Current and Emerging Therapies of Severe Epileptic Encephalopathies Abeer J. Hani, MD, * and Mohamad A. Mikati, MD † 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 pathophysi- ology 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. Semin Pediatr Neurol ]:]]]-]]] C 2016 Published by Elsevier Inc. Introduction Recent advances in genetics have markedly affected our understanding of multiple epilepsy syndromes and are expanding our therapeutic options. Epileptic encephalopathies (EEs) comprise a group of clinical entities each with a specific disease course and with electroencephalographic (EEG) abnor- malities that cause progressive disturbances of cerebral func- tions. 1 Failure to appropriately recognize an EEs in question results in ongoing cognitive and behavioral impairments. EEs are often resistant to conventional antiepileptic drugs (AEDs), hence the interest in new and emerging therapies. Studies have shown that early initiation of therapy often correlates with better outcomes. For example, the United Kingdom Infantile Spasms Study demonstrated that delayed treatment of infantile spasms correlated with poor outcomes. 2 Also, in children with tuberous sclerosis, time of cessation of spasms correlates with the degree of subsequent intellectual disability. 3 Given the importance of therapy of EEs, we in the following sections review the current and emerging treatments of pediatric EE (Table 1). 4-6 Early Infantile EEs: EIEE or Ohtahara Syndrome, and Early Myoclonic Encephalopathy Traditional treatment of early infantile EE (EIEE) usually con- sists of trials of AEDs, most commonly vigabatrin (VGB), which has some chance of success, as well as phenytoin, topiramate (TPM), levetiracetam (LEV), zonisamide (ZNS), phenobarbital, or combinations of these AEDs. 4 In some cases, the use of the steroids or the ketogenic diet has been helpful. There have been reports of the use of functional hemispherectomy or even focal resection surgeries in cases of unilateral hemispheric dysplasias presenting with EIEE with good seizure control and good neurodevelopmental outcomes in some. 7 The emerging data that multiple channelopathies (such as SCN2A and KCNQ 2 mutations) may cause this and other forms of epileptic encephalopathy have raised interest in the search for speci fic targets of therapy. 8 This now is being translated into clinical applications (Fig. ). In addition, it may prove to be help- ful, in some conditions, to treat secondary biochemical changes. It has been reported that in SCN2A–mutation-associated EE, there can exist secondary neurotransmitter deficiency, and that treatment with 5-hydroxytryptophan, L-dopa-carbidopa, and dopa agonists to correct for such a deficiency may help with seizure control. 9 Therapy for early myoclonic encephalopathy focuses on treating the underlying metabolic etiology if one is identi fied and on the use of therapies similar to those used in ohtahara syndrome, although vigabatrin may not be as useful. West Syndrome West syndrome comprises the triad of infantile spasms, psychomotor regression, and the characteristic EEG pattern http://dx.doi.org/10.1016/j.spen.2016.06.001 1 1071-9091/11/& 2016 Published by Elsevier Inc. From the *Department of Pediatrics and Neurology, Lebanese American University, Byblos, Lebanon. †Division of Pediatric Neurology, Children’ s Health Center, Duke University Medical Center, Durham, NC. Address reprint request to Mohamad Mikati, MD, Division of Pediatric Neurology, Duke University Medical Center, T0913 Children’s Health Center, Box 3936, 2301 Erwin Road, Durham, NC 27710. E-mail: mohamad.mikati@duke.edu