Inadvertent intrathecal vincristine administration: report of a fatal case despite cerebrospinal fluid lavage and a review of the literature.

Accidental intrathecal vincristine administration results in progressive ascending radiculomyeloencephalopathy usually leading to fatal outcome. No specific therapy for intrathecal vincristine toxicity has been reported. We report a 63-year-old man with diffuse large B-cell lymphoma at the right testis who inadvertently received intrathecal vincristine. Direct CSF aspiration and irrigation was done 30 minutes after the incident. Ventriculostomy and lumbar drain was placed. Intrathecal irrigation was started at 6.5 hours using FFP-containing lactate solution and continued for 11 days. In addition, antineurotoxic and neuroprotective agents were given. His neurological symptom deteriorated slowly and he died on day 12. Among 16 reported cases undergoing lumbar drainage and/or irrigation, 56.3% can survive 30 days or more and 37.5% had survive more than 6 months. Immediate CSF drainage and early irrigation is related to good outcome (prolonged survival with no encephalopathy). In our case, his poor outcome might be due to the delayed starting of irrigation. In conclusion, the appropriate and effective management of this complication is unknown. However, emergency cerebrospinal fluid drainage and irrigation remains the principal of management.

Intrathecal vincristine: fatal myeloencephalopathy despite cerebrospinal fluid perfusion.

BACKGROUND: Vincristine, an antineoplastic agent, must never be injected intrathecally because of its devastating neurotoxic effects, which are usually fatal. We report a case of fatal myeloencephalopathy secondary to inadvertent intrathecal administration of vincristine. CASE REPORT: Intrathecal vincristine was inadvertently injected into a twelve-year-old girl with acute lymphocytic leukemia. The error was immediately recognized and treated with cerebrospinalfluid drainage and cerebrospinal fluid exchange. Clinical evolution during the 83 days until death is described Multiple samples of cerebrospinal fluid were assayed for vincristine sulfate. Neuropathological post-mortem changes in the brain and spinal cord are reported CONCLUSION: We compare our case with other previously reported cases in which patient survival was achieved with the same treatment. We summarize preventive measures to avoid such unfortunate occurrences.

Cerebrospinal fluid concentrations of vincristine after bolus intravenous dosing: a surrogate marker of brain penetration.

BACKGROUND: Vincristine (VCR) is used widely in oncology practice, and regular dosing is commonly associated with the development of sensorimotor or autonomic neuropathies. However, the incidence of VCR-related central nervous system (CNS) toxicity is comparatively low, suggesting that the blood-brain barrier may limit drug penetration into the brain parenchyma. This study determined whether measurable concentrations of VCR could be detected in the cerebrospinal fluid (CSF), as a surrogate marker of brain parenchyma penetration, after bolus intravenous injection in children without primary CNS pathology. METHODS: The authors studied 17 pediatric patients ages 2.5-14.1 years (median, 6.8 years) with acute lymphoblastic leukemia or non-Hodgkin lymphoma without evidence of leptomeningeal disease. Patients received VCR 1.5 mg/m2 by intravenous bolus injection followed at varying intervals by lumbar puncture for scheduled intrathecal methotrexate administration under general anesthesia. Paired VCR concentrations in both plasma and CSF were measured in each patient simultaneously at times ranging from 8 minutes to 146 minutes after the VCR injection. Three patients were studied twice. The paired samples were stored at -40 degrees C until analysis using a high performance liquid chromatography assay with a sensitivity of 0.1 microg/L in CSF and 0.4 microg/L in plasma. RESULTS: Plasma VCR concentrations ranged from 2.2 microg/L to 91.2 microg/L. No measurable VCR concentrations were detected in the CSF samples. CONCLUSIONS: Measurable concentrations of VCR in CSF are not achieved after the administration of standard intravenous bolus doses of VCR. The current observations are consistent with the relative rarity of VCR-related CNS neurotoxicity compared with the commonly observed sensorimotor and autonomic neuropathies. These findings suggest that the penetration of VCR into the brain parenchyma of patients with a relatively intact blood-brain barrier is low and that VCR may have a limited role in the CNS-directed therapy of these patients.

Cerebrospinal fluid lavage in the treatment of inadvertent intrathecal vincristine injection.

