levoleucovorin and Seizures

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

Rett syndrome is characterized by the development of stereotypic hand movements and seizures, which are often difficult to treat. Previous studies have shown conflicting results during add-on folinic acid. Here, the authors reevaluate the response to folinic acid in terms of epilepsy control and electroencephalography features. They performed a randomized, placebo-controlled, double-blind crossover trial, with a follow-up of more than 2 years. Twelve girls with Rett syndrome participated, comparable in clinical stage and disease severity. The Rett syndrome patients were given either folinic acid or placebo, for 1 year each. Only 3 girls benefited to some extent: 2 had a reduction and/or decrease in seizures, and all 3 showed some decreased epileptiform activity on electroencephalography during the addition of folinic acid. Despite this, antiepileptic drugs were adjusted. Because the effect of added folinic acid was limited and did not prevent antiepileptic drug increase, the authors do not recommend adding on folinic acid in Rett syndrome girls with epilepsy.

Topics: Brain Waves; Child; Child, Preschool; Cross-Over Studies; Double-Blind Method; Electroencephalography; Female; Follow-Up Studies; Humans; Leucovorin; Male; Rett Syndrome; Seizures; Severity of Illness Index; Spectrum Analysis

Rett disorder (RD) is a progressive neurodevelopmental entity caused by mutations in the MECP2 gene. It has been postulated that there are alterations in the levels of certain neurotransmitters and folate in the pathogenesis of this disease. Here we re-evaluated this hypothesis.. We evaluated CSF folate, biogenic amines and pterines in 25 RD patients. Treatment with oral folinic acid was started in those cases with low folate. Patients were clinically evaluated and videotaped up to 6 months after therapy.. CSF folate was below the reference values in 32% of the patients. Six months after treatment no clinical improvement was observed. Three of the four patients with the R294X mutation had increased levels of a dopamine metabolite associated to a particular phenotype. Three patients had low levels of a serotonin metabolite. Two of them were treated with fluoxetine and one showed clinical improvement. No association was observed between CSF folate and these metabolites, after adjusting for the patients age and neopterin levels.. Our results support that folinic acid supplementation has no significant effects on the course of the disease. We report discrete and novel neurotransmitter abnormalities that may contribute to the pathogenesis of RD highlighting the need for further studies on CSF neurotransmitters in clinically and genetically well characterized patients.

Topics: Administration, Oral; Child; Child, Preschool; DNA Mutational Analysis; Female; Fluoxetine; Folic Acid; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Leucovorin; Methyl-CpG-Binding Protein 2; Mutation; Neurotransmitter Agents; Polymerase Chain Reaction; Rett Syndrome; Seizures; Selective Serotonin Reuptake Inhibitors; Stereotyped Behavior; Treatment Outcome; Vitamin B Complex

Posterior reversible encephalopathy syndrome is a clinical and imaging syndrome characterized by endothelial dysfunction, blood-brain barrier disruption, and vasogenic edema. The common clinical symptoms of posterior reversible encephalopathy syndrome include headache, altered consciousness, visual disturbances, and seizures, among which headache and seizures are the most common. The classic imaging patterns usually reveal vasogenic edema.. We describe the case of a middle-aged woman with gastric cancer. She was under treatment by fluorouracil, leucovorin, oxaliplatin, and docetaxel regimen and thrombocytopenia regimen after tumor progression, but developed unconsciousness, irritability, and headache shortly after initiation of treatment. Her magnetic resonance imaging in our hospital shows abnormal signals in bilateral frontal parietal occipital lobes with hyperintensities on T2-weighted magnetic resonance imaging and fluid-attenuated inversion recovery imaging, accompanied by the increased value of apparent diffusion coefficient. And T1-weighted images illustrate hypointense foci, with increased diffusion-weighted imaging signals.. After admission, she was treated to control blood pressure, reduce brain edema, expand blood vessels, improve consciousness, and symptomatic support treatment. 3 days after the onset of the disease, her headache symptoms and state of consciousness gradually improved, and her blood pressure can be controlled at about 130/80 mmHg.. This is the first report that posterior reversible encephalopathy syndrome is caused by a thrombocytopenia regimen, and our case highlights the pathogenic role of a thrombocytopenia regimen in posterior reversible encephalopathy syndrome. However, the association between the thrombocytopenia regimen and previous fluorouracil, leucovorin, oxaliplatin, and docetaxel regimens needs further study.

