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Year : 2016  |  Volume : 11  |  Issue : 3  |  Page : 188-192

Pyridoxine-dependent convulsions among children with refractory seizures: A 3-year follow-up study

1 Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
2 Department of Clinical Neurosciences, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
3 Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India

Date of Web Publication3-Nov-2016

Correspondence Address:
Sadanandavalli Retnaswami Chandra
Professor of Neurology, Faculty Block, Neurocentre, National Institute of Mental Health and Neurosciences, Bengaluru . 560 029, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1817-1745.193361

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Introduction: Epilepsy accounts for 1% of the global disease burden and about 8–10 million epilepsy patients live in India. About 30–40% of these patients become drug-resistant and land up with palliative or disease-modifying surgeries. This is a situation causing great concern in view of the psychosocial and economic burden on the patient and the family apart from severe cognitive and motor consequences, especially in children. Therefore, it is mandatory to have an insight into the wide spectrum of causes with reference to refractoriness to antiepileptic medications in children with epilepsy. Patients and Methods: Children admitted under our team with refractory epilepsy as per the International League Against Epilepsy (ILAE) criteria in the last 3 years were included in the study. Results: Refractory epilepsy constituted 13.3% of inpatients in the pediatric group. Males dominated with 68.9% of these patients. Nearly 34.4% of these patients were found to suffer from various neurometabolic diseases. Almost 3.5% were due to pyridoxine-dependent convulsions. This group of patients showed an excellent response to dietary manipulation, disease-modifying treatment for the metabolic disorder, and supportive small-dose anticonvulsants. During follow-up, they showed very good response with reference to global development and seizure control. Conclusion: Pyridoxine-dependent convulsions are relatively rare forming about 3.5% of refractory epilepsies in this series. With initiation of appropriate therapy, results with reference to seizure control as well as neurodevelopment became evident within 2 weeks, and at 1-year follow-up, complete independence for majority of the needed activities is achieved with minimum cost, almost zero side effects, and absolute elimination of the need for palliative surgery.

Keywords: Neurometabolic disorders, pyridoxine-dependent seizures, refractory seizures

How to cite this article:
Chandra SR, Issac TG, Deepak S, Teja R, Kuruthukulangara S. Pyridoxine-dependent convulsions among children with refractory seizures: A 3-year follow-up study. J Pediatr Neurosci 2016;11:188-92

How to cite this URL:
Chandra SR, Issac TG, Deepak S, Teja R, Kuruthukulangara S. Pyridoxine-dependent convulsions among children with refractory seizures: A 3-year follow-up study. J Pediatr Neurosci [serial online] 2016 [cited 2021 Apr 21];11:188-92. Available from: https://www.pediatricneurosciences.com/text.asp?2016/11/3/188/193361


Nearly 30–40% of patients with seizures become refractory to the medical management in spite of proper compliance and appropriate treatment chosen based on the seizure diagnosis. It is mandatory to take a sincere effort to get the complete phenotypic description of the seizure type and categorize it as whether it is localization-related, generalized, or an epilepsy syndrome.[1] ILAE has proposed the term as “Drug-resistant epilepsy” instead of “refractory epilepsy” and has defined it as “failure of adequate trials of two tolerated and appropriately chosen and used antiepileptic drug (AED) schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom”.[2] Refractory epilepsy or drug-resistant epilepsy constitutes 10–20% of epilepsy cases in children.[2] The scheme of assessment consists of outcome measures and adverse effect of treatment. This approach helps categorize the patients into two groups: one is those who are seizure-free and the other who are not seizure-free. The seizure-free groups are further categorized into those with adverse effects and those without serious adverse effects, which is of great help in deciding other interventions even in the seizure-free group. The drug chosen should be appropriate for the seizure type, and it should be in the optimum recommended dose and previously shown to be effective in the right context.[2] With reference to children having drug-resistant epilepsy, there are major complications in learning and behavior as well as regression of acquired milestones secondary to epilepsy-induced encephalopathy. The other known consequences are increased mortality including sudden unexplained death, poor employment opportunities, infertility, and lifelong stigma.[3] The wrong choice of anticonvulsant chosen may even result in aggravation of certain seizure types. Catastrophic encephalopathy can result in patients with seizures complicating conditions such as mitochondrial cytopathy with the use of mitochondrial toxins such as sodium valproate and phenobarbitone.[4],[5] Neurometabolic disorders with seizures need appropriate metabolism-based intervention rather than polypharmacy with antiepileptic drugs, making it very mandatory to have a proper clinical framework to choose the appropriate drug. For defining seizure-free, two main factors are considered which takes into account the preintervention seizure frequency in the following manner. A seizure-free duration three times the premorbid interseizure interval if observed or an absolute seizure freedom of a minimum period of 12 months is considered a good response. Adverse effects apply to the occurrence of unintended responses to the intervention, but the gravity of it has a lot of subjectivity.[2]

