimes, cause fatal outcomes. Increase of pro-inflamatory cytokines in serum and cerebrospinal fluid of epileptic patients were reported. Association with specific HLA antigens was described by several authors (HLA-DR7, HLA-A7, HLA-DRw52, and HLA-DR5). Auto-antibodies to brain antigens, of several natures (N-methyl-d-aspartate glutamate receptor, gangliosides, brain tissue extract, synaptic membrane, and others), were described in epileptic patients and in epileptic syndromes. Experimental epilepsy studies with anti-brain antibodies demonstrated that epileptiform discharges can be obtained, producing hyperexcitability leading to epilepsy. We speculate that in genetically prone individuals, previous cerebral lesions may sensitize immune system and trigger an autoimmune disease. Antibody to brain antigens may be responsible for impairment of T cell function, due to plasma inhibitory effect and also cause epilepsy in immature brains. © 2008 Bentham Science Publishers Ltd.

Corticosteroides vs dosis bajas de adrenocorticotropina en el tratamiento de espasmos infantiles. Revisión sistemática de la literatura

Antecedentes: El tratamiento de los espasmos infantiles generalmente se realiza con ACTH a pesar de perfil de efectos secundarios y el alto costo financiero. Se ha propuesto el uso de los corticoides como primera línea de tratamiento para la enfermedad, no obstante no existe certeza sobre la eficacia de este esquema. Objetivos: Evaluar la eficacia del uso de los corticoides comparados con la ACTH como primera línea de tratamiento en el manejo de pacientes con espasmos infantiles. Metodología: Se realizó una revisión sistemática de la literatura. La búsqueda se efectuó en las bases de datos Pubmed, Embase, Ovid, LiLaCs y en el registro de ensayos clínicos de Estados Unidos. Se incluyeron estudios en portugués, ingles y español, no se fijo límite de tiempo para la publicación. Se realizó un análisis de riesgo de sesgo y de calidad de la evidencia utilizando el programa GRADEPRO. Se estimaron OR y sus respectivos intervalos de confianza al 95%. Resultados: Se incluyeron 4 estudios, un ensayo clínico y tres estudios de cohorte retrospectiva. Dos estudios aportaron evidencia de calidad moderada y alta. No se encontraron diferencias en la eficacia a corto plazo entre el uso de los corticoides y la ACTH sobre desenlaces clínicos o electroencefalográficos. No se encontraron estudios de seguridad a largo plazo. La seguridad a corto plazo no mostró diferencias. Conclusiones: Es muy probable que el uso de los corticoides como primera línea de tratamiento puedan reemplazar el uso de la ACTH, se requiere estudios de seguridad a largo plazo. La decisión de su uso rutinario debería estar basada en un análisis de costo efectividad y bajo la mirada del balance riesgo/beneficio.

Unravelling Molecular and Cellular Disease Mechanisms in Infantile Neuronal Ceroid Lipofuscinosis (INCL)

