levoleucovorin and Brain-Diseases

A 60-year-old woman was administered mFOLFOX6 therapy as postoperative adjuvant chemotherapy for fStage III a ascending colon cancer. The patient developed a disorder of consciousness(Japan Coma Scale[JCS]III-200)immediately after the completion of the therapy. Blood ammonia levels were high at 319 mg/dL, and a diagnosis of disturbance of consciousness due to hyperammonemia was made. The patient's state of consciousness improved on the following day as blood ammonia levels decreased due to treatment with branched chain amino acid(BCAA)formulation and oxygen. Two months later, mFOLFOX6 therapy was again administered with strengthening measures for side effects to nausea and vomiting and reducing 5-FU, but the patient again developed a disorder of consciousness(JCS III-200). The 5-FU administration rate was considered as a potential cause of hyperammonemia. Hyperammonemia induced by 5-FU is relatively rare, with a reported incidence of 5-9%; however, caution is required with high dosage regimens of 5-FU that are currently recommended for colorectal cancer therapy because hyperammonemia is an important side effect.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Diseases; Chemotherapy, Adjuvant; Colon, Ascending; Colonic Neoplasms; Female; Fluorouracil; Humans; Hyperammonemia; Leucovorin; Middle Aged; Organoplatinum Compounds

Cerebral folate deficiency (CFD) is defined as any neurological syndrome associated with a low cerebrospinal fluid (CSF) concentration of 5-methyltetrahydrofolate (5MTHF) in the presence of normal peripheral folate status. CFD has a wide clinical presentation, with reported signs and symptoms generally beginning at around 4 months of age with irritability and sleep disturbances. These can be followed by psychomotor retardation, dyskinesia, cerebellar ataxia and spastic diplegia. Other signs may include deceleration of head growth, visual disturbances and sensorineural hearing loss. Identification of CFD is achieved by determining 5MTHF concentration in CSF. Once identified, CFD can in many cases be treated by administering oral folinic acid. Supplementation with folic acid is contraindicated and, if used, may exacerbate the CSF 5MTHF deficiency. Generation of autoantibodies against the folate receptor required to transport 5MTHF into CSF and mutations in the folate receptor 1 (FOLR1) gene have been reported to be causes of CFD. However, other mechanisms are probably also involved, as CFD has been reported in Aicardi-Goutiere's and Rett syndromes and in mitochondriopathies. Several metabolic conditions and a number of widely used drugs can also lead to a decrease in the concentration of CSF 5MTHF, and these should be considered in the differential diagnosis if a low concentration of 5MTHF is found following CSF analysis.

Topics: Administration, Oral; Autoantibodies; Brain Diseases; Dietary Supplements; Folate Receptor 1; Folic Acid Deficiency; Folic Acid Transporters; Genetic Predisposition to Disease; Humans; Leucovorin; Mutation; Risk Factors; Tetrahydrofolates; Treatment Outcome

An 80-year-old man underwent laparoscopic rectal high anterior resection with perineal dissemination for the management of RS rectal cancer. Following the diagnosis of RS rectal cancer with muc, pT4a, N3(14/15), M1c, P1, pStage Ⅳc, RAS/BRAF: wild type, treatment was initiated with mFOLFOX6 plus panitumumab(Pmab). Laboratory examination on admission revealed mild renal dysfunction(Cr 1.45 mg/dL). The patient became confused on day 3 of chemotherapy(JCS Ⅲ-200). Furthermore, laboratory findings revealed a serum ammonia level of 338μg/dL. He was diagnosed with 5-FU- induced hyperammonemic encephalopathy. Discontinuation of high-dose 5-FU and branched-chain amino acid solutions improved his mental status and decreased serum ammonia levels. We switched his chemotherapy regime to CPT-11 plus Pmab, but it was discontinued after 1 course on his request.

Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Brain Diseases; Fluorouracil; Humans; Leucovorin; Male; Panitumumab; Rectal Neoplasms

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Brain Diseases; Female; Fluorouracil; Humans; Leucovorin; Medical Illustration; Organoplatinum Compounds; Rectal Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Diseases; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Treatment Outcome

For several decades, 5-Fluorouracil (5-FU) has been the backbone of many chemotherapy regimens for various tumor types. Its most common side effects are gastrointestinal disorders, mucositis, myelosuppression, hand-foot syndrome, and rarely cardiac toxicity. More rarely, 5-FU infusion can induce hyperammonemic encephalopathy. 5-FU toxicities can be worsened by complete or partial genetic and/or phenotypic dihydropyrimidine dehydrogenase deficiency. Here, we report the case of a patient who initially developed a 5-FU-induced hyperammonemic encephalopathy after receiving FOLFIRINOX (oxaliplatin, irinotecan, folinic acid, and 5-FU) chemotherapy with bevacizumab to treat a metastatic gastrointestinal cancer of unknown primary. Thereafter, the patient was rechallenged successfully by the same chemotherapy regimen (FOLFIRINOX) for more than 6 months with a protocol consisting in a free protein diet, and administration of ammonium chelators, and Krebs and urea cycle intermediates, to prevent further hyperammonemia. We also present a review of the literature on 5-FU rechallenge after 5-FU-induced hyperammonemic encephalopathy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Brain Diseases; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Hyperammonemia; Irinotecan; Leucovorin; Neoplasms, Unknown Primary; Oxaliplatin; Prognosis; Retreatment

Stroke mimics, especially those involving chemotherapy related neurotoxicity, can confound the clinical diagnosis of acute stroke. Here we describe the case of a 63year-old male with a recent history of stage IIIC colon cancer who presented with confusion on the second day of modified FOLFOX6 (5-fluorouracil/oxaliplatin) chemotherapy and subsequently received alteplase, tissue plasminogen activator therapy (tPA), for presumed ischemic stroke. Magnetic resonance imaging scans after tPA administration did not reveal evidence of an infarction and the patients' neurological symptoms resolved completely after discontinuation of 5-fluorouracil (5-FU). Although this patient did not experience any side effects from tPA, fibrinolytic therapy may have been avoided with a better understanding of potential chemotherapy related adverse reactions. Our experience suggests that 5-FU induced reversible encephalopathy can present with acute stroke-like symptoms and emergency medicine personnel evaluating patients for tPA treatment should be aware of this differential diagnosis.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Aphasia; Brain Diseases; Colonic Neoplasms; Confusion; Diagnosis, Differential; Fibrinolytic Agents; Fluorouracil; Headache; Humans; Leucovorin; Magnetic Resonance Imaging; Male; Middle Aged; Organoplatinum Compounds; Stroke; Tissue Plasminogen Activator

To report new manifestations of cerebral folate deficiency, a rare metabolic autoimmune syndrome,in an adult.. Case report.. University teaching hospital.. A 58-year-old woman with progressive memory loss and myoclonus presented for medical attention. Results of cerebral spinal fluid analysis showed low levels of tetrahydrobiopterin and 5-methyltetrahydrofolate. The patient's serum folate level was normal. Serum contained folate receptor 1 blocking and binding antibodies.. The patient was treated successfully with folinic acid supplementation, and after 6 months of treatment,clinical symptoms had resolved.. To our knowledge, we report the first case of adult-onset cerebral folate deficiency. Furthermore, this condition could represent a treatable form of early-onset dementia.

Topics: Brain Diseases; Cerebral Cortex; Female; Humans; Leucovorin; Middle Aged; Vitamin B Deficiency

Cerebral folate deficiency is characterized by low cerebrospinal fluid (CSF) concentrations of 5-methyltetrahydrofolate and a broad spectrum of clinical signs and symptoms. A patient with progressive spasticity, gait disturbance, speech difficulties, initially diagnosed as a recessive spastic paraplegia recovered on folinic acid (15-30 mg/day) and her 5-methyltetrahydrofolate in CSF normalized. This report demonstrates the importance of CSF investigation in the diagnosis of cerebral folate deficiency and efficiency of folinic acid (5-formyltetrahydrofolate) supplementation.

