Alkylating Agents

NITROGEN MUSTARD MECHLORETHAMINE

Nitrogen mustard (NM) administered intravenously in a dose of 0.4 mg/kg is not usually associated with neurotoxicity. Hemiplegia, coma, chills, and fever, with increased intracranial pressure and CSF pleocytosis, however, were reported in one patient 7 days after each of two standard intravenous doses of NM (0.4 mg/kg). y On both occasions the signs and symptoms subsided after therapeutic measures to decrease intracranial pressure. When the patient died four years later, from unrelated reasons, a gross and microscopical examination of the brain revealed focal areas of gliosis with loss of neurons. Massive intravenous injections of NM have caused hearing loss, and vertigo, presumably from damage to the eighth cranial nerve, seizures, somnolence, and confusion. y Intracarotid NM injection has been associated with hemiplegia, seizures, coma, and death. y One pathological study showed diffuse cerebral edema, which was greater on the side of the injection, and

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TABLE 55-8 -- ANTICANCER DRUGS AND NEUROTOXINS

Encephalopathy

Parkinsonism

BCNU

Cyclophosphamide

Cisplatin

Cytosine arabinoside

Cytosine arabinoside

Melthotrexate

5-Fluorouracil

5-Fluorouracil

Ifosfamide

L-Asparaginase

Peripheral neuropathy

Methotrexate

Cisplatin

Procarbazine

Cytosine arabinoside

Interferon

Hexamethylmelamine

Interleukin-2

Procarbazine

Vincristine

Cerebellar syndromes

Cytosine arabinoside

Stroke-like syndromes

5-Fluorouracil

Cytosine arabinoside

Procarbazine

BCNU

L-Asparaginase

Myelopathy

Methotrexate

Adriamycin (intrathecally)

Methotrexate (intrathecally)

Cytosine arabinoside

Thiotepa

Vincristine (intrathecally)

extensive gliosis and demyelination, presumably from a previous injection. [1

extensive gliosis and demyelination, presumably from a previous injection. [1

CYCLOPHOSPHAMIDE

One of the most widely used alkylating agents, cyclophosphamide, is associated with very little neurological toxicity. Rapid intravenous infusion of cyclophosphamide has been associated with facial or scalp burning, oropharyngeal tingling, nasal congestion, rhinorrhea, sneezing, and lacrimation. These uncomfortable sensations of the skin and mucous membranes occur more frequently than was previously noted, and changing infusion duration or the concentration of cyclophosphamide, or administering anticholinergics intranasally, can result in variable degrees of improvement. y

Inappropriate secretion of antidiuretic hormone has occurred rarely and is exacerbated by the high fluid loading required in high-dose cyclophosphamide therapy to prevent renal toxicity. Biopsy-proven progressive multifocal leukoencephalopathy (PML) has been described in a man treated with cyclophosphamide and prednisone for Wegener's granulomatosis. On discontinuation of immunosuppression, dramatic recovery took place. y

CHLORAMBUCIL

Seizures have rarely been reported with chlorambucil administration. They occur almost exclusively in children, in the setting of overdosage or nephrotic syndrome. They consist of myoclonic seizures followed by generalized tonic clonic seizures. The EEG can show paroxysmal discharges that continue for several days after seizure activity. [ii Although the drug is generally considered to be non-neurotoxic, acute CNS abnormalities consisting of lethargy, ataxia, seizures, and coma have been reported with overdose.y Progressive multifocal leukoencephalopathy has occurred in a patient with rheumatoid arthritis after treatment with chlorambucil. Of interest is that progressive multifocal leukoencephalopathy can develop as a late complication, even after the medicine is stopped. y

THIOTEPA

Owing to its low neurotoxicity, thiotepa, an intravenously administered alkylating agent, is one of the few anticancer drugs that can be injected into the CSF. In one series of 10 patients with meningeal leukemia and carcinomatosis treated with multiple courses of intrathecal thiotepa, clinical neurotoxicity developed in only two. ^ This neurotoxicity consisted of progressive myelopathy, manifested as progressive lower extremity weakness, back and leg pain, areflexia, and sensory deficits. EMG revealed diffuse lower motor neuron abnormalities. The histopathological changes in the spinal cord were localized to the white matter and consisted of demyelination and gliosis of the posterior columns and the nerve roots of the cauda equina. y

BUSULFAN

Generalized seizures are a frequent side effect of high-dose busulfan (total dose 16 mg/kg) as part of a preparative regimen for allogeneic bone marrow transplantation. No neurological deficits are found after the episodes, and there are no recurrences. Maintenance of therapeutic blood concentrations of anticonvulsant prophylactic regimens is recommended.y There has been one case of busulfan administration associated with the development of myasthenia gravis, although the relationship among the myasthenia, the busulfan, and the leukemia was not clarified. [ii

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