Current and Emerging Therapies of Severe Epileptic Encephalopathies

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Abstract

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.

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) abnormalities that cause progressive disturbances of cerebral functions.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, 5, 6

Section snippets

Early Infantile EEs: EIEE or Ohtahara Syndrome, and Early Myoclonic Encephalopathy

Traditional treatment of early infantile EE (EIEE) usually consists 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

West Syndrome

West syndrome comprises the triad of infantile spasms, psychomotor regression, and the characteristic EEG pattern of hypsarrhythmia. The goals of treatment include complete cessation of the seizures and disappearance of the hypsarrhythmia. The first-line treatment in West syndrome is adrenocorticotropic hormone (ACTH).10, 11, 12 The recommended dose of ACTH has ranged from low to high doses.10 The Food and Drug Administration recommended regimen of ACTH is a daily dose of 150 units/m2 divided

Lennox Gastaut Syndrome

Lennox Gastaut syndrome (LGS) is an electroclinical syndrome with multiple etiologies that may evolve from West syndrome or may appear de novo in early childhood. Seizures are of multiple types, but as a rule include tonic and atypical absence seizures as well as atonic and myoclonic seizures. Patients with LGS have a characteristic slow generalized (<2.5 Hz) spike-wave pattern dominating the interictal EEG. Review of randomized controlled trials done in patients with LGS shows that, although no

EE-CSWS and Landau Kleffner Syndrome

Epileptic Encephalopathy with Continuous Spikes and Waves during Sleep (EE-CSWS) is an epileptic encephalopathy characterized by seizures, developmental regression, and a characteristic EEG pattern of electrical status epilepticus of sleep (ESES, CSWS). Landau Kleffner Syndrome (LKS) is characterized by onset of auditory verbal agnosia with language regression and specific EEG changes. Seizures are seen in 75% of cases. EEG in patients with LKS shows focal or bilateral centrotemporal spikes

Severe Myoclonic Epilepsy of Infancy (Dravet Syndrome)

Dravet syndrome is an epilepsy syndrome that starts during the first year of life and is characterized by prolonged febrile hemiclonic and generalized clonic seizures often with occurrence of status epilepticus and psychomotor delay. Multiple genetic mutations, most notably of the SCN1A gene, have been found to cause this syndrome. This mutation affects mostly GABAergic interneuronal function. Treatment options of Dravet syndrome have been investigated in a number of trials. These have provided

Epilepsy of Infancy with Migrating Focal Seizures, or Malignant Migrating Partial Seizures in Infancy

This is an epilepsy syndrome that starts in the first year of life and is characterized by nearly continuous seizure activity seen in multiple independent areas of both hemispheres with arrest in psychomotor development. Treatment options have included LEV, rufinamide, bromide, stiripentol, ketogenic diet, vagal nerve stimulation, and acetazolamide with variable, usually poor efficacy.48, 49 Recent discoveries have shown that gain-of-function KCNT-1 mutations are the underlying etiology in some

Autoimmune EEs

The term autoimmune epileptic encephalopathy is used to refer to an epileptic encephalopathy with an underlying proven or presumed autoimmune etioloy.53 Such conditions are often characterized by the presence of neuronal antibodies in serum or CSF and by a clinical presentation of seizures, movement disorder, neuropsychiatric features, and cognitive decline.52 Several immune-mediated epilepsies have now been identified. These include limbic encephalitis, anti-NMDA receptor encephalitis,

Emerging Therapies Based on Underlying Pathophysiology

Therapies targeting the underlying pathophysiology either at the receptor level or at the cellular signal transduction pathways level are beginning to emerge.6 These include mechanistic target of rapamycin pathway inhibition in mTORopathies such as tuberous sclerosis with agents such as everolimus. They also include the use of N-methyl-d-aspartate receptor (NMDA) receptor antagonists in Rett syndrome and mGluR5 receptor antagonists in Fragile X syndrome.57 Some emerging therapies can even be

Conclusion

Proper identification of the specific EE can lead to the proper choice of therapy among the usually several available AED options. In addition, the increased knowledge and enhanced technology currently available to identify the different etiologies of the various EEs has yielded better identification of the underlying genetic, structural, and autoimmune pathogenic mechanisms. Proper identification of such etiologies has resulted in more targeted treatments and in avoidance of exacerbating

Acknowledgment

We thank Miss Lindsay Johnson for her help in preparing the article.

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