A relatively less common cause for drug-resistant epilepsy is pyridoxine-dependent convulsions. However, once recognized, treatment response to both seizure control and neurodevelopment is excellent. A high degree of suspicion is needed in suspecting these cases as it will considerably reduce the cost of treatment in addition to the reduction in morbidity and adverse effects of the drugs. Pyridoxine exists in three chemically distinct forms which are: (1) pyridoxal, (2) pyridoxamine, and (3) pyridoxine. The active form is pyridoxal 5-phosphate. It is an important cofactor in many enzymatic reactions involving amino acids, glucose, and lipid metabolism. Pyridoxic acid is the catabolite excreted in urine. All three forms are interconvertible. Absorbed pyridoxamine is converted to pyridoxamine 5-phosphate by pyridoxal kinase. This is converted to pyridoxal 5-phosphate by pyridoxamine phosphate transaminase or pyridoxine 5-phosphate oxidase. This is dependent on flavin mononucleotide which is produced from riboflavin. The neurotransmitters which involve Vitamin B6 in their synthesis are dopamine, norepinephrine, epinephrine, histamine, and gamma-aminobutyric acid (GABA). With reference to hemoglobin synthesis, Vitamin B6 serves as a coenzyme for aminolevulinic acid synthesis.[6],[7] The common medical use of Vitamin B6 is the prevention of isoniazid-induced neuropathy, hyperemesis of pregnancy, attention-deficit hyperactivity disorders, autism, depression, alcohol hangover, carpal tunnel syndrome, etc.[8]

Pyridoxine and seizures

This condition was first described in 1954 by Hunt et al., as responsive to an intravenous multivitamin.[9] The point prevalence of pyridoxine (Vitamin B6) deficiency seizures in the UK is 1/687000 and birth incidence is 1/783,000 population, and approximately only 100 such cases have been reported so far in literature.[10] Pyridoxine-dependent seizures are a group of extremely rare autosomal recessive disorder which is a typical example of metabolic epilepsy. These seizures occur despite normal Vitamin B6 level due to defective binding of pyridoxine to its apoenzyme which converts glutamic acid to GABA. Therefore, GABA levels are very much reduced causing very much lowered seizure threshold.[11],[12] Seizures can start prenatally, natally, postnatally, or neonatal period and typically resistant to antiepileptic drugs. The underlying genetic defect has been identified as a mutation in ALDH7A1 causing deficiency of alpha-aminoadipic semialdehyde dehydrogenase. This is involved in cerebral lysine catabolism.[12] There are atypical types of pyridoxine-dependent epilepsies which may first respond to anticonvulsants but relapse later, seizures not controlled by pyridoxine initially but which respond later.[13] The typical clinical seizure phenotype is seizures in the early neonatal period which are recurrent in the form of either generalized tonic–clonic seizures or partial motor seizures, infantile spasms, and recurrent status. There are associated features such as vomiting abdominal distension, irritability, paroxysmal facial grimacing, and eye movement abnormalities clubbed with severe developmental and intellectual delay. Based on phenotypic characters, these patients are classified into three groups: Group 1 consists of complete seizure control and normal development; Group 2 consists of complete seizure control but with developmental delay; Group 3 consists of persistent seizures and developmental delay. However, the genotypic markers for these varying phenotypes are not known. Electroencephalography (EEG) is nonspecific; however, the EEG patterns reverse with intravenous pyridoxine. Magnetic resonance imaging is also nonspecific with varying findings from diffuse atrophy, white matter changes, thin corpus callosum, as well as normal brain appearance.[12],[13] The treatment consists of lifelong pyridoxine supplementation in pharmacological doses. In an acutely convulsing infant, 100 mg can be given intravenously followed by oral doses of 15–30 mg/kg/day up to a maximum of 200 mg in adults and 500 mg in adults per day based on the clinical response. Regular monitoring for neuropathy is needed in patients who are taking higher doses. Breakthrough seizures can occur in febrile illness, and therefore, dosages can be doubled in systemic infections. Prenatal diagnosis is indicated in families where parents are homozygous for mutation in the genes ATQ (Y380X) and (E399Q). Prenatal supplementation of pyridoxine to mothers with 100 mg/day from early pregnancy is indicated followed by the postnatal treatment of the baby. In such situations, it is mandatory to carry out biochemical and genetic testing in the child also to avoid high-dose pyridoxine treatment to the child. Some patients respond to pyridoxal phosphate (15–30 mg/kg/day) and some respond to folinic acid (3–5 mg/kg/day) as an add-on in pyridoxine hydrochloride nonresponders. Arginine is given as a supplementation and believed to act by reducing lysine influx into the brain. Lysine restricted the diet benefits by inactivating the accumulation of lysine degradation products which are toxic. Novel treatment options include using antisense oligonucleotide is reported to be successful in a small group of patients and believed to prevent neurological damage.[11],[13],[14]

