Pyridoxine dependency

Epilepsy Action is indebted to Dr Richard Appleton, a Consultant Paediatric Neurologist who specialises in children’s epilepsy, and to Dr Rachel Kneen, Consultant Paediatric Neurologist and Dr Stewart Macleod, Specialist Registrar in paediatric neurology, at Alder Hey at Alder Hey Children’s Hospital, Liverpool, who have kindly prepared the information on this page.

Pyridoxine

Pyridoxine (also called vitamin B6, which is one of the B-complex vitamins) dependency is a very rare condition that has been recognised for about 50 years. The condition is also sometimes called pyridoxine responsive epilepsy.

Although it is not exactly known how rare the condition really is, it probably occurs in no more than 1 in 200,000-400,000 children. The condition usually presents in the first few days or weeks of life but may present in the week or two before the baby is born (called in-utero seizures) or as late as 15 or 18 months of age.

The seizures may be all types - myoclonic, clonic, tonic, tonic-clonic or even infantile spasms. It is in fact quite common for an infant with pyridoxine-dependency to have many different types of seizures, all at the same time.

No specific tests

Occasionally young children who present with infantile spasms in the first year of life (and these children have a type of epilepsy called West Syndrome) will respond to pyridoxine but this does not always mean that they will have pyridoxine-dependency. In view of this, a number of doctors - particularly in Japan and some Eastern European countries - will give pyridoxine as the very first drug when an infant presents with infantile spasms, in case they may have pyridoxine-dependency. However, less than 10 per cent of children who present with infantile spasms as their first or only seizure type actually turn out to have genuine pyridoxine-dependency. Clearly this means that at least 90 per cent of children with infantile spasms do not have pyridoxine-dependency.

There are no specific tests that can diagnose pyridoxine-dependency including blood and urine tests or brain scans (either a computerised tomography (CT), or magnetic resonance imaging (MRI) scan). The electroencephalogram (EEG) is usually very abnormal in children with pyridoxine-dependency and may even look like the EEG pattern in infants who have West Syndrome who have infantile spasms and which is called hypsarrhythmia. The diagnosis of pyridoxine-dependency is usually based on what is called a drug trial, or ‘therapeutic challenge’.

A therapeutic challenge

This means the following: When a child is thought to have the condition, pyridoxine (vitamin B6) is given for a period of time, varying from a few days, or ideally, for three or four weeks.

If the child’s seizures continue after a three or four week trial of pyridoxine, then it is very unlikely that they have pyridoxine-dependency.

If the child’s seizures show a dramatic reduction or cease altogether, then the pyridoxine is stopped immediately (not withdrawn gradually first). If the child’s seizures then recur, the pyridoxine is restarted. If the seizures then stop again after the pyridoxine has been restarted, then this makes the diagnosis of pyridoxine-dependency very likely.

The pyridoxine is then continued, either indefinitely or certainly for the next 12 months before deciding whether to undertake another ‘therapeutic challenge’ by stopping the drug.

Pyridoxine is given by mouth, usually twice a day. Sometimes the drug may be injected into a vein while the child is having an EEG to see if the EEG becomes normal during or immediately after the injection. Clearly this must only be carried out in specialist centres. It is also important to understand that even if the EEG remains abnormal during or just after the injection of pyridoxine, this does not necessarily exclude a diagnosis of pyridoxine-dependency. For this reason most specialists (paediatric neurologists) would recommend giving pyridoxine by mouth for at least three or four weeks.

The dose of pyridoxine is based on the child’s weight; some children need only a small dose, while others need quite high doses, depending on how quickly the seizures stop after pyridoxine is prescribed. Pyridoxine is given either once or twice a day. When given by mouth, pyridoxine has very few long-term side effects.

A very rare condition

Most, if not all children who have pyridoxine-dependency do not respond to the commonly used antiepileptic drugs (also called anticonvulsants), such as carbamazepine, sodium valproate, lamotrigine, topiramate, phenobarbitone, phenytoin or diazepam. In view of this and the fact that, once diagnosed, pyridoxine-dependency is so easily treated, most specialists would always consider giving a three or four week course (a ‘therapeutic trial’) of pyridoxine to all children who present with epileptic seizures in the first year of life and where the seizures do not respond to the usual antiepileptic drugs. However, it is again important to emphasise that despite this approach pyridoxine-dependency remains a very rare condition, and a very rare cause of epilepsy in children. In 11 years at Alder Hey I have often thought about the diagnosis and given a trial of pyridoxine but have never actually found or diagnosed a child with pyridoxine-dependency!

Possible causes

It is not entirely clear why pyridoxine-dependency causes epilepsy. However the most likely explanation is that pyridoxine is used by the body to make a substance within the brain called gamma aminobutyric acid (GABA). GABA is one of a group of chemicals found within the brain called neurotransmitters which are very important in epilepsy.

The other most important neurotransmitter in the brain is one called glutamic acid, which is an excitatory neurotransmitter. GABA is an inhibitory neurotransmitter - which means that it has a crucial function in inhibiting or preventing epileptic seizures. If pyridoxine is not being used properly (as occurs in pyridoxine-dependency), then GABA will not be present in sufficient amounts and therefore seizures will not be prevented, and are likely to occur very frequently.

The inheritance factor

Pyridoxine-dependency is a genetic disorder - which means that it is inherited. The pattern of inheritance is what is called ‘autosomal recessive’, which means that both parents are carriers of the disorder but do not have the disorder themselves. At the current time the gene or genes that may be responsible for pyridoxine-dependency have not been found and therefore there is no test to find out who may be carriers.