AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Although rare, pyridoxine-dependent seizure (PDS) is a recognized cause of intractable seizures in neonates, psychomotor developmental delay, and, sometimes, death in untreated patients (Gupta, 2001; Baxter, 2001; Yoshikawa, 1999). Hunt et al first described PDS in 1954 (Gupta, 2001; Burd, 2000). Since then, fewer than 100 cases have been reported worldwide (Gupta, 2001; Yoshikawa, 1999). Later onset seizures due to pyridoxine deficiency have been reported (Gupta, 2001; Grillo, 2001). The 2 types of presentations are classic and atypical. The classic presentation 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 (Gupta, 2001). A trial of pyridoxine is recommended in all seizures that have no clear etiology and occur before the child is aged 18 months (Grillo, 2001).

PDS is probably an underdiagnosed and underreported condition. All medical specialists should be aware of its existence and potentially favorable outcome (Gupta, 2001). Lifelong supplementation of pyridoxine is required (Gupta, 2001; Yoshikawa, 1999).

Vitamin B-6 (pyridoxine)

• Pyridoxine is water-soluble.
• Sources include meat, nuts, and whole-grain products (especially wheat) (Krause, 2001).
• Deficiency usually occurs in conjunction with inadequate intake of other B vitamins due to poor diet or malabsorption states.
• Isolated pyridoxine dependency can occur during treatment with isoniazid, which is a pyridoxine antagonist.
• Pyridoxine requirements are increased in the presence of other drugs, including penicillamine, contraceptive steroids, and hydralazine.
• Clinical features of deficiency in young infants include abnormal CNS activity (eg, irritability, aggravated startle response, seizures) and gastrointestinal distress (eg, distension, vomiting, diarrhea).
• Other manifestations include anemia, peripheral neuropathy, and dermatitis.
• Treatment consists of pyridoxine 5 mg intramuscularly followed by 0.5 mg per day orally for 2 weeks. Correct dietary deficiency.
• Consider pyridoxine dependency in the differential diagnosis of neonatal seizures when other more common causes have been eliminated. Rapid treatment with pyridoxine, 100 mg intramuscularly, is recommended.

The recommended daily dietary intake for pyridoxine is as follows (Krause, 2001):

• Infants 0-6 months, 0.25 mg/d
• Infants 7-12 months, 0.45 mg/d
• Children 1-3 years, 0.6-0.9 mg/d
• Children 4-7 years, 0.8-1.3 mg/d
• Boys 8-11 years, 1.1-1.6 mg/d
• Boys 12-15 years, 1.4-2.1 mg/d
• Boys 16-18 years, 1.5-2.2 mg/d
• Girls 8-11 years, 1-1.5 mg/d
• Girls 12-15 years, 1.2-1.8 mg/d
• Girls 16-18 years, 1.1-1.6 mg/d

Pathophysiology

PDS is an autosomal recessive inborn disorder of metabolism (Gupta, 2001; Grillo, 2001). Some studies suggest that, as well as seizure activity, the neurobehavioral phenotype of the defective gene in PDS may include cognitive and other neuropsychologic impairment (Burd, 2000). Some suggest that PDS is possibly caused by a glutamic acid decarboxylase abnormality (Kuo, 2002).

Frequency

United States

The frequency of PDS in the United States is unknown. Fewer than 100 cases have been reported in the literature; thus, the full range of symptomatology is unknown (Burd, 2000).

International

Burd et al reports prevalence data of 1 per 20,000-100,000 live births. Data from the United Kingdom suggest a very low prevalence (Burd, 2000). A birth incidence of 1 in 783,000 and a point of prevalence of 1 in 687,000 (for definite and probable cases in children <16 y) have been reported from the United Kingdom and the Republic of Ireland in 1999 (Gupta, 2001; Burd, 2000).

Mortality/Morbidity

The literature has not reported mortality and morbidity rates.

Race

No particular race has been identified as more or less susceptible to the condition. Studies have mostly come from the United Kingdom because of misdiagnosis in less developed countries. Gupta et al (2001) report that PDS is underdiagnosed and underreported in India.

Sex

The literature has not identified sex differences in susceptibility to PDS.