Topics: Calcium; Cisplatin; Docetaxel; Edema; Female; Fluorouracil; Headache; Humans; Leucovorin; Middle Aged; Oxaliplatin; Posterior Leukoencephalopathy Syndrome; Seizures; Thrombocytopenia

Cerebral folate deficiency (CFD) is a neurological disease, hallmarked by remarkable low concentrations of 5-methyltetrahydrofolic acid (5-MTHF) in cerebrospinal fluid (CSF). The primary causes of CFD include the presence of folate receptor (FR) autoantibodies, defects of FR encoding gene FOLR1, mitochondrial diseases and congenital abnormalities in folate metabolism.. Here we first present a Chinese male CFD patient whose seizure onset at 2 years old with convulsive status epilepticus. Magnetic Resonance Imaging (MRI) revealed the development of encephalomalacia, laminar necrosis in multiple lobes of the brain and cerebellar atrophy. Whole Exome Sequencing (WES) uncovered a homozygous missense variant of c.524G > T (p.C175F) in FOLR1 gene. Further laboratory tests demonstrated the extremely low level of 5-MTHF in the CSF from this patient, which was attributed to cerebral folate transport deficiency. Following the intravenous and oral treatment of calcium folinate, the concentrations of 5-MTHF in CSF were recovered to the normal range and seizure symptoms were relieved as well.. One novel variation of FOLR1 was firstly identified from a Chinese male patient with tonic-clonic seizures, developmental delay, and ataxia. The WES and laboratory results elucidated the etiology of the symptoms. Clinical outcomes were improved by early diagnosis and proper treatment.

Topics: Age of Onset; Cerebral Cortex; Child; Encephalomalacia; Exome Sequencing; Folate Receptor 1; Folic Acid Deficiency; Homozygote; Humans; Leucovorin; Magnetic Resonance Imaging; Male; Seizures; Status Epilepticus; Tetrahydrofolates

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

Folinic acid-responsive seizures and pyridoxine-dependent epilepsy are two treatable causes of neonatal epileptic encephalopathy. The former is diagnosed by characteristic peaks on cerebrospinal fluid (CSF) monoamine metabolite analysis; its genetic basis has remained elusive. The latter is due to alpha-aminoadipic semialdehyde (alpha-AASA) dehydrogenase deficiency, associated with pathogenic mutations in the ALDH7A1 (antiquitin) gene. We report two patients whose CSF showed the marker of folinic acid-responsive seizures, but who responded clinically to pyridoxine. We performed genetic and biochemical testing of samples from these patients, and seven others, to determine the relation between these two disorders.. CSF samples were analyzed for the presence of alpha-AASA and pipecolic acid. DNA sequencing of the ALDH7A1 gene was performed.. Both patients reported here had increased CSF alpha-AASA, CSF pipecolic acid, and known or likely pathogenic mutations in the ALDH7A1 gene, consistent with alpha-AASA dehydrogenase deficiency. Analysis of CSF samples from seven other anonymous individuals diagnosed with folinic acid-responsive seizures showed similar results.. These results demonstrate that folinic acid-responsive seizures are due to alpha-AASA dehydrogenase deficiency and mutations in the ALDH7A1 gene. Thus, folinic acid-responsive seizures are identical to the major form of pyridoxine-dependent epilepsy. We recommend consideration of treatment with both pyridoxine and folinic acid for patients with alpha-AASA dehydrogenase deficiency, and consideration of a lysine restricted diet. The evaluation of patients with neonatal epileptic encephalopathy, as well as those with later-onset seizures, should include a measurement of alpha-AASA in urine to identify this likely underdiagnosed and treatable disorder.

Topics: Aldehyde Dehydrogenase; Biogenic Monoamines; DNA Mutational Analysis; Humans; Infant; Leucovorin; Linear Models; Lysine; Male; Mutation; Pipecolic Acids; Pyridoxine; Seizures; Tandem Mass Spectrometry; Vitamin B Complex

Pyridoxine-dependent seizures (PDS) is an autosomal recessive disorder characterized by seizures presenting in neonates or infants up to 3 years of age which respond to pharmacological doses of pyridoxine. Alpha-aminoadipic semialdehyde dehydrogenase (antiquitin) deficiency was identified as an underlying defect in PDS characterized by accumulation of alpha-aminoadipic semialdehyde (alpha-AASA) as a specific marker and recently folinic acid-responsive seizures (FRS) were found to be allelic to PDS as the putative mutations were identified in the antiquitin gene (ALDH7A1). alpha-AASA is known to be in reversible equilibrium with its cyclic Shiff base, delta(1)-piperideine-6-carboxylate (P6C). Pipecolic acid (PA) is another biomarker often elevated but is not specific to PDS. Here, we developed the liquid chromatography-mass spectrometry (LC-MS/MS) method to determine the analytes of alpha-AASA, P6C and PA simultaneously in plasma and validated the assay using samples from confirmed cases. This approach eliminates the extra time and expense of running multiple assays and provides valuable information for the rapid diagnosis and treatment of patients with PDS and FRS which potentially could lead to a better outcome with improved quality of life. The stability study showed that alpha-AASA and P6C were unstable even at -20 degrees C. A careful sample handling with immediate freezing and testing is required for reliable result.

