The diagnosis, evaluation, and management of infantile spasms (IS) continue to pose significant challenges to the treating physician. Although an evidence-based practice guideline with full literature review was published in 2004, diversity in IS evaluation and treatment remains and highlights the need for further consensus to optimize outcomes in IS. For this purpose, a working group committed to the diagnosis, treatment, and establishment of a continuum of care for patients with IS and their families—the Infantile Spasms Working Group (ISWG)—was convened. The ISWG participated in a workshop for which the key objectives were to review the state of our understanding of IS, assess the scientific evidence regarding efficacy of currently available therapeutic options, and arrive at a consensus on protocols for diagnostic workup and management of IS that can serve as a guide to help specialists and general pediatricians optimally manage infants with IS. The overall goal of the workshop was to improve IS outcomes by assisting treating physicians with early recognition and diagnosis of IS, initiation of short duration therapy with a first-line treatment, timely electroencephalography (EEG) evaluation of treatment to evaluate effectiveness, and, if indicated, prompt treatment modification. Differences of opinion among ISWG members occurred in areas where data were lacking; however, this article represents a consensus of the U.S. approach to the diagnostic evaluation and treatment of IS.

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Infantile spasms: A U.S. consensus report

Few population-based studies of infantile spasms have been done, and most reports have not included comparison groups. In spite of these limitations, this review attempts to summarize what is known about the distribution, etiology, and natural history of infantile spasms in populations; discusses the limitations of current data; and includes suggestions for further population-based research. Most estimates of the incidence of infantile spasms are between 0.25 and 0.42 per 1000 live births per year. Among children less than 10 years of age, the annual prevalence of infantile spasms is 0.14 to 0.19 per 1000. The peak age at onset of spasms is 4 to 6 months, and there appears to be a slight excess of male cases. The etiology of infantile spasms is unknown for 40% to 50% of affected children. Selected syndromes (eg, Aicardi syndrome, Down syndrome, etc) and inherited disorders (eg, tuberous sclerosis) may account for as many as one third of cases. Other factors, such as intrauterine infection, "birth injury," and head trauma have not been systematically evaluated, and thus, their contribution to the etiology of infantile spasms is uncertain. Areas for future etiologic research include controlled studies of immunologic factors and in utero and postnatal infections and further exploration of the interrelationship between infantile spasms and Lennox-Gastaut syndrome.

The epidemiology and natural history of infantile spasms.

Infantile spasms is a unique disorder peculiar to infancy and early childhood. In this article, the clinical manifestations and electroencephalographic features of the disorder are described. The possible pathophysiologic mechanisms underlying infantile spasms and the relation of this disorder to other childhood encephalopathies are discussed. Finally, the treatment of patients with infantile spasms and their long-term outcome are briefly reviewed.

Infantile epileptic encephalopathy with hypsarrhythmia (Infantile spasms/West syndrome)

http://clok.uclan.ac.uk/12392/1/__lha-014_pers-J_00051247_My%20Documents_Publications_2014_Chris%20Sherer%20review_To%20Send_Response%20to%20referees_Sherer_Snape%20MS_Amended_ii.pdf

Heterocyclic scaffolds as promising anticancer agents against tumours of the central nervous system: Exploring the scope of indole and carbazole derivatives.

Infantile spasms is a severe epileptic encephalopathy of infancy. The fundamental cause is unknown, although a number of predisposing conditions are recognized. In this article, the authors critically review current knowledge concerning the pathophysiologic basis of infantile spasms and propose a new model based on developmental desynchronization. It is suggested that infantile spasms may result from a particular temporal desynchronization of two or more central nervous system developmental processes, resulting in a specific disturbance of brain function. The disturbance of function is postulated to be crucially dependent on an unbalanced maturational pattern, in which certain brain systems become dysfunctional owing to divergent developmental status. An important aspect of this model is the idea that disturbed function of a specific kind can result from multiple causative factors, and so can be associated with a variety of different anatomic and/or biochemical abnormalities. Thus, this concept is compatible with the observed diversity of pathologic findings and multiplicity of etiological associations observed in infantile spasms patients.

Pathogenesis of infantile spasms: a model based on developmental desynchronization.

We investigated humoral and cellular immune response to brain tissues in 15 patients with West syndrome, in 9 patients with Lennox-Gastaut syndrome and in 20 healthy children. High levels of a precipitating antibody to a saline extract of brain tissue were detected in all patients; leucocyte migration inhibition test with the same antigen was found to be positive in most of them. The role of this autoimmune response in the pathogenesis of West and Lennox-Gastaut syndromes remains to the elucidated.

