Background. Intrathecal chemotherapy, radiation therapy, and systemic
chemotherapy are used for both prophylaxis and treatment of central ne
rvous system (CNS) disease in hematologic malignancies. Twenty-three c
ases of myelopathy that occurred in patients who received intensive CN
S-directed therapy were evaluated to identify the determinants of this
severe CNS toxicity. Methods. Nine cases treated by the authors and 1
4 collected from the literature are discussed. Twelve had Burkitt's le
ukemia/lymphoma. Patient ages ranged from 3 to 30 years (median, 15 ye
ars). The dose intensity of CNS-directed therapies, including intrathe
cal cytosine arabinoside (ara-C), intrathecal methotrexate (MTX), syst
emic high dose (HD) MTX, systemic HD ara-C, systemic thiotepa, and CNS
radiation, was evaluated by the determination of single drug doses an
d cumulative total drug or irradiation doses over elapsed treatment du
rations.Results. Central nervous system treatment was prophylactic in
10 cases; active CNS disease was being treated in 13 cases. One patien
t received only intrathecal ara-C before toxicity occurred; others rec
eived intrathecal ara-C and varying combinations of intrathecal MTX, H
D ara-C, HD MTX, CNS radiation, and systemic thiotepa. Eight patients
died of toxicity, of whom 6 had autopsy-proven cord necrosis; 3 were v
entilator-dependent; 10 had persistent paraplegia or paraparesis; and
2 recovered completely. Conclusion. Both highly intensive, short CNS t
reatment sequences and lower intensity, long term cumulative treatment
s may result in this rare but severe myelopathy. The cause is multifac
torial, with systemic chemotherapy, intrathecal chemotherapy, and radi
ation therapy contributing to toxicity. Multiple intrathecal ara-C and
/or MTX doses given at frequent (daily) intervals should be avoided. C
oncurrent intrathecal ara-C and systemic HD ara-C also appear to be es
pecially toxic. Intrathecal hydrocortisone given with intrathecal ara-
C does not protect against myelopathy. Multiple, frequently spaced cou
rses of CNS-directed therapies must be avoided, especially in patients
who have received prior CNS radiation.