Vitamin Supplementation

A number of treatable metabolic disorders, including vitamin-responsive conditions, present with medically resistant seizures in the first year of life. Response to empirical treatment may have to guide further investigative work-up.

Disorders of vitamin B6 metabolism

Pyridoxal 5′-phosphate (PLP) is the B6 vitamer, which has co-factor activity and acts with several enzymes that are involved in the metabolism of neurotransmitters (e.g. dopamine, serotonin, glutamate and y-aminobutyric acid [GABA]). Progress in the understanding of disorders caused by deficiency of cerebral PLP has been made recently. Increased consumption of PLP through inactivation or defects of its biosynthesis in liver and brain involving pyridox(am)ine phosphate oxidase underlie two disorders with infantile presentations.

Table Non-epileptogenic paroxysmal disorders in infancy

Pyridoxine-dependent Epilepsy

A mutation of the aldehyde dehydrogenase (ALDH) 7A1 gene on chromosome 5q31 encoding antiquitin (a-aminoadipic semialdehyde dehydrogenase) has recently been discovered as a major cause of pyridoxine-dependent epilepsy [21]. Dysfunction of the enzyme antiquitin, which is part of the pipecolic pathway of lysine catabolism, results in accumulation of a metabolite (L-Al-piperideine-6-carboxylate) that condenses with PLP and inactivates the co-factor. A lead to the discovery of this phenomenon was the observation of raised pipecolic acid in the cerebrospinal fluid of patients with pyridoxine-dependent epilepsy prior to treatment and the decrease following pyridoxine supplementation. Measurement of urinary α-aminoadipic semialdehyde, another accumulating metabolite in the above-mentioned pathway, has been suggested as a biomarker for pyridoxine-dependent epilepsy. The typical clinical presentation of this disorder is in the first days of life with intractable, often multiple, seizure types and encephalopathy, observed in one-third of cases, with hyperalertness, irritability, abnormal cry or startle.

Table Treatable metabolic epileptic encephalopathies

Additional systemic features that can mimic sepsis are abdominal distension, vomiting, hypothermia, respiratory distress and metabolic acidosis. Associated cerebral malformations have been described and include hypoplasia of the posterior part of the corpus callosum, cerebellar hypoplasia, focal cortical dysplasia and hydrocephalus. The electroencephalogram is commonly grossly abnormal and a ‘burst suppression’ pattern is often seen. Infants show a prompt response to 100-mg pyridoxine given intravenously. Close cardiorespiratory monitoring during the first injection is recommended as apnoea and cardiovascular instability with isoelectric electroencephalogram can occur. More commonly, children may show cerebral depression with hypotonia and sleepiness. The late-onset form presents up to the age of 3 years and is not associated with encephalopathy or structural brain abnormalities. There may be a partial response to anti-epileptic medication initially but seizures eventually became intractable. Seizures respond to 100 mg/day pyridoxine orally within 1-2 days and lifelong supplementation with 15mg/ kg/day up to 500mg is necessary. Untreated cases develop severe motor disorder with sensory impairments. The outcome is variable in treated cases and worse motor, cognitive and language functions are associated with early onset of the condition.

Pyridox(am)ine Phosphate Oxidase Deficiency

A defect in the enzyme that oxidizes phosphorylated pyridoxine and pyridoxamine to form PLP in liver and brain has been reported in five neonates of three families presenting with an epileptic encephalopathy that showed no or incomplete response to pyridoxine. One of these neonates responded to treatment with pyridoxal phosphate (10 mg/kg by nasogastric tube given 6-hourly) at the age of 2 weeks. All neonates were born prematurely, had signs of fetal distress (one requiring intubation post delivery), metabolic acidosis was common and the seizure onset was in the first 12 h of life. The electroencephalogram demonstrated a suppression-burst pattern that was reversed in the neonate treated with PLP. Cerebral depression with hypotonia and unresponsiveness was observed in this neonate following the first dose. All patients had a similar pattern of biochemical changes, implicating a dysfunction of the PLP-dependent enzymes including aromatic L-amino-acid decarboxylase: low cerebrospinal fluid concentrations of homovanillic acid (dopamine metabolite) and 5-hydroxyindolacetic acid (serotonin metabolite), raised cerebrospinal fluid methoxytyrosine, threonine and glycine. Subsequently, homozygous mutations in the Pyridox(am)ine Phosphate Oxidase gene situated on chromosome 17q21 were found with expression studies demonstrating null activity or marked reduced activity of pyridox(am)ine phosphate oxidase.

The condition was fatal in four neonates and the infant that was treated with PLP had a severe dystonic motor disorder, global developmental delay and acquired microcephaly at 2 years and 8 months. These patients may represent the severe end of the phenotypic spectrum. Recently, six children with Pyridox(am)ine Phosphate Oxidase deficiency and atypical biochemical findings were reported: two who received treatment within the first month of life showed normal development or moderate psychomotor retardation thereafter, whereas four with no or late treatment died or showed severe psychomotor delay.

Wang et al. report response of medically intractable seizures to PLP in 11 of 94 children with epilepsy of unknown aetiology. Seizure onset was in the first year of life in 10 patients and at 15 months in one patient. Six patients presented with infantile spasms. Five of the 11 PLP responders could be successfully controlled with pyridoxine, whilst six required PLP. Unfortunately, biochemical data from cerebrospinal fluid and urine were not available for this cohort. PLP and pyridoxine may have other anti-epileptic properties independently from the mechanisms described above that may contribute to improvement of seizure control as adjunct to conventional anti-epileptic treatment.

PLP has a role in the empirical treatment of neonatal-onset epileptic encephalopathies and should be the next step after intravenous (i.v.) pyridoxine (PLP 100mg). In addition, there is a wider indication for drug-resistant epilepsy with unknown aetiology, especially early-onset forms including West syndrome. PLP doses of 10-50 mg/kg/day have been used. Other disorders of vitamin B6 metabolism that are associated with milder types of epilepsy have been described.

Folinic Acid-Responsive Seizures

This condition was discovered by coincidence. A 6-month-old patient with neonatal-onset, medication-resistant and pyridoxine-unresponsive epilepsy became seizure free after folinic acid was commenced because of a misunderstanding. Since then, further cases have been reported in the literature. High-performance liquid chromatography, used to measure neurotransmitter metabolites, revealed an unknown compound which is a marker for this disorder. This compound decreased on treatment with folinic acid. cerebrospinal fluid neopterin, 5-methyltetrahydrofolate and dopamine, as well as serotonine metaobolites, were normal. Although the described patients presented breakthrough seizures and frequent episodes of status epilepticus on treatment with folinic acid, seizure control was regained with increased doses. The children exhibited global developmental delay, despite seizure control. Magnetic resonance imaging showed diffuse cerebral atrophy, cerebellar atrophy or signal abnormalities in the white matter. Although the underlying pathomechanism is unknown, this appears to be an autosomal recessive inherited condition, as some of the index cases had siblings that died with intractable neonatal-onset seizures. Empirical treatment with folinic acid (2-5 mg/kg/day orally) should therefore be considered in neonatal-onset seizures that are unresponsive to pyridoxine and pyridoxal phosphate.