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Demonstration of antibody and cellular immune response to brain extract in West and Lennox-Gastaut syndromes

STUDY OBJECTIVE: The purpose of this study was to assess the extent of immune dysfunction in a well-defined group of epileptic patients: children with diagnosis of West syndrome (WS) or with transitions to another age-related EEG patterns, the multifocal independent spikes (MIS), and the slow spike-wave complexes (Lennox-Gastaut syndrome - LGS). Thus, WS was studied at different points of the natural evolutive history of the disease. METHOD: A group of 50 patients (33 with WS, 10 with LGS and 7 with MIS) and 20 age-matched healthy controls were submitted to enumeration of T lymphocyte subsets: CD1, CD3, CD4, CD8, CD4/CD8 ratio and lymphocyte proliferation assay to phytohaemagglutinin (PHA), in the presence of autologous and AB, homologous plasma. Dinitrochlorobenzene (DNCB) skin test sensitization was performed only in patients. Determinations of IgG, IgA, and IgM serum levels were compared to standard values for Brazilian population in different age ranges. RESULTS: Sensitization to DNCB showed absent or low skin reactions in 76% of the patients. High levels of IgG (45.7%) and IgM (61.4%), and lower levels of IgA (23.9%) were detected in the serum of the patients. Enumeration of lymphocyte subsets in peripheral blood showed: low CD3+ (p<0.05), low CD4+ (p<0.05), high CD8+ (p<0.01) and low CD4+ / CD8+ ratio (p<0.001). The proportion of CD1+ cells in the control group was less than 3%, while ranged between 6 and 11 % in 18% of the patients. The in vitro PHA-induced T cell proliferation showed significantly low blastogenic indices only when patients, cells were cultured in presence of their own plasma. No differences in blastogenic indices were observed when the cells of patients and controls were cultured with human AB plasma. CONCLUSION: The immunodeficiency in WS was mainly characterized by anergy, impaired cell-mediated immunity, altered levels of immunoglobulins, presence of immature thymocytes in peripheral blood and functional impairment of T lymphocytes induced by plasma inhibitory factors.

https://www.arquivosdeneuropsiquiatria.org/wp-content/uploads/articles_xml/1678-4227-anp-S0004-282X2003000500006/1678-4227-anp-S0004-282X2003000500006.pdf

Immunologic aspects of West syndrome and evidence of plasma inhibitory effects on T cell function

RESUMO - O objetivo deste estudo e analisar o resultado de intervencoes psicopedagogicas no desempenhointelectual e em algumas funcoes cognitivas especificas em criancas provenientes de familias de baixa renda,expostas a fatores pessoais e sociais adversos, como desnutricao, stress familiar, ambientes domestico e deestimulacao empobrecidos. Foram examinadas 63 criancas, alunas de escola, gratuita e em regime de semi-internato, que recebe criancas consideradas sob risco pessoal e social. Quarenta e tres criancas receberamatividades que objetivam ativacao cognitiva, durante periodo minimo de 1 ano. Vinte criancas eram recem-admitidas. As tecnicas da ativacao escolhidas foram: metodo de aprendizagem ativa, com base em Piagete metodo de ativacao cognitiva para, atraves de exercicios psicomotores, desenvolver os pre-requisitos paraaprendizagem e prevencao de dificuldades escolares, segundo Lambert. A avaliacao das funcoes cognitivasmostrou: nivel intelectual insatisfatorio em 30% e medio ou superior em 70% e deficiencias cognitivas espe -cificas (nocao do esquema corporal, percepcao viso-motora, percepcao de forma e perseveracao) em 74%.Maior prevalencia de criancas com inteligencia superior (p < 0,05) associou-se a dois fatores: 1

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[Cognitive function evaluation in school-age children from economically impoverished community: results of enriched education program].

