New treatment paradigms in neonatal metabolic epilepsies

Abstract

Neonatal seizures represent a major challenge among the epilepsies vis-à-vis seizure classification, electroclinical correlation, inherent excitability of neocortex, ontogenic characteristics of neurotransmitter receptors, and responsiveness to standard antiepileptic drugs. Each of these factors renders neonatal seizures more difficult to treat, and therapy has been a vexing area for recent advances in this seizure category. Conversely, specific metabolic disorders have very special therapeutic considerations in the clinical setting of neonatal seizures which require a high index of clinical suspicion and rapid intervention for a successful outcome. The prototype is pyridoxine dependency, although pyridoxal 5'-phosphate dependency is a recently recognized but treatable neonatal epilepsy that deserves earmarked distinction. Clinicians must remain vigilant for these possibilities, including atypical cases where apparent seizure-free intervals may occur. Folinic acid-dependent seizures are allelic with pyridoxine dependency. Serine-dependent seizures and glucose transporter deficiency may present with neonatal seizures and have specific therapy. A vital potassium channel regulated by serum ATP/ADP ratios in the pancreas and brain may be mutated with a resultant neuroendocrinopathy characterized by development delay, epilepsy, and neonatal diabetes (DEND). This requires oral hypoglycaemic therapy, and not insulin, for neurological responsiveness. The startle syndrome of hyperekplexia, which mimics neonatal epilepsy, has been associated with laryngospasm and sudden death but is treated with benzodiazepines.

Seizures and Epilepsy: An Overview for Neuroscientists

“…The type of seizure and syndrome dictates the extent of the metabolic workup (Pearl 2009). For example, a child with IS or Lennox -Gastaut syndrome is more likely to have a metabolic or degenerative disorder than one presenting with simple partial seizures.…”

Partial Pyridoxine Responsiveness in PNPO Deficiency

“…The neonatal onset neurotransmitter disorders include both pyridoxine and PLP-responsive epilepsies (Pearl 2009). PLP, the biologically active form of B6, is a cofactor in approximately 120 enzymatic reactions, many of which involve amino acid and neurotransmitter metabolic pathways (Stockler et al 2011).…”

Metabolic Causes of Epilepsy

“…Defects in the synthesis of L-serine lead to a syndrome of congenital microcephaly, neurodevelopmental disability, and epilepsy which may have neonatal onset (Pearl 2009). Two serine-deficiency syndromes have been described, namely 3-phosphoglycerate dehydrogenase (3-PGDH) deficiency and 3-phosphoserine phosphatase (3-PSP) deficiency (de Koning and Klomp 2004).…”