levoleucovorin and Epilepsy

Neurodegeneration due to cerebral folate transport deficiency is a rare autosomal recessive disorder caused by biallelic pathogenic variants in FOLR1. Onset typically occurs in late infancy and is characterized by psychomotor regression, epilepsy, and a hypomyelinating leukodystrophy on magnetic resonance imaging. If left untreated, progressive neurodegeneration occurs. However, early treatment with folinic acid has been shown to stabilize or reverse neurological features. Approximately thirty patients have been described worldwide. Here, we report the first two cases with genetically proven cerebral folate transport deficiency from South-Eastern Europe, describe the effect of oral folinic acid therapy on clinical and neuroradiological features and review the literature.. Two siblings presented in childhood with clinical and radiological findings consistent with a hypomyelinating leukodystrophy. Exome sequencing revealed a novel homozygous pathogenic variant in FOLR1 (c.465_466delinsTG; p.W156G), confirming the diagnosis of neurodegeneration due to cerebral folate transport deficiency. Folinic acid treatment was promptly initiated in both patients. The younger sibling was treated early in disease course at 2 years of age, and demonstrated complete recovery in clinical and MRI features. The older sibling, who was 8 years of age at the time of diagnosis and treatment, demonstrated partial but substantial improvements.. We present the first account in the literature that early treatment initiation with oral folinic acid alone can result in complete neurological recovery of both clinical and radiological abnormalities in neurodegeneration due to cerebral folate deficiency. Moreover, through the report of these patients along with review of the literature, we provide information about the natural history of the disease with comparison of treatment effects at different stages of disease progression. This report also reinforces the importance of universal access to genetic testing to ensure prompt diagnoses for treatable disorders.

Topics: Epilepsy; Folate Receptor 1; Folic Acid Deficiency; Humans; Leucovorin; Neuroaxonal Dystrophies

Metabolic disorders constitute an important cause of neurologic disease, including neonatal epilepsy. Epilepsy rarely dominates the clinical presentation, which is more frequently associated with other neurologic symptoms, such as hypotonia and/or vigilance disturbances. In most cases, epilepsy secondary to inherited metabolic disorders presents with polymorphic clinical and electrographic features that are difficult to classify into precise epileptic syndromes. However, specific types of seizures, such as myoclonic seizures or distinctive electroencephalographic patterns, such as suppression burst patterns, epileptic syndrome or early myoclonic encephalopathy, may suggest a specific metabolic disease. The aim of this article is to help clinicians in reviewing potential metabolic diagnoses and approaching metabolic evaluations.

Topics: Age Factors; Anticonvulsants; Biotin; Brain; Electroencephalography; Epilepsies, Myoclonic; Epilepsy; gamma-Aminobutyric Acid; Humans; Infant, Newborn; Leucovorin; Metabolism, Inborn Errors; Pyridoxine; Seizures; Time Factors; Vitamin B Complex

Topics: Anemia, Macrocytic; Animals; Anticonvulsants; Blood-Brain Barrier; Chemical Phenomena; Chemistry; Epilepsies, Partial; Epilepsy; Folic Acid; Humans; Leucovorin; Mice; Phenobarbital; Phenytoin; Primidone; Rabbits; Rats; Seizures

Topics: Clinical Trials as Topic; Cognition; Epilepsy; Evaluation Studies as Topic; Folic Acid; Humans; Leucovorin; Personality; Phenobarbital; Phenytoin; Primidone; Psychological Tests

We report an unusual case of acute acquired toxoplasmosis (AAT) presenting as lymphadenopathy and recurrent seizures in an immunocompetent 15-year-old boy.. The patient reported an 18-day vacation to Africa (Ethiopia), 39 days prior to the first seizure. Electroencephalogram (EEG) showed sporadic single-spike or sharp-wave paroxysms and the magnetic resonance imaging (RMI) of the brain was negative. The serology for T. gondii was compatible with an acute infection defined as positive for both toxoplasma-specific IgG and IgM and a low avidity (6 %), confirmed by a reference laboratory. The patient reported other two episodes of seizures, occurring 7 days apart. He was treated with pyrimethamine plus sulfadiazine and leucovorin for 4 weeks, with an improvement of lymphadenitis and normalization of EEG. After 5 months, new seizures were reported and a diagnosis of epilepsy was done. Toxoplasma polymerase chain reaction (PCR) of cerebrospinal fluid (CSF) and blood were negative. A treatment with valproic acid was started, obtaining control of the neurological disease.. Awareness of this neurologic manifestation by clinicians is required, also in immunocompetent patients. The relationship between toxoplasmosis and recurrent seizure needs to be investigated by new studies.

