Early Pyridoxine Administration to Avoid Late Diagnosis of Pyridoxine-Dependent Epilepsy; Comment on the ILAE Guidelines Proposal on the Treatment of Seizures in the Neonate

The ILAE Task Force on Neonatal Seizures has recently published consensus-based guidelines and recommendations for the treatment of neonatal seizures (https://www.ilae.org/guidelines/guidelines-and-reports/treatment-of-seizures-in-the-neonateguidelines-and-consensus-based-recommendations).

The Task Force suggests that a trial of pyridoxine should be provided as an add-on to ASM (antiseizures medications) treatment in neonates with seizures of unidentified etiology that are unresponsive to second-line ASM. Both daily clinical practice (including our experience with three patients with pyridoxine-dependent epilepsy [PDE]) and published literature support the possibility that patients with vitamin B6-dependent epilepsy may show an initial response to common ASMs, but can relapse with status epilepticus later in life. A brief review of the literature revealed 53 reports of newborns with seizures that showed initial response to first- and second-line ASMs including phenobarbital, phenytoin, midazolam, levetiracetam, and valproic acid. These same patients relapsed with seizures and in some cases with status epilepticus later in life and were diagnosed with PDEs.[1] [2] [3] [4] [5] [6]

We are aware that PDE is an extremely rare condition that can mimic other more common causes for neonatal seizures and that pyridoxine's administration is not devoid of side effects, although rare, preventable, and known. Nevertheless, based on the above evidence, we believe that postponing pyridoxine administration and restricting its use only as an add-on therapy to ASMs in treatment unresponsive patients might lead to a dramatic delay in PDE. We believe that there is an urgent need to addend these guidelines after thoroughly examining this matter to at least cite the possibility of missing an early PDE diagnosis and to consider the possibility of suggesting a trial of pyridoxine in all patients with seizures of unknown etiology as first-line treatment even before ASM administration, especially in newborns presenting with clinical and/or electroencephalography features suggestive of PDE.

Publication History

Received: 13 July 2023

Accepted: 03 December 2023

Article published online:
09 January 2024

• References

• 1 Kluger G, Blank R, Paul K. et al. Pyridoxine-dependent epilepsy: normal outcome in a patient with late diagnosis after prolonged status epilepticus causing cortical blindness. Neuropediatrics 2008; 39 (05) 276-279
• 2 Lin J, Lin K, Masruha MR, Vilanova LC. Pyridoxine-dependent epilepsy initially responsive to phenobarbital. Arq Neuropsiquiatr 2007; 65 (4A): 1026-1029
• 3 Mastrangelo M, Gasparri V, Bernardi K, Foglietta S, Ramantani G, Pisani F. Epilepsy phenotypes of vitamin B6-dependent diseases: an updated systematic review. Children (Basel) 2023; 10 (03) 553
• 4 Falsaperla R, Vari MS, Toldo I. et al; Italian Society of Pediatric Neurology (SINP: Società Italiana di Neurologia Pediatrica). Pyridoxine-dependent epilepsies: an observational study on clinical, diagnostic, therapeutic and prognostic features in a pediatric cohort. Metab Brain Dis 2018; 33 (01) 261-269
• 5 Coughlin II CR, Swanson MA, Spector E. et al. The genotypic spectrum of ALDH7A1 mutations resulting in pyridoxine dependent epilepsy: a common epileptic encephalopathy. J Inherit Metab Dis 2019; 42 (02) 353-361
• 6 Bok LA, Maurits NM, Willemsen MA. et al. The EEG response to pyridoxine-IV neither identifies nor excludes pyridoxine-dependent epilepsy. Epilepsia 2010; 51 (12) 2406-2411