Topics: Brain Diseases; Child; Child, Preschool; Dietary Supplements; Dose-Response Relationship, Drug; Female; Folic Acid Deficiency; Gait; Humans; Leucovorin; Life Style; Movement Disorders; Paraplegia; Pregnancy; Speech Disorders; Tetrahydrofolates

Topics: Adult; Aminophylline; Brain Diseases; Female; Humans; Leucovorin; Magnetic Resonance Imaging; Methotrexate; Neurotoxicity Syndromes; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; 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

A 61-year-old man was treated with combination chemotherapy incorporating cisplatinum, etoposide, high-dose 5-fluorouracil (2,250 mg/m2/24 hours) and folinic acid for an inoperable gastric adenocarcinoma. He developed acute neurologic symptoms of mental confusion, disorientation and irritability, and then lapsed into a deep coma, lasting for approximately 40 hours during the first dose (day 2) of 5-fluorouracil and folinic acid infusion. This complication reappeared on day 25 during the second dose of 5-fluorouracil and folinic acid, which were then the only drugs given. Because folinic acid was unlikely to be associated with this condition, neurotoxicity due to high-dose 5-fluorouracil was highly suspected. The pathogenesis of 5-fluorouracil neurotoxicity may be due to a Krebs cycle blockade by fluoroacetate and fluorocitrate, thiamine deficiency, or dihydrouracil dehydrogenase deficiency. High-dose 5-fluorouracil/folinic acid infusion therapy has recently become a popular regimen for various cancers. It is necessary that both oncologists and neurologists be fully aware of this unusual complication.

Topics: Acute Disease; Brain Diseases; Coma; Confusion; Fluorouracil; Humans; Leucovorin; Male; Middle Aged

A case of treatment-related leukoencephalopathy is presented. A patient with medulloblastoma was postoperatively treated with craniospinal axis irradiation. One month after irradiation, weekly intrathecal administration of methotrexate was performed 4 times to treat cerebrospinal fluid dissemination of the tumor. Two months after the initiation of intrathecal chemotherapy, the patient became somnolent and developed decerebrate posturing. Magnetic resonance imaging showed diffuse leukoencephalopathy. Positron emission tomography revealed a diffuse decrease in glucose uptake in the deep white matter. Auditory evoked potential also showed diffuse abnormalities, not only in the cerebrum, but also in the brain stem. High dose intravenous leucovorin rescue was attempted without any neurologic improvement.

Topics: Blood Proteins; Brain Damage, Chronic; Brain Diseases; Cerebellar Neoplasms; Cerebrospinal Fluid Proteins; Cerebrospinal Fluid Shunts; Child; Combined Modality Therapy; Cranial Irradiation; Decerebrate State; Diagnostic Imaging; Female; Humans; Injections, Spinal; Leucovorin; Magnetic Resonance Imaging; Medulloblastoma; Methotrexate; Radiation Injuries; Tomography, Emission-Computed; Tomography, X-Ray Computed

Cerebral toxoplasmosis related to AIDS was treated with a combination regimen of pyrimethamine, clindamycin, and spiramycin, and in a second trial with a combination of pyrimethamine and clindamycin. Both regimens proved to be equally effective. The experience with the second trial shows that spiramycin does not provide additional benefit. Myelosuppressive side-effects due to pyrimethamine were prevented in most cases by addition of folinic acid to the regimen at the start of the antitoxoplasmic therapy. These data suggest that the combination of pyrimethamine and clindamycin is an effective alternative to the commonly used regimen consisting of pyrimethamine and sulfonamides.