Topics: 2-Aminoadipic Acid; Aldehyde Dehydrogenase; Animals; Calibration; Cattle; Child; Child, Preschool; Chromatography, Liquid; Humans; Leucovorin; Mass Spectrometry; Picolinic Acids; Pipecolic Acids; Protein Stability; Seizures; Temperature; Time Factors

The authors describe a 6-year-old girl with developmental delay, psychomotor regression, seizures, mental retardation, and autistic features associated with low CSF levels of 5-methyltetrahydrofolate, the biologically active form of folates in CSF and blood. Folate and B12 levels were normal in peripheral tissues, suggesting cerebral folate deficiency. Treatment with folinic acid corrected CSF abnormalities and improved motor skills.

Topics: Adaptation, Physiological; Autistic Disorder; Cerebral Cortex; Child; Developmental Disabilities; Disease Progression; Female; Folic Acid; Folic Acid Deficiency; Genetic Predisposition to Disease; Humans; Intellectual Disability; Leucovorin; Mutation; Recovery of Function; Reduced Folate Carrier Protein; Seizures; Tetrahydrofolates; Transcription Factors; Treatment Outcome

To describe three unrelated children with a distinctive variant of Aicardi-Goutières syndrome (AGS) characterized by microcephaly, severe mental and motor retardation, dyskinesia or spasticity, and occasional seizures.. Neuroimaging showed bilateral calcification of basal ganglia and white matter. CSF glucose, protein, cell count, and interferon alpha were normal. Abnormal CSF findings included extremely high neopterin (293 to 814 nmol/L; normal 12 to 30 nmol/L) and biopterin (226 to 416 nmol/L; normal 15 to 40 nmol/L) combined with lowered 5-methyltetrahydrofolate (23 to 48 nmol/L; normal 64 to 182 nmol/L) concentrations in two patients. The absence of pleocytosis and normal CSF interferon alpha was a characteristic finding compared to the classic AGS syndrome. Genetic and enzymatic tests excluded disorders of tetrahydrobiopterin metabolism, including mutation analysis of GTP cyclohydrolase feed-back regulatory protein. CSF investigations in three patients with classic AGS also showed increased pterins and partially lowered folate levels.. Intrathecal overproduction of pterins is the first biochemical abnormality identified in patients with AGS variants. Long-term substitution with folinic acid (2-4 mg/kg/day) resulted in substantial clinical recovery with normalization of CSF folates and pterins in one patient and clinical improvement in another. The underlying defect remains unknown.

Topics: Basal Ganglia; Brain Diseases; Decalcification, Pathologic; DNA Mutational Analysis; Dyskinesias; Female; Fibroblasts; Folic Acid; Humans; Infant; Infant, Newborn; Intellectual Disability; Intracellular Signaling Peptides and Proteins; Leucovorin; Male; Microcephaly; Muscle Hypertonia; Phenotype; Proteins; Psychomotor Disorders; Pterins; Seizures; Syndrome; Tomography, X-Ray Computed

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

To report a probable drug interaction between phenytoin and fluorouracil.. A 66-year-old white man started adjuvant chemotherapy for colon cancer with weekly bolus injections of fluorouracil and leucovorin calcium. He had been taking phenytoin 300 mg/d for epilepsy for more than four years. Eleven weeks later, the patient was reported to be unsteady on his feet and had fallen several times. The serum phenytoin concentration at that time was 36 microg/mL. The phenytoin dosage was decreased and the symptoms resolved. Phenytoin concentrations were monitored and the dosages were adjusted accordingly throughout the remaining 15 weeks of treatment with fluorouracil. After completion of chemotherapy, the phenytoin dose was gradually increased to the original dose with no signs of toxicity.. Phenytoin is principally metabolized by CYP2C9. Inhibition of that isoenzyme by fluorouracil, and possible interference with its synthesis, appears to be the most likely cause of this interaction. The reduction in saturating substrate concentration of phenytoin was reduced as a result of this interaction, thus causing decreased clearance and increased serum concentrations. No previous interaction between phenytoin and fluorouracil has been reported. Both phenytoin and warfarin are metabolized by CYP269 and therefore exhibit the same spectrum of interactions when that isoenzyme is inhibited. Interactions have been reported with concurrent administration of warfarin and fluorouracil.. The nature and extent of this phenytoin-fluorouracil interaction should be elucidated by in vitro investigations and a prospective study. Until then, clinicians should be aware of this potentially serious drug interaction and monitor patients closely for phenytoin toxicity.

