This drug, long used in the treatment of acute nonlymphocytic leukemia, is not neurotoxic when given in the usual systemic daily doses of 100 to 200 mg/m2. The administration of very high doses (up to 30 times the usual dose) induces remissions in patients’ refractory to conventional treatments. It also may produce, however, a severe degree of cerebellar degeneration in a considerable proportion of cases (4 of 24 reported by Winkelman and Hines). Ataxia of gait and limbs, dysarthria, and nystagmus develop as early as 5 to 7 days after the beginning of high-dose treatment and worsen rapidly. Postmortem examination has disclosed a diffuse degeneration of Purkinje cells, most marked in the depths of the folia, as well as a patchy degeneration of other elements of the cerebellar cortex. Other patients receiving high-dose ara-C have developed a mild, reversible cerebellar syndrome with the same clinical features. Because patients older than 50 years of age are said to be far more likely to develop cerebellar degeneration than those younger than 50 years of age, the former should be treated with a lower dosage (Herzig et al).
Calcineurin Inhibitors (Cyclosporine, Tacrolimus, Sirolimus)
These immunosuppressive drugs are used to prevent transplant rejection and to treat aplastic anemia and certain intrinsic immune diseases. Tremor is perhaps the most frequent side effect and myoclonus may be added. Sometimes these impart a stuttering character to speech. Headache and insomnia are common. Seizures may be a manifestation of toxicity, but the cause may lie with the other complications of organ transplantation and immunosuppression. Wijdicks has reviewed the neurologic effects of these drugs.
A posterior leukoencephalopathy syndrome (PRES, see Chap. 33) resembling hypertensive encephalopathy—headache, vomiting, confusion, seizures, and visual loss (cortical blindness)—may follow the use of either drug and with an expanding list of other agents including some of the new monoclonal antibodies used in the treatment of cancer and autoimmune diseases (Table 41-1). There does not seem to be a consistent dose-response effect, drug levels often being in the therapeutic range.
The appearance on CT and MRI of nearly symmetrical changes mainly in the posterior white matter conform to the pattern that is seen in hypertensive encephalopathy (reversible posterior leukoencephalopathy [RPLE] or PRES). Lesions may also appear subcortically in the frontal and parietal lobes as well as in deep structures and the brainstem. Interferon treatment for malignant melanoma and a number of other chemotherapeutic agents have been associated with the same condition. Hinchey and colleagues have described several such cases and suggested that cyclosporine alters the blood–brain barrier and that the fluid overload and hypertension which accompanies the use of cyclosporine underlies the radiologic changes. A variety of psychotic syndromes with delusions, paranoia, and visual hallucinations also have been ascribed to the use of these drugs (see Wijdicks).
Despite the catastrophic effects of thalidomide on the developing fetus (following its introduction as a soporific in 1957), this drug has now found several specific uses in the treatment of immunologic, neoplastic, and infectious diseases. It is effective in the treatment of leprosy, erythema nodosum, and the oral ulcerations of AIDS and Behçet disease. Experimental uses include suppression of graft-versus-host reactions and inhibition of blood vessel proliferation in vascular tumors such as renal cell cancer. A dose-dependent sensory neuropathy is the limiting factor in its use, and serial electrophysiologic testing is recommended if the medication is to be prescribed for protracted periods. Of course, it must not be given to a woman who is or might be pregnant.