Topics: Adolescent; Antibodies, Protozoan; Anticonvulsants; Antiprotozoal Agents; Epilepsy; Ethiopia; Humans; Immunoglobulin G; Immunoglobulin M; Leucovorin; Male; Pyrimethamine; Recurrence; Seizures; Sulfadiazine; Toxoplasma; Toxoplasmosis; Travel; Treatment Outcome; Valproic Acid

Ohtahara syndrome is a severe condition with early onset of recurrent unprovoked seizures associated with abnormal electroencephalography and global developmental delay. Folinic acid-responsive seizures are treatable causes of Ohtahara syndrome, which is thought to be due to recessive mutations in the ALDH7A1 gene, resulting in deficiency of antiquitin.. Here we report a girl with Ohtahara syndrome who exhibited transient folinic acid responsiveness but without evidence of antiquitin dysfunction.. She was later found to have a known missense mutation (c.1439 C > T, p.P480 L) in exon 16 of the STXBP1 gene.. For infants presenting with Ohtahara syndrome with responsiveness to folinic acid and negative antiquitin deficiency analyses, genetic testing for other possible causative genes such as STXBP1 mutation is recommended.

Topics: Aldehyde Dehydrogenase; Anticonvulsants; Brain; Diagnosis, Differential; Electroencephalography; Epilepsy; Exons; Female; Humans; Infant, Newborn; Leucovorin; Magnetic Resonance Imaging; Munc18 Proteins; Mutation, Missense; Spasms, Infantile; Treatment Outcome

α-Amino adipic semialdehyde (α-AASA) accumulates in body fluids from patients with pyridoxine-dependent epilepsy because of mutations in antiquitin (ALDH7A1) and serves as the biomarker for this condition. We have recently found that the urinary excretion of α-AASA was also increased in molybdenum cofactor and sulfite oxidase deficiencies. The seizures in pyridoxine-dependent epilepsy are caused by lowered cerebral levels of pyridoxal-5-phosphate (PLP), the bioactive form of pyridoxine (vitamin B(6)), which can be corrected by the supplementation of pyridoxine. The nonenzymatic trapping of PLP by the cyclic form of α-AASA is causative for the lowered cerebral PLP levels. We describe 2 siblings with clinically evident pyridoxine-responsive seizures associated with increased urinary excretion of α-AASA. Subsequent metabolic investigations revealed several metabolic abnormities, all indicative for molybdenum cofactor deficiency. Molecular investigations indeed revealed a known homozygous mutation in the MOCS2 gene. Based upon the clinically evident pyridoxine-responsive seizures in these 2 siblings, we recommend considering pyridoxine supplementation to patients affected with molybdenum cofactor or sulfite oxidase deficiencies.

Topics: 2-Aminoadipic Acid; Aldehyde Dehydrogenase; Brain; Child, Preschool; Consanguinity; Developmental Disabilities; Diagnosis, Differential; Diffusion Magnetic Resonance Imaging; DNA Mutational Analysis; Electroencephalography; Epilepsy; Exons; Female; Genetic Carrier Screening; Homozygote; Humans; Infant; Infant, Newborn; Leucovorin; Male; Metal Metabolism, Inborn Errors; Molybdoferredoxin; Neurologic Examination; Pyridoxal Phosphate; Pyridoxine; Sequence Analysis, DNA; Sulfurtransferases