Topics: Aged; Anticonvulsants; Antidotes; Antimetabolites, Antineoplastic; Colonic Neoplasms; Drug Interactions; Fluorouracil; Humans; Leucovorin; Male; Phenytoin; Seizures

Topics: Amino Acid Metabolism, Inborn Errors; Anticonvulsants; Brain Diseases, Metabolic; Chromatography, High Pressure Liquid; Fatal Outcome; Female; Humans; Infant, Newborn; Leucovorin; Male; Neurotransmitter Agents; Seizures

Topics: Adult; Aged; Humans; Leucovorin; Middle Aged; Neoplasms; Seizures

The mechanism of the transient encephalopathy induced by high dose systemic administration of methotrexate (HDMTX) is unknown. Metabolic and vascular hypothesis have been formulated but convincing evidence is lacking. We report the first case of vascular disturbances (thinness of cortical arteries on angiography, reversible fall down of cerebral flow and increase of carotid resistance) in a young Algerian patient treated for an osteogenic osteosarcoma. This observation might lead to the exploration by non invasive and easily repeatable techniques of the cerebral vascular dynamic in patients submitted to HDMTX and thus contributed to the elucidation of the mechanism and to the prevention of these neurological side effect.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cerebral Arteries; Cerebrovascular Circulation; Cisplatin; Cyclophosphamide; Doxorubicin; Female; Humans; Leucovorin; Methotrexate; Osteosarcoma; Seizures; Syndrome

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Epilepsy, Complex Partial; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Seizures

Hyperphenylalaninemia in infants and children may be caused by a deficiency of dihydropteridine reductase (DHPR). Recommended therapy includes folinic acid as a source of tetrahydrofolate, a phenylalanine-restricted diet, and both dopamine and serotonin precursors. We report a child with progressive basal ganglia and other subcortical calcifications prior to the use of folinic acid. Six other reported cases of DHPR deficiency demonstrated similar calcifications prior to folinic acid therapy. Since this pattern of calcification also resembles that seen in CNS folate deficiency caused by both congenital folate deficiency and that which is methotrexate-induced, we propose that intracranial calcification in DHPR deficiency is caused by inadequate CNS tetrahydrofolate and may be prevented by the use of folinic acid. Our patient achieved excellent seizure control following the use of folinic acid, suggesting either a direct or indirect anticonvulsant effect of this compound in patients with DHPR deficiency.

Topics: Brain; Brain Diseases; Calcinosis; Female; Humans; Infant, Newborn; Leucovorin; NADH, NADPH Oxidoreductases; Phenylketonurias; Seizures; Tomography, X-Ray Computed

Eleven patients with astrocytoma were treated with high-dose methotrexate (HDMTX) and citrovorum factor rescue (CFR). Clinical response was observed in eight patients, including four of four with grade 3 disease, one of one with grade 2 to 3, two of four with grade four, and one of one with unspecified low-grade tumor. Two patients with grade 4 and one with grade 1 disease failed to respond. Six of the eight responses were documented radiographically. Three of these patients are alive and well without further treatment for periods of 15+, 4.5+, and 1.5+ years. The fourth living patient is surviving 2+ years and improving under continued treatment. The four surviving patients had recurrent grade 2 to 3 or grade 3 disease. HDMTX-CFR is effective in astrocytoma. Its greatest value may be in recurring grade 3 disease.

Topics: Adolescent; Adult; Angiography; Antineoplastic Combined Chemotherapy Protocols; Astrocytoma; Brain Neoplasms; Child; Female; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Neurologic Examination; Seizures; Tomography, X-Ray Computed

Carbamazepine and valproate each afforded protection against seizures induced by electroshock or by inhalation of hexafluorodiethyl ether (HFDE). After injections of either anticonvulsant for 10 days, plasma folate concentration decreased, but brain folate concentration did not change. Folinic acid administration had no effect on the concentration of either anticonvulsant in plasma or brain. These findings are in contrast with the demonstrated effects of other anticonvulsants on folate biochemistry.

Topics: Animals; Brain; Carbamazepine; Drug Interactions; Flurothyl; Folic Acid; Leucovorin; Male; Rats; Rats, Inbred Strains; Seizures; Valproic Acid

Topics: Aminobenzoates; Animals; Calcium; Central Nervous System Stimulants; Cerebral Cortex; Electroencephalography; Folic Acid; Glutamates; Leucovorin; Methotrexate; Pterins; Rats; Seizures; Sodium; Somatosensory Cortex; Tetrahydrofolates