[TAG:2]Patients and Methods[/TAG:2]

This study was conducted in the pediatric neurology inpatient department of a tertiary-level neuropsychiatric center in South India. The period of study was from November 2012 to October 2015. Inclusion criteria included children <16 years of age with “Drug resistant epilepsy” as per ILAE guidelines. Exclusion criteria included children with demonstrable structural pathology, traumatic brain injury, encephalitis, migration disorders, and known metabolic disorders. A detailed history was taken from the parents regarding the seizure onset, semiology, frequency, drug history, and their response pattern as well as cognitive, behavioral, and developmental problems. Their blood samples were submitted to tandem mass spectroscopy for inborn errors of metabolism, urine for abnormal metabolites and organic acids. Serum lactate and ammonia levels were also estimated to rule out metabolic causes especially mitochondrial etiology EEG and imaging studies were done in all cases.


Of 435 children treated as inpatients over a period of 3 years (November 2012–October 2015), 58 patients satisfied the criteria for refractory epilepsy which constituted 13.3% of the inpatients. Of 435 inpatients in the last 3 years, refractory epilepsy constitutes 13.3%. Males constituted majority of the refractory epilepsy cases (68.9%) as compared to females (31.1%). Pyridoxine-dependent seizures were detected in two patients who constitute 0.45% of all inpatients and 3.5% of refractory epilepsy cases. There was no gender difference among patients with pyridoxine-dependent seizures. The other causes for refractory seizures in children found in our study are as follows: out of the refractory seizures, West syndrome constituted 20.6%, progressive myoclonic epilepsy constituted 17.24%, Lennox–Gastaut syndrome, glutaric aciduria, and Leigh's syndrome constituted 10.3% each. Postencephalitic seizures constituted 8.6%, phenylketonuria constituted 5.1%. Propionic aciduria, Myoclonic Epilepsy, Lactic Acidosis, and Stroke-like syndrome, hypocalcemia, and porencephalic cyst constituted 1.72% each of the refractory seizures in this series [Figure 1].
Figure 1: The distribution of drug-resistant epilepsy in our inpatient children

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Case 1

The patient is a 2-year-old male child born to nonconsanguineous parents by Lower Segment Caesarean Section from Orissa, the indication for which was not clear. His birth weight was 2.8 kg, and there was no neonatal jaundice, hypoxia, ischemia, or intracerebral hematomas. The child developed seizures within the first 2 h of delivery which was left focal as well as generalized tonic–clonic in semiology. The frequency was about 8–10 attacks/day. The child was kept in the Intensive Care Unit for 30 days; however, the seizures were not controlled. The child was diagnosed as primary uncontrolled epilepsy with catastrophic epileptic encephalopathy and was treated with phenobarbitone, levetiracetam, diphenylhydantoin, sodium valproate, steroids, as well as adrenocorticotrophic hormone (ACTH). At 2 years, the child was bedbound and making just cooing sounds. He had auditory startle in addition to seizures about 30–40 times a day. His routine investigations were negative, but urine chromatogram showed a mild increase in succinic acid, adipic acid, and ethylmalonic acid. Cerebrospinal fluid studies were normal. EEG showed diffuse delta activity. Computed tomography scan of the brain showed diffuse atrophy with relative sparing of the cerebellum [Figure 2]. There was a family history of the 1st day convulsion in the elder child who had a similar presentation and died at the age of 1 year. This clinical picture made us suspect the possible pyridoxine-dependent convulsions. Therefore, we gave 100 mg of intravenous pyridoxine, and the delta background reverted to beta [Figure 3]a and [Figure 3]b. This child was initiated on lysine-free diet, 100 mg of oral pyridoxine hydrochloride with 150 mg of arginine, and 10 mg of folic acid in addition to clobazam. The child became seizure-free in 10 days, and at 6-month follow-up, the child was standing with support and vocalizing. At 2-year follow-up, the child was walking independently, was able to communicate in small sentences; toilet trained but had mild features of attention-deficit hyperactivity.
Figure 2: Computed tomography scan showing diffuse atrophy with relative sparing of cerebellum in Case 1 with pyridoxine-dependent convulsions

