Investigation of neuronal auto-antibodies in children diagnosed with epileptic encephalopathy of unknown cause.

AIM: Cryptogenic forms of epileptic encephalopathies (EE) with their well-known features of drug-resistance, mental deterioration and partial response to immunotherapies are ideal candidates for screening for neuronal autoantibodies (NAA). METHOD: Fifty consecutive pediatric patients with a diagnosis of EE of unknown cause were included. Nine NAAs were tested by ELISA, RIA or cell-based assays. Clinical features of seronegative and seropositive patients were compared. RESULTS: NAAs were found in 7/50 (14%) patients. They were N-methyl-d-aspartate receptor in two (4%), glycine receptor in two (4%), contactin-associated protein-like 2 in one (2%), glutamic acid decarboxylase in one (2%) and type A gamma aminobutyric acid receptor in one patient (2%). Furthermore, serum IgGs of two patients negative for well-characterized NAAs, showed strong reactivity with the uncharacterized membrane antigens of live hippocampal neurons. There were no significant differences between seropositive and seronegative patients by means of epilepsy duration, anti-epileptic drug resistance, EE type, types of seizures, seizure frequencies, EEG features or coexisting autoimmune diseases. Some seropositive patients gave good-moderate response to immunotherapy. DISCUSSION: Potential clues for the possible role of autoimmunity in seropositive patients with EE were atypical prognosis of the classical EE type, atypical progression and unusual neurological findings like dyskinesia.

Inflammation in Epileptic Encephalopathies.

West syndrome (WS) is an infantile epileptic encephalopathy that manifests with infantile spasms (IS), hypsarrhythmia (in ~60% of infants), and poor neurodevelopmental outcomes. The etiologies of WS can be structural-metabolic pathologies (~60%), genetic (12%-15%), or of unknown origin. The current treatment options include hormonal treatment (adrenocorticotropic hormone and high-dose steroids) and the GABA aminotransferase inhibitor vigabatrin, while ketogenic diet can be given as add-on treatment in refractory IS. There is a need to identify new therapeutic targets and more effective treatments for WS. Theories about the role of inflammatory pathways in the pathogenesis and treatment of WS have emerged, being supported by both clinical and preclinical data from animal models of WS. Ongoing advances in genetics have revealed numerous genes involved in the pathogenesis of WS, including genes directly or indirectly involved in inflammation. Inflammatory pathways also interact with other signaling pathways implicated in WS, such as the neuroendocrine pathway. Furthermore, seizures may also activate proinflammatory pathways raising the possibility that inflammation can be a consequence of seizures and epileptogenic processes. With this targeted review, we plan to discuss the evidence pro and against the following key questions. Does activation of inflammatory pathways in the brain cause epilepsy in WS and does it contribute to the associated comorbidities and progression? Can activation of certain inflammatory pathways be a compensatory or protective event? Are there interactions between inflammation and the neuroendocrine system that contribute to the pathogenesis of WS? Does activation of brain inflammatory signaling pathways contribute to the transition of WS to Lennox-Gastaut syndrome? Are there any lead candidates or unexplored targets for future therapy development for WS targeting inflammation?

Current and Emerging Therapies of Severe Epileptic Encephalopathies.

In this article, we review the treatment options for the pediatric epileptic encephalopathies and provide an update on the new and emerging therapies targeted at the underlying pathophysiology of many of these syndromes. We illustrate how the identification of the specific genetic and autoimmune causes has made possible the evaluation and development of novel, better targeted therapies, as and at times, avoidance of potentially offending agents.