Transient loss of consciousness in pediatric recipients of dimethylsulfoxide (DMSO)-cryopre-served peripheral blood stem cells independent of morphine co-medication

Toxicity related to the infusion of dimethylsulfoxide-cryopreserved peripheral blood stem cells (DMSO-PBSC) manifests mostly as cardiovascular side effects. Neurotoxicity¹ including transient global amnesia,^2,3 seizures,^4,5 and stroke^6,7 has been reported as a rare complication primarily in adults. In children, data⁸ are sparse. In light of a recent report implicating morphine co-medication as a major contributing factor,⁸ we evaluated retrospectively our own data base, including all infusions of DMSO-PBSC applied in our pediatric center between January 1^st 2002 and December 31^st 2008. We report on 2 incidences of transient loss of consciousness following 131 infusions of DMSO-PBSC.

Case 1

A 17-year old female suffering from recurrent medulloblastoma was admitted for prolonged pancytopenia due to topotecan maintenance therapy. Throughout her medical history, this patient had received intensive therapy, including high-dose chemotherapy and autologous peripheral blood stem cell transplantation, craniospinal irradiation, as well as CNS-directed therapy, namely intrathecal chemotherapy and radioimmunotherapy (Table 1). Thirty minutes after receiving a cryopreserved autologous stem cell boost, the patient initially complained of bilateral loss of vision. Fifteen minutes later, she became unconscious (Glasgow coma scale 3/15). The patient’s cardiorespiratory condition was stable. During transport to emergency CT, she developed one short episode of clonic seizure restricted to both arms, which responded promptly to dexamethasone. Her CT scan revealed no signs of ischemia or bleeding, her EEG displayed moderate dysrhythmia. Cerebrospinal fluid analysis revealed normal lactate, protein and glucose, and no leukocytes or malignant cells. Likewise, serum electrolytes, glucose, LDH were within normal ranges. The patient remained unconscious for approximately two hours. When she woke up, she was disoriented for an additional hour. Three hours after the incident, she had completely recovered, but showed retrograde amnesia for the complete episode. She was discharged the following day without any neurological symptoms. Following the stem cell boost, she recovered from neutropenia and thrombocytopenia after 14 days. Follow-up MRT one month later showed no specific findings.

Table 1.

Patients’ characteristics, medical history, clinical presentation and outcome.

Case 2

A 7-month old male infant diagnosed with fibrosarcoma of his lower back who had responded well to preceding chemotherapy, but still had non-operable residual disease extending into his spinal canal was considered eligible for haploidentical stem cell transplant as consolidation therapy after extensive consultation and written parental consent. Following the standard conditioning regimen of fludarabin, thiotepa and melphalan, he was transplanted with a cryopreserved CD3/CD19-depleted haploidentical stem cell graft from his father. Forty minutes following infusion, he suddenly lost consciousness. His cardiorespiratory condition was stable. Serum electrolytes and blood gases were within normal ranges. Emergency cranial ultrasound revealed no pathology, EEG was normal. In addition, he showed no clinical signs of seizure. One hour after the onset of symptoms, the infant gradually regained consciousness. Two hours after the onset, he had completely recovered.

DMSO is currently the only sufficiently validated reagent for cryopreservation of hematopoietic stem cells; standard practice in most centers is cryoconservation with 10% DMSO.⁹ However, stem cell washing¹⁰ before infusion or cryopreservation with DMSO mixed with hydroxyethyl starch¹¹ may represent alternative approaches. In children, few data on neurotoxicity following infusion of DMSO-PBSC are available.⁸ The incidence in our series of consecutive stem cell infusions was found to be 2/131 (1.5 %). The only other report in children⁸ thus far had implicated morphine co-medication as contributing factor which can be ruled out in our 2 patients. Furthermore, post-thaw viability of both products was within the expected range (78% and 74%, respectively) excluding the assumption that an inadequately high number of dead or apoptotic cells might have contributed to neurotoxicity. Other triggers such as disturbances of electrolytes, glucose or blood gases, intravascular activation of coagulation could be excluded in both patients. The time to onset was within the first 60 min after infusion, in accordance with the majority of reports in adults.^1,2,3,5

Toxicology analysis of DMSO in rodents indicates a dose-dependent increase in neurotoxicity.¹² The first patient who had received only a relatively small amount of DMSO (146 mg/kg), may have been more sensitive to the neurotoxic effects due to her brain tumor and to prior intensive CNS-directed therapy. The second patient, an infant without prior CNS history, developed symptoms at a dose level of 814 mg/kg, which is at the higher end of the applicable dose range.² Certainly, children with a body weight of 10kg and below are at risk for receiving higher dosage of DMSO. As a consequence of the observed toxicities, our institutional policy has changed to keep the maximum volume applied at 4 mL/kg cryopreserved stem cells containing 10% DMSO and to recommend splitting doses on subsequent infusion days if necessary.