Cell-mediated and humoral immunity were investigated in 18 patients with West syndrome, 12 with Lennox-Gastaut syndrome and 19 healthy controls. The study included determination of T and B peripheral blood lymphocytes, serum levels of IgG, IgA and IgM, skin sensibilization with DNCB, intracutaneous PHA, leucocyte migration inhibition test and lymphocyte blastic transformation in the presence of PHA. Cell-mediated deficiency was detected in 28 children whereas low levels of immunoglobulins were observed only in 6 children. Immunological disturbances were more prominent in children with West syndrome.

https://repositorio.unesp.br/bitstream/handle/11449/27456/S0004-282X1984000200005.pdf;sequence=1

Immunological disturbance in West and Lennox-Gastaut syndromes

Œ Depressed natural killer (NK) cell activity has been showed in family members of patients withdifferent types of cancer. The present work aimed to evaluate T cell subsets and NK cell cytotoxic activity in 15members of a family with high incidence of tumors, such as glioblastoma, gastric, pancreas and colon rectalcarcinoma, chronic myelocitic leukemia, melanoma and osteoblastoma. As controls, 19 healthy subjects withthe age range equivalent were studied. The enumeration of CD3+ lymphocytes and their CD4+ and CD8+subsets were defined by monoclonal antibodies and NK cell cytotoxicity towards K562 target cells were evaluatedby single cell-assay. The results showed in family members low percentage of total T cells (CD3+), and theirCD4+ subset and impairment of CD4/CD8 ratio in relation to control group. All family members presentedpercentage of NK-target cell conjugate formation bellow the minimum value observed in control group.Thirteen people were examined and followed up during five years, in order to assure that there was noundiagnosed or unsuspected disease at the moment of evaluation. One of them developed osteoblastomaand other malignant melanoma. Two cancer patients, with glioblastoma and chronic myelocytic leukemiawere studied during illness. All the corresponding values were comparable. The persistence of low percentageof conjugate formation may be related to a defect on adhesion molecules expression in the surface of NK cellsthat was probably responsible for the low activity of these cells presented by the family group. Thus, theinheritance mechanism of low adherence of NK cells should have a prognostic value in determining the risk ofdeveloping tumors.KEY WORDS: familial cancer, glioblastoma, cytotoxic activity, natural killer cells, T cell subsets.Câncer familiar: depressao da atividade citotoxica de cOlulas natural killer em individuos sadios e pacientescom diferentes tipos de câncerRESUMO - Este estudo se reporta as funcies de cOlulas natural killer (NK), como adesao, lise e citotoxicidadee de subpopulacies de cOlulas T em uma familia com alta prevalŒncia de pacientes com câncer e queapresentaram: glioblastoma, leucemia mieloide cronica, osteoblastoma, melanoma e carcinomas gAEstrico,pancreAEtico e colon retal. Quinze membros dessa familia foram estudados, sendo 13 sadios, acompanhadospor 5 anos e dois com câncer: glioblastoma e leucemia mieloide cronica. Duas pessoas sadias, no momento daavaliacao, desenvolveram posteriormente osteoblastoma mandibular ou melanoma maligno. Como controle,foram avaliados 19 individuos saudAEveis de faixa etAEria equivalente. A determinacao de linfocitos T CD3+ e desuas subpopulacies CD4+ e CD8+ foi realizada empregando-se anticorpos monoclonais e a atividade citotoxicade cOlulas NK, avaliada pelo teste de single-cell contra cOlulas alvo da linhagem eritroleucŒmica K562. Osresultados mostraram que as percentagens de cOlulas T totais (CD3+), da subpopulacao CD4+ e da relacaoCD4/CD8 foram significativamente menores nos individuos da familia estudada em comparacao aos valoresobservados no grupo controle. Em todos os membros dessa familia a percentagem de formacao de conjugadosentre cOlulas NK-cOlulas alvo foi inferior ao valor minimo observado nos controles. Essa alteracao poderia estarrelacionada a defeito na expressao de molOculas de adesao, presentes na membrana de cOlulas NK, comoprovAEvel causa das alteracies funcionais dessas cOlulas. A heranca dos mecanismos determinantes destadeficiŒncia pode ser um fator de risco, com valor prognostico para o desenvolvimento de cancer. PALAVRAS-CHAVE: cancer familiar, glioblastoma, atividade citotoxica, cOlulas NK, subpopulacies de cOlulas T.

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Terezinha C. B. Montelli

Papers

Demonstration of antibody and cellular immune response to brain extract in West and Lennox-Gastaut syndromes

Immunologic aspects of West syndrome and evidence of plasma inhibitory effects on T cell function

[Cognitive function evaluation in school-age children from economically impoverished community: results of enriched education program].

Immunological disturbance in West and Lennox-Gastaut syndromes

Familial cancer: depressed NK-cell cytotoxicity in healthy and cancer affected members.