Bone Marrow Transplantation (2000) 25, 79–83 2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt Central nervous system dysfunction as the first manifestation of multiple organ dysfunction syndrome in stem cell transplant patients B Gordon1, E Lyden2, J Lynch2, S Tarantolo3, ZS Pavletic3, M Bishop3, E Reed3, A Kessinger3 and W Haire3 Departments of 1Pediatrics, 2Preventive and Societal Medicine, and 3Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA Summary: Organ system dysfunction is a frequent complication of hematopoietic stem cell transplantation. Single and multior- Development of CNS dysfunction in the setting of hema- gan dysfunction may be due to the culmination of an uncon- topoietic stem cell transplant (HSCT) has been pre- trolled inflammatory response to some initial event, viously shown to predict for subsequent second organ mediated by an as yet incompletely understood interplay of dysfunction and death. In this paper, we describe the cytokines, complement, and the coagulation system. In the characteristics of this isolated CNS dysfunction, and its setting of acutely ill non-transplant patients, this has been relationship to multiple organ dysfunction syndrome termed the systemic inflammatory response syndrome.1 (MODS) after HSCT. Twenty-one of 186 patients This syndrome has been well described in patients with undergoing HSCT developed CNS dysfunction as their trauma or severe infection,1–3 but has only recently been first organ dysfunction a mean of 22.8 ± 0.9 days after recognized in patients undergoing HSCT. the start of the preparative regimen. Compared with The occurrence of single organ system dysfunction in 137 patients who developed no organ dysfunction, the post-transplant period has been shown to predict for patients presenting with CNS dysfunction were more subsequent development of multiple organ dysfunction and likely to have undergone allogeneic HSCT (P = 0.001) death. McDonald and coworkers4 showed that development and to have received a total body irradiation-based regi- of hepatic dysfunction, manifesting as veno-occlusive dis- men (P = 0.001), and were less likely to have been trans- ease, predicted for subsequent multiorgan failure and death. planted for lymphoma (P = 0.008). Patients who We have previously shown that development of pulmonary developed CNS dysfunction were more likely to die than dysfunction predicted for and preceded multiorgan failure those with no organ dysfunction (P Ͻ 0.001). Of the 21 in another group of patients undergoing HSCT.5 Although patients who developed CNS dysfunction, 48% resolved the first organ involved differed in these two reports, the their dysfunction by a mean of 4.6 days later without combined data support the contention that single organ progression to second organ dysfunction, and 90% of dysfunction is not a disorder confined to one organ, but a these patients survived to day 100. Fifty-two percent of manifestation of a more generalized abnormality. patients with CNS dysfunction progressed to second The latter study also assessed the development of CNS organ dysfunction (pulmonary or hepatic) a mean of 5.5 dysfunction, defined as lethargy or confusion, and showed days later, and only 36% survived to day 100 (P = 0.02). a significant correlation between CNS dysfunction and sub- The patients who progressed to second organ dysfunc- sequent second organ dysfunction and death. As part of tion and those who did not were not different in terms a larger study of organ dysfunction following HSCT, we of type of HSCT (allogeneic vs autologous), stem cell identified a group of patients who developed evidence of source (blood vs bone marrow), age, diagnosis or pre- mental status changes in the absence of any other detectable parative regimen. Development of CNS dysfunction in organ dysfunction. Herein, we describe the characteristics the setting of HSCT, as with other organ dysfunctions of this isolated CNS dysfunction, and its relationship to (such as hepatic veno-occlusive disease), probably rep- multiple organ dysfunction syndrome (MODS) after HSCT. resents an early manifestation of a systemic disorder predisposing for MODS, increasing the risk of trans- plant-related mortality. Early systemic therapies Methods directed at modulating this systemic disorder are prob- ably indicated. Bone Marrow Transplantation (2000) 25, Patients 79–83. Keywords: CNS dysfunction; multiple organ dysfunc- This analysis was based on 186 adult patients (mean age tion; stem cell transplant 44.0 years, range 19–70) undergoing autologous or allo- geneic HSCT at the University of Nebraska Medical Center over an 18-month period between December 1995 and May Correspondence: Dr B Gordon, Department of Pediatrics, University of Nebraska Medical Center, 982168 Nebraska Medical Center, Omaha, NE 1997. Patient characteristics are shown in Table 1. Various 68198-2168, USA preparative regimens were used, based on diagnosis. How- Received 