Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Twenty-three children surviving more than 5 years from the diagnosis of leukemia, lymphoma, or malignant histiocytosis were evaluated for clinical evidence of central nervous system disease. Severe impairment, consisting of seizures, paraplegia, and dementia was present in 4, all of whom received methotrexate (MTX) and other agents for 2 to 7 years. Brain biopsies in 3 of these children showed white-matter gliosis and no evidence of viral or other infections or leukemic infiltrates. Of the remaining children 10/19 were found to have mild clinical or EEG abnormalities. All had received i.v. MTX with other drugs for 2-6 years; 5 did not receive cranial irradiation. Common to all impaired patients was the administration of intravenous methotrexate in relatively high doses over a prolonged period of time. Impairment in nervous system function may present as a spectrum of deficiencies, with the most severe resulting in death, or as in the 4 patients described here, profound dementia and dependence. Less dramatic changes in functioning, may, however, result from various combinations of chemotherapy and radiation therapy. Methods of assessing their etiology and impact on survivors need now to be devised.
Cancer 1976 Feb
PMID:Effects of chemotherapy on the central nervous system. A study of parenteral methotrexate in long-term survivors of leukemia and lymphoma in childhood. 76 54

Pathological type complications associated with 46 cases of neurofibromatosis in children under 12 are reported. It is noted that in 65.2% of the cases there are mental retardation, usually serious. More than 50% (24 cases) had some type of tumoration. All were benign with the exception of a suprarenal neuroblastoma that caused arterial hypertension and histological characteristics of malignancy. Fifteen tumors were located in the optica ways, one in the mediastinum, one in the abdomen, one in the paravertebral area, one which was a craneal plexiform tumor and four of the moluscum pendulum type on the eyelids or in neighbouring regions. Twelve children suffered from some type of seizures (Salaam's spasms, tonic-clonic, myoclonic, atonic and versive). Radiological abnormalities were very frequent in the simple X rays as well as in those in which contrast medium was used. In four cases malformations of the midline were observed, three of which were non-communicating cysts of the septum pellucidum, the other agenesis of the corpus callosum. Neurofibromatosis was further seen associated iwth Bourneville's syndrome, Morquio's syndrome, Batten's type of lipofuscinosis, facial or generalized hemihypertrophia and stenosis of the aqueduct. Heredity was dominant autosomic in 16 cases, the rest being due to possible recent mutations.
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PMID:[Pathological complications in 46 cases of neurofibromatosis in children (author's transl)]. 82 74

Thirteen adult Rhesus monkeys were repeatedly perfused through the ventriculocisternal or ventriculolumbar spaces with Elliott's B solution containing various concentrations of methotrexate (MTX) and trace amounts of [3H]MTX and [carboxy-14C]inulin. The concentrations of MTX ranged from 4.8 to 0.15 mg/ml representing perfusion dosages of 551 mg/sq m to 16 mg/sq m. The average steady-state concentration out-concentration in (Co/Ci) value for MTX was 0.78 +/- 0.04 for the ventriculocisternal and 0.66 +/- 0.01 for the ventriculolumbar routes. MTX treatments did not significantly affect mean inulin steady-state Co/Ci values or CSF formation rate. With the exception of a monkey perfused with MTX at an inflow concentration of 4.8 mg/ml, body weight, food intake, and urine output, analyzed at weekly intervals, generally were not remarkably affected by MTX perfusions. In five monkeys perfused with MTX in concentrations of 4.8 to 0.6 mg/ml, gross neurological toxicity was observed, principally in the form of seizures and hypokinesia during perfusion series with occasional residual motor deficit. Significant cerebral damage was associated with the brains of two monkeys perfused with MTX at concentrations of 2.4 and 0.6 mg/ml and two monkeys perfused at concentrations of 1.2 and 0.3 mg/ml; there of the four animals displayed signs of gross neurotoxicity, and two animals developed permanent motor deficits. However, the extent to which neurotoxic signs could be attributed solely to MTX was difficult to judge because some changes in central nervous system morphology were associated with the mechanical aspects of the procedure. Overall behavioral performance as measured by a visual pattern discrimination reinforced by avoidance or escape from an electric shock was not significantly affected by repeated perfusions of MTX (0.6 mg/ml) in two monkeys not otherwise studied in detail.
Cancer Res 1976 Oct
PMID:Neuropharmacological effects of methotrexate perfused through the cerebrospinal fluid system of the rhesus monkey. 82 6

