Vitamin B-6 Dependency Syndromes Clinical Presentation

The 2 forms of pyridoxine (vitamin B-6)–dependent seizure (PDS) are classic PDS and atypical PDS.

• The classic presentation of PDS consists of intractable seizures that appear within hours of birth and are resistant to conventional anticonvulsants. The seizures respond rapidly to administration of parenteral pyridoxine (vitamin B-6).^[1] A history suggestive of intrauterine convulsive movements (reported as a sustained hammering sensation lasting 15-20 min) at 5 months' gestation or later (reported retrospectively), fetal distress during labor, and meconium staining of the amniotic fluid may be present.^{[1, 2]} These symptoms, in addition to flaccidity and early neonatal seizures, frequently lead to the misdiagnosis of perinatal asphyxia (approximately 10% of cases reported early have features of birth asphyxia or suspected hypoxic-ischemic encephalopathy).^{[1, 12]} Typically, seizures begin in the first few days of life.^[2]
• The atypical form is more frequently reported and may be more common than the classic form.^{[1, 2]} Atypical cases were described soon after PDS was recognized and may not appear until later in life, sometimes as late as age 3 years.^[2] Atypical presentations described in the literature include the following:

  • An initial response to anticonvulsant therapy
  • Seizures occurring 6 weeks after the successful cessation of phenobarbital used to control neonatal seizures
  • Seizure-free intervals of up to 5.5 months occurring after the discontinuation of pyridoxine
  • Initial failure of pyridoxine used to control neonatal seizures during the first 8 months of life, followed by the successful treatment of seizures with pyridoxine administration^{[1, 2]}
• Considering the number of atypical presentations of PDS, research has suggested that the diagnosis of PDS should be suspected in all children with convulsions in the first 18 months of life. The clinical features may be misleading, and early treatment appears to be beneficial.^{[1, 13, 12]}
• Wide ranges of neuropsychiatric outcomes have been described with the diagnosis of PDS.

Physical signs include flaccidity of the limbs at birth and early neonatal seizures.^[1]

• Clinical diagnosis is often delayed, and severe neurologic sequelae are common.
• Typically, children with PDS experience seizures that are long-lasting, and generalized tonic-clonic seizures often evolve in status. Seizures typical of other conditions have also been described in the literature: brief seizures (both partial and generalized); atonic, myoclonic, and visual seizures; and infantile spasms.^{[1, 6]} External stimuli can also trigger seizures.
• Associated presenting features include restlessness, irritability, and vomiting. These features may be noted several hours before the seizures occur.^[1]
• Mental development, specifically expressive verbal ability, is usually impaired; however, evidence suggests that appropriate dosing of pyridoxine may prevent or even reverse impairment.^[1]
• Baxter reports an unusual symptom of apparent acute abdominal obstruction or respiratory distress, usually accompanied by irritable behavior in addition to seizure activity.^[13]
• Hydrocephalus is also present in many cases.^{[6, 13, 12]}
• A history suggestive of intrauterine convulsive movements (reported as a sustained hammering sensation) at 5 months' gestation or later (reported retrospectively), fetal distress during labor, and meconium staining of the amniotic fluid may be present.^{[1, 2]} These symptoms, in addition to flaccidity and early neonatal seizures, frequently lead to the misdiagnosis of perinatal asphyxia (approximately 10% of cases reported early have features of birth asphyxia or hypoxic-ischemic encephalopathy).
• Pyridoxine dependency remains a clinical diagnosis and is based on the following criteria, which have been deemed simple enough for widespread use and broad enough to recognize both typical and atypical cases:

  • Cessation of clinical seizures with the administration of pyridoxine, either orally or parenterally
  • Complete seizure control on pyridoxine monotherapy
  • A recurrence of seizures caused by the withdrawal of pyridoxine^{[1, 2, 3]}
• Associated findings supportive of the diagnosis include a typical EEG pattern, seizures resistant to conventional antiepileptic agents, normalization of the EEG after pyridoxine administration, a positive family history, intrauterine seizures, and neonatal onset of seizures. If parents refuse to withdraw pyridoxine therapy, the first 2 criteria alone are sufficient for diagnosis.^{[1, 6]}
• The parenteral pyridoxine injection test is a highly effective and reproducible test in confirming the diagnosis of PDS.^[1]

PDS is genetically mediated. Researchers have identified defects in the antiquitin gene;^{[14, 15, 16]} however, another unidentified disease-causing gene may also be responsible.^[15]