Topics: Acquired Immunodeficiency Syndrome; Acute Disease; Brain Diseases; Clindamycin; Drug Therapy, Combination; Humans; Leucovorin; Pyrimethamine; Spiramycin; Toxoplasmosis

An AIDS patient with cerebral toxoplasmosis had a folate deficiency-induced acute pancytopenia, which was rapidly reversed by the administration of folic acid. This observation is particularly important as a possible preventive therapy to be given to all HIV-infected patients because of the anti-folic activity of the majority of anti-infectious agents used during the course of this disease and the many potential sites of hematopoietic involvement. The patient's condition is stressed because the undernourished subject is at greater risk for this type of manifestation.

Topics: Acquired Immunodeficiency Syndrome; Acute Disease; Adult; Brain Diseases; Folic Acid Antagonists; Folic Acid Deficiency; HIV-1; Humans; Leucovorin; Male; Pancytopenia; Pyrimethamine; Toxoplasmosis

Topics: Acquired Immunodeficiency Syndrome; Adult; Brain Diseases; Diagnosis, Differential; False Negative Reactions; Female; HIV Seropositivity; Humans; Infant, Newborn; Kidney Transplantation; Leucovorin; Magnetic Resonance Imaging; Pregnancy; Pyrimethamine; Sulfisoxazole; Tomography, X-Ray Computed; Toxoplasmosis

A retrospective study was made of the cases of cerebral toxoplasmosis (CT) diagnosed since 1985 in patients with AIDS. In the period studied, out of a total of 70 patients with AIDS, 13 (18.5%) were diagnosed with CT. In eight cases (11%) CT was the first illness indicating AIDS. The clinical, neuro-radiological and serological findings were analyzed. Also the response to treatment with pyrimethamine and sulfadiazine. Although the rate of mortality from CT has been very low among our patients, relapses have been frequent, even in patients who were on maintenance treatment with pyrimethamine, and in the medium term the prognosis is made more gloomy by the appearance of other opportunistic infections.

Topics: Acquired Immunodeficiency Syndrome; Adult; Brain Diseases; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Pyrimethamine; Retrospective Studies; Sulfadiazine; Toxoplasmosis

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

Topics: Adrenal Cortex Hormones; Brain Diseases; Child; Child, Preschool; Humans; Leucovorin; Leukemia, Lymphoid; Male; Methotrexate

The rationale for and the clinical use of regimens that utilize methotrexate (MTX) in high dose (greater than 500 mg/m2) are reviewed. Advantages of high pulse doses are (a) increased cell kill; (b) prevention or delay of resistance; (c) penetration into the cerebrospinal fluid (CSF); and (d) relative lack of toxicity, if used with appropriate monitoring and patient surveillance. Disadvantages are its cost and the cost of patient followup required. Some examples of its use in combination illustrate the point that antagonistic as well as synergistic antitumor or antinormal cell effects can result, depending upon the sequence of administration of MTX and another drug.

Topics: Animals; Asparaginase; Brain Diseases; Child, Preschool; Cisplatin; Cytarabine; Drug Administration Schedule; Drug Resistance; Drug Therapy, Combination; Fluorouracil; Humans; Infant; Injections, Spinal; Leucovorin; Leukemia L1210; Leukemia, Lymphoid; Methotrexate; Mice

An unusual neurological syndrome occurred in 4 of 158 patients treated for osteogenic sarcoma with combination chemotherapy. There was an abrupt onset of focal cerebral deficits approximately ten days after chemotherapy with vincristine and high-dose methotrexate plus citrovorum factor rescue. The syndrome was short lived and always occurred early in the course of treatment. Prolonged neurological deficits remained in 2 patients. When similar chemotherapy was reinstituted in the 4 patients, no further neurological complications ensued. Possible causes include a leukoencephalopathy related to methotrexate or an embolic cerebral vasculopathy related to necrotic tumor microemboli emanating from the lungs.

Topics: Adolescent; Adult; Bone Neoplasms; Brain Diseases; Drug Therapy, Combination; Female; Femoral Neoplasms; Humans; Humerus; Leucovorin; Male; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Pelvic Bones; Syndrome; Vincristine

Topics: Brain Diseases; Central Nervous System; Child; Folic Acid; Humans; Leucovorin; Leukemia, Lymphoid; Methotrexate