The authors present the case of a child aged 7 years who suffered from relapsing acute lymphocytic leukemia. Treatment consisting mainly of oral and intrathecal methotrexate and x-ray therapy produced remission of the hematologic symptoms. Three years after the onset of the leukemia, mental deterioration gradually appeared. Radiography of the skull revealed diffuse bilateral calcium deposits in both cerebral and cerebellar hemispheres. Four years after the onset of the disease, a hematologic relapse occurred. Behavioral disorders became more severe and the child died after a period of seizures and unconsciousness. The main pathologic data obtained by the study of a brain biopsy and after a complete postmortem examination consisted of calcifications located bilaterally in the cerebral and cerebellar cortex. No signs of leukemia were present. Cerebral calcification is an extremely rare complication in the course of the therapy of lymphocytic leukemia. Its possible causes are discussed.
Cancer 1975 Feb
PMID:Intracerebral calcifications appearing during the course of acute lymphocytic leukemia treated with methotrexate and X-rays. 105 35

Twenty-three leukemic children were studied prospectively to detect chronic effects of therapy. All patients received CNS prophylaxis, including 2400 R cranial irradiation, and intermittent maintenance therapy with intravenous methotrexate, cyclophosphamide and cytosine arabinoside. Neurologic symptoms were observed in 12 patients, all of whom had intermittent limping and mild incoordination, between the 10th and 18th month of maintenance therapy. Five of the 12 sustained seizures and four of these had subsequent abnormalities in motor, perceptual, behavioral or language development. Three school-aged children have learning disability and perceptual-motor defects. Studies of CSF folate and MTX content are presented but not helpful in delineating the etiology of these neurologic symptoms.
Cancer 1976 Feb
PMID:Chronic neurologic disturbance in childhood leukemia. 106 30

Among 1,459 autopsied patients with cancer, 12 had multifocal infarcts of the brain that appeared to be caused by intravascular coagulation. Most of these patients were women with leukemia or lymphoma, and all had a clinical course in which neurologic signs and symptoms were prominent. All had evidence of generalized brain disease (delirium and stupor or coma), and several also had focal brain disease (focal seizures, hemiparesis). All patients had laboratory evidence of coagulation abnormalities, although these were often not severe when neurologic symptoms began. Pathologically, there were multifocal hemorrhagic or ischemic infarcts in the distribution of several cerebral vessels, without a systemic source for cerebral emboli. Fibrin thrombi were identified in cerebral vessels and in vessels of several other organs. The clinical findings fit the pathologic picture, and in most instances the correct diagnosis might have been made earlier had it been considered.
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PMID:Neurologic manifestations of intravascular coagulation in patients with cancer. A clinicopathologic analysis of 12 cases. 117 2

We reviewed our experience for adult patients receiving oral anticonvulsant therapy during high-dose chemotherapy and autologous bone marrow re-infusion for primary malignant tumors of the central nervous system. Nineteen patients received either iv carmustine (BCNU) 900-1050 mg/m2 and 6120 cGy cranial irradiation (N = 10), iv carmustine 900-1050 mg/m2 and iv cisplatin 200 mg/m2 (N = 8), or iv carmustine 600 mg/m2, iv cisplatin 200 mg/m2, and iv etoposide 2400 mg/m2 (N = 1). Anticonvulsant therapy consisted of phenytoin alone (N = 8), phenobarbital alone (N = 4), carbamazepine alone (N = 2), phenytoin and carbamazepine (N = 2), carbamazepine and phenobarbital (N = 1), and no anticonvulsant therapy (N = 2). Serum anticonvulsant concentrations were monitored frequently and doses adjusted to keep values in the therapeutic range. While phenobarbital and carbamazepine doses remained relatively stable, all patients required increased doses of phenytoin anticonvulsant therapy after beginning chemotherapy (mean onset 3.7 days after initiation of chemotherapy). The increase in phenytoin dose ranged from 50% to 300% above baseline (mean 134%). By the time of discharge from the hospital (approximately 3-4 weeks after the start of chemotherapy) anticonvulsant dose was decreased to near pre-therapy levels. These swings coincided with the initiation of dexamethasone therapy for antiemetic effect and were more pronounced in patients also receiving cisplatin therapy. Due to close monitoring of serum phenytoin concentrations, no instances of toxicity due to excessive drug concentration, or seizures due to subtherapeutic doses, were noted in patients with primary CNS malignancies. Serum phenytoin concentrations fluctuate markedly during high-dose chemotherapy and must be analyzed frequently during the course of therapy.
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PMID:Fluctuation of serum phenytoin concentrations during autologous bone marrow transplant for primary central nervous system tumors. 131 52

