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DMSO-associated encephalopathy during autologous peripheral stem cell infusion: a predisposing role of preconditioning exposure to CNS-penetrating agents?

Bone Marrow Transplantation volume 44, pages 133–135 (2009)Cite this article

Hematopoietic reconstitution after high-dose chemotherapy is usually achieved through DMSO-cryopreserved PBSC. DMSO-related neurotoxicity, including transient global amnaesia, cerebral infarction, migraine, seizures, encephalopathy and coma, has been described, mostly as anecdotal events.1, 2, 3, 4, 5, 6 The heterogeneity of neurologic syndromes and the pleiotropic actions of DMSO have hampered the formulation of univocal pathogenetic hypotheses and the understanding of their putative clinical correlates. Efforts to identify predisposing factors for DMSO-related neurotoxicity have been unsuccessful, and even the presence of preexisting cerebral disease does not predict for such risk.7 Here, we describe a peculiar episode of neurotoxicity and propose a synoptic review of previously reported cases both suggesting that the preconditioning exposure to central nervous system (CNS)-penetrating agents might contribute to the occurrence of DMSO-associated neurologic toxicity.

Among 124 procedures performed from January 2004 to June 2008, we observed a severe encephalopathy in a 27-year-old woman who had undergone upfront transplantation because of high-risk aggressive non-Hodgkin's lymphoma. At presentation, she had cervical, axillary and bulky mediastinal lymphadenopathy, B symptoms and extra nodal involvement of stomach and kidneys. BM biopsy was negative and the patient was staged as IVB with an age-adjusted International Prognostic Index of 3. Owing to the presence of risk factors for CNS involvement, she underwent lumbar puncture, which disclosed large lymphoma cells in the cerebrospinal fluid. The patient was treated with four courses of R-MegaCHOP14 (rituximab, CY, doxorubicin, vincristine and prednisone), and received treatment for leptomenigeal disease consisting of four biweekly administrations of intrathecal liposome-encapsulated cytarabine followed by two courses of R-MAD (rituximab, mitoxantrone, high-dose cytarabine and dexamethasone), with PBSC apheresis being performed at day +16 after the first course, yielding to a total harvest of 5.15 × 106 CD34+ cells/kg. Cells (total volume of 488 ml) were divided in five bags, cryopreserved in 10% DMSO by controlled rate, freezing and stored at −180 °C. A CR was obtained with the complete clearance of lymphoma cells from cerebrospinal fluid. The patient was conditioned with BEAM (carmustine, etoposide, cytarabine and melphalan), and the regime was delivered from day −7 to −2 without complications. On day 0, the patient was premedicated with diphenhydramine (50 mg) and hydrocortisone (200 mg) i.v., and the first PBSC bag was thawed at 37 °C and infused at a rate of 10 ml/min. Five minutes after the end of the infusion (105 ml; 1.08 × 106/kg CD34+ cells), the patient appeared confused and disoriented; soon afterwards, she sequentially developed limb weakness and tetraparesis with symmetric loss of tendon reflexes. After 10 min, she developed a complete loss of consciousness accompanied by mydriasis and urine incontinence, without clonic convulsions or focal neurologic signs. Throughout the entire episode, pulse oxymetry showed adequate saturation, signs of cardiac ischaemia or other electrocardiographic changes, and the patient was normotensive and without arrhythmia. No laboratory abnormalities, including electrolytes, osmolarity, serum glucose and enzymes, were evidenced upon repeated testing. The patient was given hydrocortisone (1000 mg) i.v. and started on forced hydration. She recovered consciousness 1 h after hyperhydration and completely regained motor functions without neuroleptic treatments. However, she was unable to form new memories, and had subtle spell disturbances and appeared anxious and disoriented. This transient global amnaesia-like picture spontaneously and completely resolved after 5 h. The computer-assisted tomography scans and magnetic resonance imaging of brain performed after 24 h were unremarkable, and no further neurological events occurred. No additional PBSC were infused. A single dose (6 mg) of pegfilgrastim was given on day +4 and the patient achieved a timely haemopoietic recovery with ANC ⩾500 × 109/l at day +14 and Plts ⩾20 × 109/l at day +16. She received consolidation mediastinal radiotherapy (36 cGy), and clinical reassessment confirmed a persisting CR without problems of late engraftment. At 10 months post-ASCT, the patient remains in CR without any neurological or behavioural sequelae.

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Acknowledgements

We are grateful to Dr Alessandra Trocino, Librarian at the NCI ‘G Pascale’of Naples, for the excellent bibliographic assistance.

Contract grant sponsors: Ministero della Salute, Ricerca Finalizzata FSN, IRCCS, Rome Italy.

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  1. Hematology–Oncology and Stem Cell Transplantation Unit, National Cancer Institute, IRCCS, Fondazione ‘G Pascale’, Naples, Italy E-mail: apinto.int.napoli@tin.it,

    G Marcacci, G Corazzelli, C Becchimanzi, M Arcamone, G Capobianco, F Russo, F Frigeri & A Pinto

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Marcacci, G., Corazzelli, G., Becchimanzi, C. et al. DMSO-associated encephalopathy during autologous peripheral stem cell infusion: a predisposing role of preconditioning exposure to CNS-penetrating agents?. Bone Marrow Transplant 44, 133–135 (2009). https://doi.org/10.1038/bmt.2008.442

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