Cerebellar degeneration caused by high‐dose cytosine arabinoside: A clinicopathological study

Abstract

Twenty-four patients with leukemia or lymphoma refractory to conventional chemotherapy were given a course of systemic, high-dose cytosine arabinoside (3 gm/m2 every 12 hours for twelve doses). Four patients developed cerebellar degeneration during treatment. Ataxia of gait and limb movements, dysarthria, and nystagmus appeared five to seven days after the first dose, worsened over the next two to three days, and then remained stable for two to six days. Incomplete improvement occurred over the following one to two weeks. Postmortem examination disclosed loss of Purkinje cells in the depths of cortical sulci with relative preservation of those at the crests of folia and those in the most posterior inferior portions of the cerebellum. Other patients developed a mild, reversible cerebellar syndrome over the same time course as that of the irreversible disorder. Manifestations ranged from nystagmus alone to dysarthria and unsteadiness of gait without limb ataxia. We conclude that cytosine arabinoside at this dosage causes a cerebellar degeneration with characteristic clinical and pathological features. Among the present patients with refractory hematological malignancies, such degeneration occurred with an incidence of 16.7%, more than twice that reported in previous series.

Rescue of Mesencephalic Dopamine Neurons by Anticancer Drug Cytosine Arabinoside

“…The apoptotic death of postmitotic neurons in the presence of ara-C has also been previously observed, in sympathetic ganglionic cultures where it mimics the effects of NGF withdrawal (Wallace and Johnson, 1989), and in cerebellar neurons, both in vitro and in vivo (Winkelman and Hines, 1983;Dessi et al, 1995), at concentrations that were neurotoxic to our cultures as well. The neuroprotective effect of low concentrations of ara-C, which is specific to dopaminergic neurons, has not previously been reported, although stimulation of neuronal differentiation and/or neurite outgrowth has been observed in cultured septal cholinergic neurons (Haynes et al, 1991) or in injured spinal neurons in vivo (Guth et al, 1985).…”

An Inhibitor of DNA Recombination Blocks Memory Consolidation, But Not Reconsolidation, in Context Fear Conditioning

“…ara-C neurotoxicity in cancer patients has been documented within the cerebellum, brainstem, medulla, and spinal cord (Lazarus et al, 1981;Winkelman and Hines, 1983;Sylvester et al, 1987;Vogel and Horoupian, 1993). The neurotoxicity of ara-C is dose dependent, requires chronic exposure, and appears to be mediated by the DNA damage-activated, p53-dependent apoptosis pathway (Lazarus et al, 1981;Wallace and Johnson, 1989;Martin et al, 1990;Deckwerth and Johnson, 1993;Tomkins et al, 1994;Dessi et al, 1995;Enokido et al, 1996;Park et al, 1998).…”

Cytosine arabinoside rapidly activates Bax-dependent apoptosis and a delayed Bax-independent death pathway in sympathetic neurons

“…Neuronal death occurs in several regions of the central nervous system, including the cerebellum, brainstem, medulla, and spinal cord, and includes motor neurons and Purkinje cells. [8][9][10][11][12] In vitro, ara-C is toxic to postmitotic sympathetic, parasympathetic and sensory neurons of the peripheral nervous system as well as cerebellar and cortical neurons of the central nervous system. [2][3][4]7,13 This neurotoxicity is dose-dependent and can be completely prevented by deoxycytidine (dC), which is the preferred substrate for most metabolic processes that are affected by ara-C. 2 In sympathetic neurons of the superior cervical ganglion (SCG), cell death after ara-C exposure shows some similarities to the programmed cell death of these neurons after the withdrawal of their trophic factor, nerve growth factor (NGF).…”