Studying neurodegeneration provides an opportunity to gain insights into normal cell physiology, and not just pathophysiology. In this thesis work the focus is on Infantile Neuronal Ceroid Lipofuscinosis (INCL). It is a recessively inherited lysosomal storage disorder. The disease belongs to the neuronal ceroid lipofuscinoses (NCLs), a group of common progressive neurodegenerative diseases of the childhood. Characteristic accumulation of autofluorescent storage material is seen in most tissues but only neurons of the central nervous system are damaged and eventually lost during the course of the disease leaving most other cell types unaffected. The disease is caused by mutations in the CLN1 gene, but the physiological function of the corresponding protein the palmitoyl protein thioesterase (PPT1) has remained elusive. The aim of this thesis work was to shed light on the molecular and cell biological mechanisms behind INCL. This study pinpointed the localization of PPT1 in axonal presynapses of neurons. It also established the role of PPT1 in early neuronal maturation as well as importance in mature neuronal synapses. This study revealed an endocytic defect in INCL patient cells manifesting itself as delayed trafficking of receptor and non-receptor mediated endocytic markers. Furthermore, this study was the first to connect the INCL storage proteins the sphingolipid activator proteins (SAPs) A and D to pathological events on the cellular level. Abnormal endocytic processing and intracellular re-localization was demonstrated in patient cells and disease model knock-out mouse neurons. To identify early affected cellular and metabolic pathways in INCL, knock-out mouse neurons were studied by global transcript profiling and functional analysis. The gene expression analysis revealed changes in neuronal maturation and cell communication strongly associated with the regulated secretory system. Furthermore, cholesterol metabolic pathways were found to be affected. Functional studies with the knock-out mouse model revealed abnormalities in neuronal maturation as well as key neuronal functions including abnormalities in intracellular calcium homeostasis and cholesterol metabolism. Together the findings, introduced in this thesis work, support the essential role of PPT1 in developing neurons as well as synaptic sites of mature neurons. Results of this thesis also elucidate early events in INCL pathogenesis revealing defective pathways ultimately leading to the neurodegenerative process. These results contribute to the understanding of the vital physiological function of PPT1 and broader knowledge of common cellular mechanisms behind neurodegeneration. These results add to the knowledge of these severe diseases offering basis for new approaches in treatment strategies.

Phenotypic overlap between infantile systemic lupus erythematosus and Aicardi-Goutières syndrome.

Case Reports

Ultrasound biomicroscopy in infantile glaucoma

Background: Glaucoma in infants has many causes. Evaluation of the anatomy of the anterior segment of eyes with infantile glaucoma may help to determine the pathogenesis of an infant's disease and influence therapeutic decisions. Methods: Eleven eyes of six infants with glaucoma were evaluated with ultrasound biomicroscopy (UBM) to evaluate the anatomic characteristics and relationships of the anterior segment structures. Results: The anterior chamber angle, iris, lens, ciliary body, and posterior chamber angle could be imaged in detail. Elongated and anteriorly placed ciliary processes were noted in all eight eyes with trabeculodysgenesis. There were no apparent anomalies in the trabecular meshwork, or anterior chamber. In three eyes with dense corneal opacities, ultrasound biomicroscopy showed severe anterior segment disorganization and thin central corneas with posterior corneal excavation. Conclusions: Ultrasound biomicroscopy is a useful non-invasive method for evaluating infants with glaucoma in cases with corneal opacities. This information can help in surgical planning for glaucoma management.

Propranolol in infantile haemangioma: simplifying pretreatment monitoring.

BACKGROUND: Infantile haemangiomas (IHs) are very common vascular tumours. Propranolol is at present the first-line treatment for problematic and complicated haemangioma. In accordance with a Swiss protocol, children are monitored for 2 days at the start of the treatment to detect possible side effects of this drug. Our study advocates a simplification of the pretreatment monitoring process. METHODS: All children with a problematic and complicated haemangioma treated with propranolol between September 2009 and September 2012 were included in the study. All patients were hospitalised under constant nurse supervision for 48 hours at the start of the treatment and subjected to cardiac and blood measurements. The dosage of propranolol was 1 mg/kg/day on the first day and 2 mg/kg/day from the second day. Demographic data, clinical features, treatment outcome and complications were analysed. RESULTS: Twenty-nine infants were included in our study. Of these, 86.2% responded immediately to the treatment. There were no severe adverse reactions. Six patients presented transient side effects such as bradycardia, hypotension after the first dose and hypoglycaemia later. No side effects occurred after the second dose. Treatment was never interrupted. CONCLUSION: Propranolol (a β-blocker) is a safe treatment for problematic IH. Side effects may occur after the first dose. A strict 48 hour monitoring in hospital is expensive and may be unnecessary as long as the contraindications for the drug are respected.

Les troubles mentaux de l'enfance : précis de psychiatrie infantile avec les applications pédagogiques et médico-légales / par le Dr Marcel Manheimer,... ; préface de M. le Pr Joffroy

Mécénat texte imprimé : Cet ouvrage a été numérisé grâce au fonds « Docteur Jean-Paul Sichel », dédié à l'histoire de la psychiatrie

Précis de chirurgie infantile

UANL