Age

Most reported cases have been in infants or young children (Gupta, 2001; Baxter, 2001; Grillo, 2001; Yoshikawa, 1999). Outcomes of PDS in older children have rarely been reported.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The 2 forms of PDS are classic PDS and atypical PDS.

• The classic presentation with 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) (Gupta, 2001). 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 (Gupta, 2001; Baxter, 2001). 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-ischemia encephalopathy) (Gupta, 2001; Baxter, 1999). Typically, seizures begin in the first few days of life (Gupta, 2001).
• The atypical form is more frequently reported and may be more common than the classic form (Gupta, 2001; Baxter, 2001). Atypical cases were described soon after PDS was recognized and may not appear until later in life, sometimes as late as age 3 years (Baxter, 2001). 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 (Gupta, 2001; Baxter, 2001)
  • 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 (Gupta, 2001; Baxter, 2000; Baxter, 1999).
  • Wide ranges of neuropsychiatric outcomes have been described with the diagnosis of PDS (Scriver, 2001).

Physical

Physical signs include flaccidity of the limbs at birth and early neonatal seizures (Gupta, 2001).

• No biological marker for the disease exists (Gupta, 2001). Clinical diagnosis is often delayed, and severe neurologic sequelae are common (Scriver, 2001).
• 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 (Gupta, 2001; Burd, 2000). 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 (Gupta, 2001).
• Mental development, specifically expressive verbal ability, is usually impaired; however, evidence suggests that appropriate dosing of pyridoxine may prevent or even reverse impairment (Gupta, 2001).
• Baxter reports an unusual symptom of apparent acute abdominal obstruction or respiratory distress, usually accompanied by irritable behavior in addition to seizure activity (Baxter, 2000).
• Hydrocephalus is also present in many cases (Burd, 2000; Baxter, 2000; Baxter, 1999).
• 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 (Gupta, 2001; Baxter, 2001). 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-ischemia 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 (Gupta, 2001; Baxter, 2001; Yoshikawa, 1999)
• 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 (Gupta, 2001; Burd, 2000).
• The parenteral pyridoxine injection test is a highly effective and reproducible test in confirming the diagnosis of PDS (Gupta, 2001).

Causes

PDS is genetically mediated. The biochemical abnormality and gene locus are still unknown (Baxter, 2001). The homocystinuria abnormality appears to inhibit the binding of vitamin B-6 to the enzyme glutamic acid decarboxylase-1, which is needed for the biosynthesis of gamma-aminobutyric acid (GABA) (Scriver, 2001).

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Homocystinuria
Myoclonic epilepsy
West syndrome

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Perform hematology tests, a sepsis screen, and metabolic (profile) tests.
• Biochemical studies have not demonstrated abnormalities in the metabolism or transport of pyridoxine or its active form, pyridoxal phosphate. Some studies suggest that an abnormality of glutamic acid decarboxylase (GAD), a pyridoxal phosphate-dependent enzyme that catalyses glutamate to GABA, is responsible for the abnormal metabolism and transport of pyridoxine and causes PDS. However, reports are conflicting, and the biochemistry and genetics of PDS remain unclear (Baxter, 2001; Grillo, 2001; Yoshikawa, 1999). Discovering this would allow new insights into a variety of conditions, including epilepsy and other cortical functions influencing intelligence quotient (IQ) and speech.

Imaging Studies

• Head CT and MRI: Despite several reports about imaging studies, no typical abnormality has been found in PDS (Gupta, 2001; Baxter, 2001). A high prevalence of structural CNS defects has been reported, as well as varying degrees of grey and white matter atrophy, thinning of the corpus callosum, and the presence of mega cisterna magna (Gupta, 2001). Progressive cortical-white matter atrophy and ventricular dilation is also present in inadequately treated patients with PDS (Gupta, 2001; Baxter, 2001). Hydrocephalus of unknown origin can also occur. Baxter reports apparent cysts adjacent to the lateral ventricles in some neonatal-onset ultrasonographic images. CT and MRI show structural abnormalities in the brain in addition to white matter abnormalities (Baxter, 2001). CT and MRI do not have a well-established role in the diagnosis of PDS (Gupta, 2001).

Other Tests

• EEG: Following pyridoxine administration, the EEG usually takes 2-6 minutes to normalize. The pattern is typically suggestive of diffuse and focal dysfunction and may show focal discharges; however, some EEG patterns have been normal (ie, bursts or runs of high-voltage, relatively bilateral synchronous sharp and slow [1-4 Hz] wave activity [either ictally or interictally]) (Gupta, 2001).