The safety of ondansetron has been carefully evaluated through laboratory studies and clinical trials. Preclinical studies demonstrated that there is no end-organ toxicity in rats and dogs administered ondansetron doses 30 to 100 times those used in humans. At near-lethal doses of ondansetron, animals developed subdued activity, ataxia, and convulsions. Modest transient increases in serum transaminase values were observed. Concurrent administration of ondansetron with chemotherapy had no effect on tumor response in animals. The clinical safety of ondansetron has been evaluated in more than 2,500 cancer patients who received intravenous doses as large as 1.5 mg/kg. In adult patients receiving single-day chemotherapy, the incidence of adverse events was 36% with ondansetron (n = 647) and 50% with metoclopramide (n = 498). Diarrhea occurred in 9% of ondansetron patients and 19% of metoclopramide patients. Headache occurred in 14% of ondansetron patients and 8% of metoclopramide patients. Extra-pyramidal symptoms were reported in none of the ondansetron patients and 5% of the metoclopramide patients. The incidence of vascular occlusive events and seizure disorders was nearly identical with ondansetron and metoclopramide and similar to the cancer population in general. In a group of 209 pediatric patients receiving chemotherapy, the incidence of adverse events was 19% with ondansetron. Serum transaminase values increased significantly in 6% to 8% of ondansetron patients and 2% of metoclopramide patients. There was no apparent relationship between the cumulative dose of ondansetron administered and the incidence of increased transaminase values. However, there was an apparent relationship between the cumulative dose of cisplatin administered and the incidence of transaminase abnormalities. These data demonstrate that ondansetron is better tolerated than metoclopramide and is safe for intravenous administration to pediatric and adult patients receiving chemotherapy.
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PMID:Toxicity and side effects of ondansetron. 138 51

Dissemination of tumor to the leptomeninges and cerebrospinal fluid represents a common pattern of metastasis for many cancers; however, few chemotherapeutic agents are available for intrathecal (i.t.) use and treatment results are often poor. We studied the neurotoxicity and pharmacokinetics of i.t. 4-hydroperoxycyclophosphamide (4-HC) in the rabbit and the activity of i.t. 4-HC in a VX2 rabbit model of leptomeningeal carcinomatosis to evaluate the potential use of 4-HC in the treatment of leptomeningeal tumors. Toxicity studies examined 4-HC doses ranging from 0.5 to 6.0 mumol administered by intraventricular injection weekly for 4 to 8 weeks. Clinical or histological neurotoxicity was not observed in rabbits treated with < 1.0 mumol 4-HC for 4 weeks. Clinical toxicity, characterized by lethargy, weight loss, seizures, or death, was apparent at doses > 2.0 mumol. Vasculitis of superficial arteries was observed in rabbits treated with > 1.0 mumol 4-HC. In cerebrospinal fluid pharmacokinetic studies, the mean drug half-life after intraventricular or intralumbar administration was 24.3 and 18.2 min. Regional inequities in drug exposure were apparent as area under the clearance curve values for cerebrospinal fluid distant from the injection site were lower than those of proximate sites (P < 0.001). Weekly intraventricular treatment of VX2 leptomeningeal tumor-bearing rabbits with 0.5 or 1.0 mumol of 4-HC resulted in an increased life span of 22.5 and 35%, respectively. These results indicate that i.t. 4-HC, at doses lower than those producing neurotoxicity in the rabbit, is effective treatment for VX2 leptomeningeal carcinomatosis.
Cancer Res 1992 Nov 15
PMID:Intrathecal 4-hydroperoxycyclophosphamide: neurotoxicity, cerebrospinal fluid pharmacokinetics, and antitumor activity in a rabbit model of VX2 leptomeningeal carcinomatosis. 142 60

Nineteen patients with advanced cancer were entered into a phase I clinical trial of Tumor Necrosis Factor (TNF) which was designed to determine the pharmacokinetic profile, safety, and maximal tolerated dose (MTD) of the recombinant human cytokine in vivo. TNF was administered by continuous infusion for 24 hours followed by pharmacokinetics and a 120-hour infusion repeated every 3 weeks. The initial dose was 40 micrograms/m2 and was ultimately escalated to 200 micrograms/m2. A total of forty 5-day cycles were administered to 18 of these patients; and all were evaluable for toxicity. Toxicities in this trial included fever, chills, rigors, hypotension, headaches, seizures, lethargy, weight loss, and malaise. At all dose levels, but more significantly at the highest doses, hematological toxicities were observed and grade 3 neurotoxicity (headache and confusion), and hypotension were noted. Two patients expired during the study, and this was felt to be related to septic episodes. Because of these severe toxicities, 160 micrograms/m2 was defined as the MTD. At 160 micrograms/m2 peak serum levels occurred within 5-20 minutes of initiation and were not detectable 1 hour later. No anti-tumor responses were observed. No measurable plasma levels of TNF were observed with the administration of doses of 80 micrograms/m2. This dose level could be further studied in phase II studies alone and in combination with other agents, utilizing a continuous infusion schedule.
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PMID:A phase I pharmacokinetic study of recombinant human tumor necrosis factor administered by a 5-day continuous infusion. 142 28


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