Folinic Acid-Responsive Neonatal Seizures

Abstract

We report three cases of folinic acid-responsive intractable neonatal seizures. All patients were born at term following normal gestation and delivery. In the first infant, seizures began on the 5th day of life and were unresponsive to phenobarbital, pyridoxine, and valproate, but stopped within 24 hours of initiation of folinic acid treatment at the age of 6 months. Her sibling had died at age 6 months with intractable seizures. In the second infant, seizures began in the 2nd hour of life. These were initially controlled with phenobarbital; however, at 3 months of age she developed status epilepticus refractory to anticonvulsants, steroids, and pyridoxine and she required repeated induction of pentobarbital coma. Seizures stopped within 24 hours of starting folinic acid. Seizures and encephalopathy were noted in the third infant on the 2nd day of life. These were controlled with phenobarbital, but at 8 weeks of age seizures recurred and were difficult to control despite the addition of phenytoin. Immediately after folinic acid was initiated the seizures stopped. Breakthrough seizures in all patients have responded to increases in folinic acid; two of the three remain on standard anticonvulsants. All patients have global developmental delay. Cranial magnetic resonance imaging in the second patient shows diffuse atrophy, and in the third patient shows increased signal on T2 images in the white matter of the frontal and parietal lobes. Analysis of cerebrospinal fluid from these patients using high-performance liquid chromatography with electrochemical detection has consistently revealed an as-yet unidentified compound, which can be used as a marker for this condition. We suggest that cerebrospinal fluid be analyzed for the presence of this compound and a trial of folinic acid be considered in neonates with unexplained early onset intractable seizures.

Folinic acid–responsive seizures are identical to pyridoxine‐dependent epilepsy

“…2,3 In others, the response to folinic acid was variable, including responsiveness to folinic acid alone or to combination therapy. [2][3][4][5][6] Interestingly, in the first report, one individual responded to pyridoxine alone. 2 Another was initially responsive to pyridoxine, but then became resistant and responded to folinic acid.…”

“…1 Folinic acid-responsive seizures have been an enigmatic clinical and biochemical entity of unknown etiology. Patients present with seizures, [2][3][4][5][6] either myoclonic 6 or clonic, 5,6 apnea, 4,5 and irritability 2,4 within 5 days after birth. The electroencephalogram (EEG) shows a discontinuous background pattern with multifocal spikes or sharp waves.…”

“…The electroencephalogram (EEG) shows a discontinuous background pattern with multifocal spikes or sharp waves. [3][4][5][6] Most patients develop brain atrophy and white matter abnormalities. [2][3][4]6 A characteristic pattern of peaks, reflecting two unidentified compounds, was recognized in the cerebrospinal fluid (CSF) when analyzed by high-performance liquid chromatography (HPCC) with electrochemical detection to quantify monoamine metabolites.…”

“…[3][4][5][6] Most patients develop brain atrophy and white matter abnormalities. [2][3][4]6 A characteristic pattern of peaks, reflecting two unidentified compounds, was recognized in the cerebrospinal fluid (CSF) when analyzed by high-performance liquid chromatography (HPCC) with electrochemical detection to quantify monoamine metabolites. 2,6 This led to the recognition of multiple other affected children [2][3][4][5] (Table 1).…”

Hyperhomocysteinemia in developing age and nutritional aspects of folates: an early cardiovascular risk factor

“…Nel corso degli anni e grazie a numerose indagini, altre potenziali manifestazioni da carenza di folato sono emerse quali: l'iperomocisteinemia con un aumento significativo di malattie vascolari occlusive [28], già segnalate nei gravi casi di omocistinuria, alcune crisi convulsive neonatali intrattabili e responsive solo all'acido folico [29], disturbi neuropsichiatrici di tipo depressivo [30] del giovane adulto, neuropatie periferiche, degenerazione subacuta combinata del midollo spinale, demenza di Alzheimer [31], malattia di Parkinson, lo sviluppo di alcuni tipi di neoplasie e la comparsa di alterazioni preneoplastiche a carico degli epiteli gastrointestinale, della cervice uterina e del polmone [32][33][34].…”