  EEG does not have a well-established role in the diagnosis of PDS. One report suggests that the abnormal EEG is a result of the administration of anticonvulsants to the patient prior to the diagnosis of PDS (Baxter, 2000).

Procedures

• Perform a cerebrospinal fluid (CSF) examination (ie, lumbar puncture).

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Recommended maintenance doses of pyridoxine have ranged from 2-300 mg/d (Gupta, 2001; Baxter, 2001). Responses to treatment have included an improvement in the IQ and reversal of mental retardation in patents with PDS, depending on the dose on pyridoxine given. The suggested mechanism of this is normalization of CSF glutamate. Some studies have also found an improvement in the quality of behavior and IQ following an increase in the dose (150-500 mg/d) of pyridoxine given to older children with PDS (Gupta, 2001; Ohtsuka, 2000).

Kuo et al suggested that pyridoxine phosphate should be considered as the drug of choice in atypical cases of children not responding to pyridoxine (Kuo, 2002). This is in an attempt to reduce failure rate and further delay in seizure control because pyridoxal phosphate is the active coenzyme for more that 100 enzymes. Further research is needed.

Consultations

• Neurologist
• Metabolic physician/Geneticist
• Eye specialist
• Rehabilitation specialists - Dietitian, physiotherapist, speech pathologist, and occupational therapist

Diet

Oral supplementation of vitamin B-6 is essential because dietary sources cannot be manipulated to achieve such a high requirement (100 mg/d). No other nutritional support specific to PDS is indicated; however, sequelae of this disease may increase the nutritional risk. According to the Dietary Guidelines for Children and Adolescents, ensuring nutritional adequacy of the diet is essential. This includes adequate vitamin B-6 intake, which meets recommended dietary intake specific to age and sex. Children with mental retardation often cannot achieve sufficient caloric requirements through oral intake alone; thus, supplementary feeding, including enteral feeding, may be indicated. A referral to a dietitian to ensure nutritional adequacy of the diet is recommended initially and then periodically as required.

Activity

No reports exist for special benefits of physical activity in children with PDS.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug Category: Vitamins

Organic substances required by the body in small amounts for various metabolic processes. Vitamins may be synthesized in small or insufficient amounts in the body or not synthesized at all, thus requiring supplementation. Deficiency may result from an inadequate diet, increased requirements, or secondary to disease or drugs. Used clinically for the prevention and treatment of specific vitamin deficiency states. Considered third-line treatment for both acute and chronic intractable seizure disorders in children younger than 2 years.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Monitor seizure activity.

Further Outpatient Care

• Continue to monitor seizure activity.

In/Out Patient Meds

• Pyridoxine (see Medication)

Complications

• Patients who are taking long-term pyridoxine for PDS must be assessed for signs of sensory peripheral neuropathy on follow-up; this should include monitoring of rombergism, ankle jerks, and joint position sense (Gupta, 2001; Baxter, 2001).
• The toxic effects of pyridoxine administration are a major concern for patients with PDS. Prolonged depression of neurologic and respiratory function, bradycardia, hypotonia and apnea, and depression of cerebral electrical activity have all been reported in patients receiving oral or parenteral test doses of pyridoxine. A reversible sensory neuropathy has been described in some individuals who have taken high doses of pyridoxine on a long-term basis. In some patients, a chronic painful neuropathy has developed (Gupta, 2001; Baxter, 2001).
• In adults, symptoms of adverse effects of megadoses of pyridoxine include unstable gait and feet numbness, followed by numbness and clumsiness of the hands, and then perioral numbness. Signs include gait ataxia, reduced or absent reflexes, decrease position, vibration, pain, and heightened temperature sensation (Baxter, 2001).
• Intercurrent illness can precipitate seizures in children whose states are usually well controlled on pyridoxine. Administration of an additional 100 mg of pyridoxine per day is recommended in these cases (Baxter, 2001); however, this is not always effective.