7 May 1999; accepted 27 July 1999 ever, 180 of 186 patients (97%) were prepared with one of CNS dysfunction and MODS after HSCT B Gordon et al 80 Table 1 Demographic information at least 2 h on the same day. (3) Renal dysfunction: defined as serum creatinine greater than 1.5 mg/dl. (4) Hepatic Type of transplant (%) veno-occlusive disease: defined as either of two clinical and Autologous bone marrow 33 (18) laboratory syndromes: (a) bilirubin Ͼ1.8 mg/dl and Autologous peripheral blood cell 99 (53) Allogeneic bone marrow 19 (10) abdominal pain and weight gain of more than 5% over 7 Allogeneic peripheral blood cell 35 (19) admission weight; or (b) bilirubin Ͼ2.0 mg/dl and two of hepatomegaly, ascites, and weight gain of more than 5% Allogeneic 54 (29) 8 Autologous 132 (71) over admission weight. Bone marrow 52 (28) Peripheral blood cell 134 (72) Statistics Disease (%) All data are expressed as means ± standard error. Analysis Non-Hodgkin’s lymphoma 68 (37) of variance (ANOVA) and t-tests were used to compare Hodgkin’s disease 11 (6) continuous variables. Fisher’s exact test was used to com- Breast carcinoma 51 (27) р Acute leukemia 20 (11) pare categorical variables. A P value of 0.05 was Chronic myeloid leukemia 19 (10) considered significant. Other 17 (9) Results six different regimens (Table 2). The preparative regimen Incidence and predisposing factors for CNS dysfunction included total body irradiation in 58 cases (31%). For the purpose of the analysis of medication intake, Of the 186 patients studied, 21 (11%) developed CNS dys- patients who developed CNS dysfunction as their first function as their first organ dysfunction, and 28 developed organ dysfunction were matched to control patients without a different organ dysfunction (either pulmonary or hepatic) organ dysfunction, based on HSCT type, diagnosis, and as their first organ dysfunction. Time to development of days post-HSCT. Total daily dose and total daily dose per first organ dysfunction was no different between these two ± body weight were recorded for CNS active medications groups (mean 22.8 0.9 days after start of the preparative ± (morphine, meperidine, diphenhydramine, lorazepam) on regimen for CNS dysfunction vs 21.1 1.1 days for other the day prior to, and the day of development of CNS dysfunctions). One hundred and thirty-seven patients dysfunction. developed no organ dysfunction (Figure 1). Comparing the 21 patients who developed CNS dysfunc- tion as their first organ dysfunction with the 137 patients Transplant practices who developed no organ dysfunction, patients developing Because adverse events occurring after HSCT were postu- CNS dysfunction as the first dysfunction were more likely = lated to be related to the toxicity of the preparative regi- to have undergone allogeneic HSCT (P 0.001) and to mens, the first day of the preparative regimen is considered have been prepared with a TBI-based preparative regimen = day 1 in this report. (P 0.001), and were less likely to be undergoing HSCT for lymphoma (P = 0.008). Development of CNS dysfunc- tion as a first dysfunction did not correlate with age or with Adverse events the source of stem cells (bone marrow vs peripheral blood). Patients were monitored daily, beginning on the first day of In a multivariate analysis utilizing the same factors, allo- the preparative regimen, for the following adverse clinical geneic stem cell source was the only statistically significant events: (1) Central nervous system (CNS) dysfunction: predictor of CNS dysfunction. Patients undergoing allogeic defined by decrease in Folstein mini-mental status exam6 by greater than four points from the baseline. Since inter- 186 Patients observer variability was ±2 points, this range approached 2 standard deviations. (2) Pulmonary dysfunction: defined by the presence of hypoxia (oxygen saturation of less than no organ dfxn CNS dfxn as other dfxn as 90% using finger oximetry) on two occasions separated by n = 137 1st organ dfxn 1st organ dfxn (22.8 ± 0.9 days) (21.1 ± 1.1 days) n = 21 n = 28 Table 2 Preparative regimens progressed to no 2nd BEAC 50 (27%) 2nd organ dfxn organ dfxn CY/thioTEPA 18 (10%) n = 11 n = 10 CY/thioTEPA/HU 35 (19%) CVB 19 (10%) other non-TBI 6 (3%) alive day 100 alive day 100 alive day 100 alive day 100 n = 4 n = 7 n = 9 n = 1 CY/TBI 34 (18%) CY/VP16/TBI 24 (13%) Figure 1 Distribution and outcome of 186 patients undergoing HSCT, with regard to development of CNS dysfunction as first organ dysfunction. Bone Marrow Transplantation CNS dysfunction and MODS after HSCT B Gordon et al 81 HSCT were more likely to develop CNS dysfunction (P dysfunction 10 patients (48%) resolved their dysfunction a value = 0.0013, odds ratio = 4.83 with confidence interval mean of 4.6 ± 5.8 days (range 1–21) later without pro- of 1.86 to 12.50). gression to second dysfunction. 90% of these patients sur- Patients who developed CNS dysfunction as their first vived to day 100.