Vincristine, a widely used antineoplastic agent, is extremely toxic to the central nervous system. If given intrathecally, it produces a rapidly ascending, usually fatal, neuromyeloencephalopathy. We report a case of this complication in a 7-year-old girl with acute lymphoblastic leukemia who was receiving maintenance chemotherapy. During one treatment 0.5 mg of vincristine was erroneously injected into the lumbar subarachnoid space. Cerebrospinal fluid lavage was established within 2 h and continued for 24 h. After 7 days she developed a progressive sensorimotor paraplegia, which eventually stabilized as a paraparesis. Neurophysiological studies were consistent with an axonal type sensorimotor neuropathy. Magnetic resonance imaging of the spine was normal. Vincristine binds to cells, blocking mitosis, thus causing cell death. The associated central nervous system lesions are those of an ascending chemical leptomeningitis and ventriculitis. Cerebrospinal fluid lavage dilutes and removes the drug, thus limiting neural damage. At present this is the only treatment for intrathecal vincristine injection, and its early use in such an event is considered mandatory.

Ascending myeloencephalopathy due to intrathecal vincristine sulfate. A fatal chemotherapeutic error.

A case of fatal myeloencephalopathy secondary to accidental intrathecal administration of vincristine is reported in a 16-year-old boy. He underwent a progressive ascending chemical meningoencephalitis leading to coma, and died 36 days after the injection. Multiple samples of cerebrospinal fluid (CSF) and serum were assayed for vincristine sulfate. CSF levels of vincristine were consistently much higher than serum levels. At autopsy, all regions of the brain that had been in direct contact with the CSF were necrotic. The spinal cord was likewise necrotic throughout its length. Microscopically there was total neuronal loss with tissue destruction in the affected regions. The presence of numerous gemistocytic astrocytes, some in arrested mitosis, was a conspicuous feature in these areas. Three previous reports of intrathecal vincristine instillation are reviewed. No treatment for this devastating iatrogenic error exists, underscoring the importance of preventive measures in chemotherapy administration.

Pharmacokinetics of vincristine in the cerebrospinal fluid of humans.

Using a sensitive radioimmunoassay, concentrations of vincristine and its products were determined in cerebrospinal fluid (CSF) and corresponding blood samples from four patients with lymphoma and two patients with leukemia who had received i.v. bolus injection of 2 mg vincristine. Serial samples of CSF were withdrawn from a CSF reservoir in two patients during a 24-hr period following injection. The first time point after injection at which measurable levels of vincristine were detected in the CSF was 30 min; the concentrations were within the lower range of sensitivity of the assay and were 20- to 30-fold lower than were corresponding serum samples. Despite a prolonged terminal half-life of vincristine in the serum (14.4 to 37.5 hr) following i.v. bolus injection, concentrations of vincristine in the CSF ranged between undetectable within the limits of the assay and 1.1 X 10(-9) M during the 24-hr period of observation. The highest CSF concentration of vincristine (2.6 X 10(-9) M) has been observed in a patient receiving cranial irradiation for active meningeal lymphoma. No measurable levels of vincristine or its products were detected in spot samples of CSF from three patients. Penetration of vincristine and its products into the CSF of humans after i.v. bolus injection appears to be very poor and may account for the uncommon occurrence of central neurotoxicity following its clinical use.

Pharmacokinetics of vincristine in the cerebrospinal fluid of subhuman primates.

Adult rhesus monkeys were given 2-mg/sq m i.v. bolus injections of radiochemically pure tritiated vincristine (VCR). Simultaneous specimens of blood and cerebrospinal fluid (CSF) were sampled from 5 min to 72 hr following injection. CSF was obtained from Ommaya reservoirs which had been implanted s.c. in each monkey. VCR and its metabolic and/or decomposition products rapidly entered the CSF producing low concentrations in this fluid; 5 min following injection, the concentration of VCR was 2.3 nM, whereas approximately a 100-fold greater concentration (203.8 nM) was attained in the plasma. Throughout a 3-day period of observation, constant, low levels of VCR and its metabolic and/or decomposition products (2.3 to 5.7 nM) were maintained in the CSF. The principal form of VCR present in the CSF 1 hr or more after i.v. injection was a water-soluble metabolite and/or decomposition product(s). Although the levels achieved in the CSF are unlikely to be lethal to tumor cells, the finding of persistent low concentrations of VCR and its metabolic and/or decomposition products in the CSF indicates prolonged exposure of neural tissue which might result in neurotoxicity, particularly cumulative neurotoxicity following multiple doses of VCR.