Pyridoxine-dependent epilepsy (PDE) is a treatable inborn error of metabolism with autosomal recessive inheritance. Antenatal and postnatal prophylactic administration of pyridoxine has been recommended to improve the developmental outcome in possible future pregnancies. We report on a male offspring of a second pregnancy at risk for PDE. While on prophylactic treatment with oral pyridoxine, the newborn developed encephalopathy and status epilepticus at age 14 days. Seizures did not respond to parenteral pyridoxine and additional treatment with folinic acid. After treatment was changed to pyridoxal 5'-phosphate, the infant's condition improved. Antiquitin deficiency was excluded by biochemical and molecular genetic testing, and cofactor treatment was stopped on day 26. He has since remained seizure-free with normal psychomotor development. In healthy newborns, high-dose treatment with pyridoxine may result in increased rather than decreased neuroexcitability. Postnatal prophylactic pyridoxine treatment of fetuses and neonates at risk for PDE should be limited to the shortest possible time, by either prenatal diagnosis or immediate postnatal biochemical and genetic testing.

Topics: Adult; Aldehyde Dehydrogenase; Epilepsy; Female; Humans; Infant; Infant, Newborn; Infusions, Parenteral; Leucovorin; Male; Pregnancy; Pyridoxal Phosphate; Pyridoxine; Secondary Prevention; Status Epilepticus; Vitamin B Complex

Topics: Age of Onset; Anticonvulsants; Brain; Brain Diseases, Metabolic; Diagnosis, Differential; Electroencephalography; Epilepsy; Humans; Infant; Leucovorin; Phenotype; Pyridoxaminephosphate Oxidase; Pyridoxine

Topics: Biomarkers; Epilepsy; Humans; Infant, Newborn; Infant, Newborn, Diseases; Leucovorin; Metabolic Diseases; Pyridoxal Phosphate; Pyridoxaminephosphate Oxidase; Vitamin B Complex

This report presents a male who developed clonic seizures on the day he was born. The next day, the diagnosis of pyridoxine-dependent seizures was made. However, contradictory to this diagnosis, seizures reappeared despite treatment with pyridoxine. Seizures ceased after folinic acid was initiated. The clinical and biochemical characteristics of folinic acid-responsive seizures are reviewed. Treatment with folinic acid should be considered in neonatal seizures of unknown origin that do not respond to pyridoxine, or manifest a transient response to pyridoxine.

Topics: Epilepsy; Humans; Infant; Infant, Newborn; Leucovorin; Male; Metabolism, Inborn Errors; Pyridoxine; Treatment Outcome; Vitamin B Complex

Topics: Administration, Oral; Anticonvulsants; Antimetabolites, Antineoplastic; Carcinoma; Drug Interactions; Epilepsy; Humans; Leucovorin; Male; Middle Aged; Phenytoin; Rectal Neoplasms; Tegafur

Neonatal seizures associated with white-matter changes on neuroimaging suggest an etiology of hypoxic-ischemic encephalopathy. Metabolic and idiopathic etiologies are also considerations but are less likely. Despite the fact that two disorders associated with neonatal seizures are diagnosed by cerebrospinal fluid neurotransmitter analysis, such an analysis is not standard in the work-up for idiopathic neonatal seizures. We describe an infant who had a prolonged delivery, seizures on the first day of life, and white-matter changes on neuroimaging. A progressive seizure disorder that was refractory to standard antiepilepsy medications developed at 2 months of age. Analysis of cerebrospinal fluid neurotransmitters at that time demonstrated a pattern consistent with folinic acid-responsive seizures. Seizures ceased 24 hours after starting folinic acid. Serial neuroimaging, electroencephalograms, and metabolic changes from this patient are presented. This case illustrates the importance of cerebrospinal fluid neurotransmitter analysis as part of the work-up for idiopathic neonatal seizures.

Topics: Anticonvulsants; Axons; Electroencephalography; Epilepsy; Humans; Hypoxia-Ischemia, Brain; Infant; Leucovorin; Magnetic Resonance Imaging; Male; Neurotransmitter Agents; Seizures

Topics: Adult; Epilepsy; Erythroblasts; Fanconi Anemia; Female; Humans; Lamotrigine; Leucovorin; Triazines

Topics: Arthritis, Rheumatoid; Epilepsy; Growth Substances; Humans; Leucovorin; Propylene Glycols; Pteridines; Schizophrenia; Structure-Activity Relationship