Prognosis

• Untreated patients usually die with a severe seizure disorder, and most infants have mental retardation despite the initiation of therapy in utero or during the first hour of life (Gupta, 2001; Burd, 2000). However, early therapy may decrease the severity of intellectual impairment (Gupta, 2001; Baxter, 2001; Baxter, 2000; Baxter, 1999). A meta-analysis of the most recent literature indicates no significant correlation between developmental outcome and the time of diagnosis and institution of pyridoxine therapy. Some studies suggest that the developmental outcome is dependent on the dose of pyridoxine used (Gupta, 2001). Approximately 60% of patients with PDS have delayed developmental milestones for walking and talking (Burd, 2000). Additionally, one study reports a specific deficit in expressive speech (Baxter, 1999).
• Patients presenting older than 1 month have a better prognosis than those presenting younger than 1 month. Infants who have early seizures that are unresponsive to routine anticonvulsants usually have a poor prognosis.

Patient Education

• Instruct parents, caregivers, and other relevant parties (eg, relatives, teachers) on the administration of pyridoxine. Compliance in young children can be poor because liquid and tablet preparations of pyridoxine have an unpleasant taste, and breakthrough seizures can occur (Baxter, 2001).
• For excellent patient education resources, visit eMedicine's Children's Health Center and Esophagus, Stomach, and Intestine Center. Also, see eMedicine's patient education articles Seizures in Children and Anatomy of the Digestive System.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failing to recognize pyridoxine dependency as a cause of intractable seizures is a pitfall.
• Litigation may result if PDS remains undiagnosed in an infant in whom severe mental retardation develops.

Special Concerns

• One study suggests that treatment with intrauterine vitamin B-6 (100 mg/d) in pregnant women with a history of intrauterine convulsive movements (reported as a sustained hammering sensation) at 5 months' gestation or later may be successful in preventing PDS (Scriver, 2001).
• Toxic effects of vitamin B-6 (>1 g/d) appear to be relatively low; however, several grams per day have produced sensory neuropathy, marked by changes in gait and peripheral sensation (Schaumberg, 1983; Krause, 2001). No studies have reported the effect of vitamin B-6 toxicity on the fetus. Signs of vitamin B-6 toxicity seem to resemble vitamin B-6 deficiency (Krause, 2001).
• A highly significant correlation of the onset of seizures in affected siblings in the same family has been reported. Similarly, variable expression in the same family has also been found (Gupta, 2001).

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Baxter P. Pyridoxine-dependent and pyridoxine-responsive seizures. Dev Med Child Neurol. Jun 2001;43(6):416-20. [Medline].
• Baxter P. Pyridoxine dependent epilepsy: a suggestive electroclinical pattern. Arch Dis Child Fetal Neonatal Ed. Sep 2000;83(2):F163. [Medline].
• Baxter P. Epidemiology of pyridoxine dependent and pyridoxine responsive seizures in the UK. Arch Dis Child. Nov 1999;81(5):431-3. [Medline].
• Burd L, Stenehjem A, Franceschini LA, Kerbeshian J. A 15-year follow-up of a boy with pyridoxine (vitamin B6)-dependent seizures with autism, breath holding, and severe mental retardation. J Child Neurol. Nov 2000;15(11):763-5. [Medline].
• Grillo E, da Silva RJ, Barbato JH Jr. Pyridoxine-dependent seizures responding to extremely low-dose pyridoxine. Dev Med Child Neurol. Jun 2001;43(6):413-5. [Medline].
• Gupta VK, Mishra D, Mathur I, Singh KK. Pyridoxine-dependent seizures: a case report and a critical review of the literature. J Paediatr Child Health. Dec 2001;37(6):592-6. [Medline].
• Hindley D, Huyton M. Pyridoxine dependent and pyridoxine responsive seizures. Arch Dis Child. Jan 2001;84(1):91-2. [Medline].
• Kuo MF, Wang HS. Pyridoxal phosphate-responsive epilepsy with resistance to pyridoxine. Pediatr Neurol. Feb 2002;26(2):146-7. [Medline].
• Ohtsuka Y, Ogino T, Asano T, et al. Long-term follow-up of vitamin B(6)-responsive West syndrome. Pediatr Neurol. Sep 2000;23(3):202-6. [Medline].
• Yoshikawa H, Abe T, Oda Y. Pyridoxine-dependent seizures in an older child. J Child Neurol. Oct 1999;14(10):687-90. [Medline].

Article Last Updated: Feb 8, 2005