levoleucovorin and Status-Epilepticus

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 discuss an unusual case of a teenage boy who presented with waxing and waning cognitive decline and gelastic-dacrystic seizures, evolving later into a rapidly progressive encephalopathy with status epilepticus. Extensive genetic and metabolic testing did not lead to a specific diagnosis. Cerebrospinal fluid studies performed during admission to the intensive care unit provided the information needed to establish a diagnosis. After implementation of specific treatment, his seizures stopped and his background electroencephalogram returned to normal. He has remained largely seizure-free experiencing a significant cognitive recovery. This case illustrates the importance of performing cerebrospinal fluid analysis in patient with refractory seizures and cognitive decline of unknown etiology.

Topics: Adolescent; Anticonvulsants; Brain; Diagnosis, Differential; Disease Progression; Epilepsies, Partial; Humans; Leucovorin; Male; Pyridoxine; Status Epilepticus

Posterior reversible encephalopathy syndrome (PRES) is one of many causes of status epilepticus (SE). Itis defined classically as a clinical radiographic entity, characterized by presentation of headache, altered mental status, visual disturbances, seizures, and typical neuroradiographic findings of symmetrical white-matter edema. Predisposing conditions include uncontrolled hypertension, eclampsia, and use of chemotherapeu- tic and immunosuppressant agents. Bevacizumab (Avastin), a monoclonal antibody against vascular endothelial growth factor (VEGF), is used in a combination with FOLFOX [FOL - Folinic acid; F - Fluorouracil (5-FU); OX - Oxaliplatin] as a first-line treatment for patients with metastatic colorectal cancer. We present a case of a 52-year-old male on systemic chemotherapy with FOLFOX and bevacizumab who presented with SE and was diagnosed with PRES. His symptoms resolved with intensive control of blood pressure and discontinuation of chemotherapy. Bevacizumab-induced vasospasm, endothelial and blood-brain-barrier dysfunction, in combination with elevated blood pressure, were likely the underlying mechanism of PRES in our patient.

Topics: Antihypertensive Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Brain; Colorectal Neoplasms; Fluorouracil; Humans; Hypertension; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Patient Care Management; Posterior Leukoencephalopathy Syndrome; Status Epilepticus; Withholding Treatment

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

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.

Topics: Anticonvulsants; Brain Damage, Chronic; Cerebrospinal Fluid Proteins; Female; Humans; Infant; Infant, Newborn; Leucovorin; Male; Risk Factors; Spasms, Infantile; Status Epilepticus; Treatment Outcome