Pyridoxine-dependent epilepsy

Roberto H Caraballo MD (Dr. Caraballo of Hospital Nacional de Pediatria Juan P Garrahan has no relevant financial relationships to disclose.)
C P Panayiotopoulos MD PhD, editor. (Dr. Panayiotopoulos of St. Thomas' Hospital has no relevant financial relationships to disclose.)
Originally released March 1, 2000; last updated September 28, 2016; expires September 28, 2019

This article includes discussion of pyridoxine-dependent epilepsy, vitamin B6-dependent seizures, pyridoxine-dependent seizures, classic neonatal pyridoxine-dependent seizures, and postneonatal pyridoxine-dependent epilepsy. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

A newborn with refractory seizures controlled with pyridoxine was first reported in 1954, and for many years, no markers to identify this condition besides the therapeutic response were known. In more recent years, mutations in the ALDH7A1 gene have been identified, as well as the disorder of alpha-aminoadipic semialdehyde dehydrogenase deficiency. In addition to the wide range of differential diagnoses with epileptic and nonepileptic crises in infants, 2 other intractable epileptic conditions should be considered that occur in the neonatal and infancy period: pyridoxal phosphate deficiency and folinic acid responsive seizures.

Key points

 

• Pyridoxine dependency should be considered if:

Family history shows:

 

-- miscarriage
-- stillbirth
-- consanguineous parents
-- a sibling with severe seizures or one who died of status epilepticus

The infant shows:

 

-- unusual fetal movements suggestive of intrauterine seizures
-- cryptogenic seizures in a previously normal infant
-- irritability, restlessness, hyperexcitability, and vomiting preceding clinical seizures
-- prolonged or recurrent seizures refractory to standard antiepileptic drugs

• In developing countries, performing genetic studies is difficult; thus, administration of pyridoxine in infants with refractory seizures with unknown etiology is still very useful, not only from a therapeutic but also from a diagnostic point of view. Once a clinical diagnosis of pyridoxine dependency has been established by demonstrating cessation of seizures after the addition of pyridoxine to the treatment, biochemical and molecular studies are recommended.

• In an infant with good response to pyridoxine, the vitamins should be withdrawn to confirm the diagnosis. If the seizures recur, lifelong pyridoxine therapy is required.

• All infants under 2 years of age with refractory seizures of unknown etiology should be given pyridoxine.

• Pyridoxine-dependent epilepsy treatment is considered to be beneficial, even though prognosis may vary even after early treatment.

Historical note and terminology

Hunt and colleagues first described a girl who began twitching at 3 hours of life; she began experiencing generalized convulsions at 5 days of age (Hunt et al 1954). The seizures were refractory to conventional anticonvulsant therapy. An intramuscular injection of multivitamins controlled the seizures for 48 to 56 hours, whereas subsequent standard doses of oral vitamin supplements did not. Pyridoxine (vitamin B6) was eventually identified as the fraction of the multivitamin preparation responsible for clinical efficacy. Withdrawal of the vitamins led to seizure recurrence within 50 hours. The entity was named “pyridoxine dependency” to distinguish it from pyridoxine deficiency as the patient had no antecedents to suspect pyridoxine deficiency, and high doses of pyridoxine were necessary to control the seizures. A related condition designated as pyridoxine-responsive seizure includes infants and young children with seizures who respond initially to pyridoxine, but who lack seizure recurrence with pyridoxine withdrawal (Baxter 2001a; Baxter 2001b). Pyridoxine-dependent epilepsy is considered as a prototypical form of metabolic epilepsy (van Karnebeek and Jaggumantri 2015).

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