LAUSR

Epileptic Encephalopathy was selected as the topic for the 15th Neurobiology of Disease in Children (NDC) conference, which was held in Washington, DC, on October 7-8, 2015. Program directors Drs Tallie Z. Baram and Shlomo Shinnar prepared an outstanding agenda that included individual presentations, question-and-answer sessions, and a future directions panel discussion with highly respected leaders in the field of epileptic encephalopathy. In the first session, Clinical Aspects, Dr Susan Koh discussed the most salient clinical presentations as well as electroencephalographic (EEG) findings, both interictally and during a seizure. Although EEG patterns in West syndrome vary considerably from patient to patient, different hypsarrhythmia patterns do not have prognostic significance. Between 60% and 70% of patients have a known etiology, including an array of genetic and metabolic causes. Dr Koh discussed treatment options; high-dose adrenocorticotropic hormone seems to be preferred as first-line treatment by most child neurologists. Many children with infantile spasms transition to LennoxGastaut syndrome, as discussed next by Dr Jim Wheless. However, only a small proportion (10% to 20%) of children with Lennox-Gastaut syndrome have had prior West syndrome. Dr Wheless discussed findings of neuroimaging studies showing how epileptiform discharges recruit widespread areas of association cortex. Genetic studies show positive findings in 10% to 15% of cases and 80% of patients continue to have epilepsy as adults. Dr Edouard Hirsch discussed electrical status epilepticus in sleep/Landau-Kleffner syndrome, including genetic and immune hypotheses. Dr Angela Vincent reviewed the autoimmune encephalopathies. Gray matter antibody diseases in children include voltage-gated potassium channels-complexantibodies with autoimmune encephalitis, N-methyl-D-aspartate receptor antibody encephalitis, glycine receptor-antibody encephalomyelitis, and g-aminobutyric acid A receptorantibody encephalitis. Encephalopathy, seizures, and cognitive and behavioral changes are common presentations of immune encephalopathies, and children are usually afebrile at presentation. The second session on Molecular Features and Pathogenesis started with a presentation by Dr Greg Holmes on vulnerability of the developing brain and potential causes of cognitive dysfunction in epileptic encephalopathy. Dr Sookyong Koh then discussed neuroinflammation, noting that immune cells have been detected in the brains of patients with refractory epilepsy and steroids have been used as anti-inflammatory treatment, with a subsequent anticonvulsant effect. She showed how there is a nonlinear, amplifying feedback loop of crosstalk between innate and adaptive immunity. The microglial activation leads to infiltration of professional antigen-presenting cells, which then cause T-cell infiltration. Some of the T cells, gamma delta T cells, function as both innate and adaptive immunity, and thus neuroinflammation predisposes, precipitates, and perpetuates epileptogenesis. In light of these findings, Dr Tallie Baram discussed potential therapeutic targets. Dr Baram showed that in epileptic encephalopathy, insults can be genetic, acquired, or both, and they have secondary results on neurons, including killing them or impairing synaptic plasticity, which will influence the neuronal network. Many different kinds of insults also change the property of neurons through large-scale epigenetic changes, and these persist. These may be associated with altered metabolism, ongoing seizures, or neurons functioning inefficiently because channels or other molecules are wrong, and this will create an augmented demand without sufficient supply. Additionally, there also may be changes in the glia that influence neurons in many different ways through metabolism, through inflammation, and through impaired synaptic function. All these together coalesce to result in abnormal function of neuronal networks, manifesting as ongoing seizures that have their own side effects as well as cognitive problems, and this results in epileptic encephalopathy. In session 3, Therapeutic Targets and Translational Opportunities, Dr Shlomo Shinnar reviewed the current state of the art on therapy. Dr Shinnar showed that in randomized controlled trials, high-dose adrenocorticotropic hormone has consistently been superior for infantile spasms and that treatment within the first month of seizure onset has a higher response