Severe neurotoxicity associated with dimethyl sulphoxide following PBSCT

Abstract

DMSO is used as a cryoprotectant for long-term storage of haematopoietic progenitor cells from the marrow or blood. 1 Until recently, there has been little information on the neurological toxicity of DMSO other than headache. 2 Recent reports suggest that this may be a more frequent problem than currently appreciated. [3][4][5][6][7] A 50-year-old woman developed a Durie-Salmon stage III IgA multiple myeloma in October 2007 and received first-line therapy consisting of thalidomide and dexamethasone. A PBSC collection was performed (highdose CY (4 g/m 2 ) and G-CSF (5 mg/kg/day)). Three million CD34 cells per kilogram were collected. The cells were cryopreserved in 10% DMSO (B. Braun Medical SA, Boulogne, France) using a controlled-rate freezer (Nicool Plus PC, Air Liquide, France) and stored at À150 1C. The final volume cryopreserved was 480 ml in six bags, with approximately 8 g of DMSO per bag (0.13 g/kg DMSO per bag). After PBSC collection, she underwent autologous PBSCT (day 0 ¼ 11 April 2008). The conditioning regimen consisted of melphalan at a dose of 200 mg/m 2 . The bags were thawed in a 37 1C water bath and infused at a rate of 10 ml/min. After the infusion of the last bag, she developed skin pallor, and loss of consciousness (Glasgow Coma Scale 4/15) with hypoxia. Pulse rate was 70/min and blood pressure 120/75 mm Hg. She had no localizing neurological signs. No obvious tonic-clonic activity was noted although she had bitten her tongue and had an evidence of trismus. A seizure was suspected and she was administered with a 15 mg/kg loading dose of phenytoin. The patient was transferred to intensive care unit for ventilation. Blood count, electrolytes, liver function tests and coagulation screen were normal. An urgent brain CT scan was unremarkable. Electroencephalogram showed diffuse abnormalities in the electric activity with irregular paroxysms of slow waves of generalized projection.The patient recovered consciousness in o3 h after assistance ventilation was started. Finally, she was extubated within 24 h, and was discharged from the ICU on day þ 1. She engrafted on day þ 11, and was discharged from our unit on day þ 19. She is now 7 months post transplant, and in CR.Various complications during infusion of cryopreserved haematopoietic stem cells have been described, including nausea, vomiting, cardiac symptoms, transient hypertension or hypotension and anaphylaxis. 8,9 Our patient developed a profound but rapidly reversible coma after infusion of 48 g of DMSO (the equivalent of 0.78 g/kg). She developed this severe complication despite an acceptable dose of DMSO reinfused at a rate generally considered to be safe. The maximal recommended dose of DMSO to be reinfused in one session is 1 g/kg of body weight or 10 ml/kg of a 10% DMSO cryopreserved solution.Other probable causes of seizures, such as metabolic abnormalities, structural brain lesions and sepsis, were ruled out. In the absence of other causes, we attribute the reaction to the DMSO toxicity. Although the pathophysiology of DMSO neurotoxici...

Dimethyl Sulfoxide Damages Mitochondrial Integrity and Membrane Potential in Cultured Astrocytes

“…Down-regulation of glutamate transporters may lead to neuronal excitotoxicity, thus exacerbating DMSO-induced neuronal damage. The results help to explain the occurrence of epilepsy in humans [14]–[18] and rats [49] following exposure to high concentration of DMSO.…”

“…Furthermore, there are several case reports that reveal severe neurotoxicity [14]–[18], encephalopathy [19]–[21] and transient global amnesia [22] associated with the infusion of DMSO-cryopreserved hematopoietic stem/progenitor cells. These results highly suggest that DMSO has neurological side effects and toxicity.…”

Historical perspectives and the future of adverse reactions associated with haemopoietic stem cells cryopreserved with dimethyl sulfoxide

“…As the clinical symptoms appeared during or soon after the Schlegel et al 2009), so bringing the total to 27 case studies. Many of these indicated the observed reactions were tenuously or convincingly associated with the DMSO (Corso et al 1993;Zenhausern et al 2000;Hoyt et al 2000;Benekli et al 2000;Windrum and Morris 2003;Bauwens et al 2005;Chen-Plotkin et al 2007;Mueller et al 2007;Junior et al 2008;Otrock et al 2008;Abdelkefi et al 2009;Ruiz-Delgado et al 2009) or the presence of lysed cells (Ruiz-Delgado et al 2009). Whilst others implicated hypothermia of the infusate (Hequet et al 2002), anaphylaxis due to DMSO (Rapoport et al 1991), the rate of infusion (Junior et al 2008) or the volume of cryopreserved stem cells (Dhodapkar et al 1994).…”

Nanoparticle‐Mediated Intracellular Protection of Natural Killer Cells Avoids Cryoinjury and Retains Potent Antitumor Functions

“…[ 3 ] However, it has been associated with severe toxicities when infused into patients. [ 4–13 ] Adverse effects of DMSO have also been studied extensively in vitro, with studies showing DMSO to be toxic to various cell types including blood cells, [ 14,15 ] mesenchymal stromal cells, [ 16 ] skin fibroblasts, [ 17,18 ] and human corneal endothelial cells. [ 19 ] DMSO also has the ability to induce unwanted epigenetic changes.…”