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Figure 3: (a) Case 1 electroencephalography before intravenous pyridoxine. (b) Electroencephalography after intravenous pyridoxine

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Case 2

A 2-year 10-month-old female child was born to consanguineous parents. Seizures started on the 1st day of delivery and continued at the rate of 50–100 attacks/day. The semiology was adversive eye movements with extensor posturing of all four limbs and rhythmic jerking. The child had not acquired any milestone including head control and had microcephaly [Figure 4]a and [Figure 4]b. There was spasticity of all four limbs with tendoachilles contracture. The child had been tried on valproate, carbamazepine, clobazam, zonisamide, topiramate, and ACTH with no response. All investigations were noncontributory. EEG showed a background of delta to theta with recurrent bursts of slow waves, spikes, and spike and waves. A slow intravenous injection of 200 mg of Vitamin B6 was given and EEG was normalized [Figure 5]a and [Figure 5]b. The child was treated with 120 mg of oral pyridoxine, 5 mg of folinic acid, clobazam 10 mg, levetiracetam 300 mg, and other AEDs were slowly tapered. Lysine-free diet and arginine were also added. The seizure frequency gradually reduced and when the child was discharged on the 7th day, attacks reduced to 11 per day. The next follow-up at 1 month, the child was completely seizure-free, started making cooing sounds, babbling, and had developed partial head control [Figure 4]b.
Figure 4: (a) Case 2 on admission. (b) Case 2 at 1-month follow-up

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Figure 5: (a) Case 2 electroencephalography before intravenous pyridoxine. (b) Case 2 electroencephalography after intravenous pyridoxine

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[TAG:2]Discussion and Conclusion[/TAG:2]

Epilepsy accounts for about 1% of global disease burden.[15] In India, 8–10 million people suffer from epilepsy and about 70%–80% of these patients can be controlled medically if proper diagnosis and appropriate treatment is made available at the earliest. Rest of the patients may need palliative or disease-modifying surgery. The disability with reference to the quality of life of patients as well the impact on family members is enormous. There is 1%/year risk of mortality due to seizure-related complications in these patients.[16] Hence, it is mandatory to make a proper clinical and laboratory assessment of these patients to decide on the appropriate treatment options. Ours is a hospital-based study conducted in an institute of national importance. Therefore, we have a wide spectrum of patients presenting with refractory epilepsy, and it was observable that proper diagnosis and management is very rewarding with reference to psychosocial stresses and disease-related problems in both patients and family members. Males constituted the majority as reported in other previous studies too.[17] Of these, 34.4% of patients turned out to be neurometabolic diseases which have to be managed with dietary manipulation, megavitamin therapy, as well as supportive anticonvulsants, with caution regarding the epileptogenicity of some of the antiepileptic medications with reference to the specific syndromes.[4],[5]

About 3.5% patients had pyridoxine-dependent seizures which were the first time diagnosed. With initiation of treatment, in these patients who were between 2 and 3 years of age, both seizure control and the development of cognitive and motor milestones became evident within 2 weeks of the initiation of therapy. During follow-up, achievement of independent activities of daily living was seen within 1 year. Therefore, it is mandatory to have a high degree of suspicion regarding the possibility of pyridoxine-dependent seizures in children who develop seizures at birth and have a drug-resistant course irrespective of the semiology. The diagnosis of this condition also has the following benefits: (1) excellent seizure control, (2) no adverse effects in the therapeutic dose, (3) completely eliminates the need for palliative or therapeutic surgery, (4) very good benefit in global development, (5) unimaginably cheap, and (6) emphasizes the role of diet in management. The lessons learned from this study are, with reference to children, a large group suffers from neurometabolic disease and their refractoriness is mostly due to failure to correct the metabolic problem with diet and appropriate medication rather than polypharmacy with anticonvulsants. Pyridoxine-dependent convulsions though rare should be recognized as an important cause for natal or neonatal convulsions of any semiology which recur several times a day and are resistant to most antiepileptic medication and produce catastrophic encephalopathy.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]


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