Central Nervous System Dysfunction As the First Manifestation of Multiple

Home , Organ dysfunction

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 transplant-related mortality. Early systemic therapies Methods directed at modulating this systemic disorder are probably 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 allogeneic 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 dysfunction 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 dysfunction 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. Of the 21 patients who developed CNS organ dysfunction were matched to control patients without dysfunction, 11 (52%) progressed to second organ dysfunc- organ dysfunction, based on HSCT type, diagnosis, and tion (either pulmonary or hepatic) a mean of 5.5 ± 5.7 days days post-HSCT. There were no consistent or clinically rel- after the CNS dysfunction (range 0–19). Only 36% evant differences in doses (total daily dose and total daily survived to day 100 (P = 0.02). dose per kilogram body weight) of CNS active medications While patients receiving allogeneic stem cell transplants (morphine, meperidine, diphenhydramine, lorazepam) or who were prepared with TBI-based regimens were at a given to patients who developed CNS dysfunction vs higher risk of developing CNS dysfunction, there were no patients who did not develop CNS dysfunction (Table 3). readily identifiable factors which predicted for progression For example, on the day prior to development of CNS dys- to MODS and death. Progression to second organ dysfunc- function, patients who would subsequently develop CNS tion was not correlated with type of HSCT (allogeneic vs dysfunction received marginally more diphenhydramine autologous), stem cell source (bone marrow vs peripheral (50 ± 35 mg vs 20 ± 7 mg, P = 0.08) but less lorazepam blood), age, diagnosis or use of a TBI-containing prepara- (1 ± 0.4 mg vs 2 ± 1.5 mg, P = 0.03). There were no statisti- tive regimen. cally significant differences in medication intake occurring on the day of development of CNS dysfunction. A larger proportion of patients who would subsequently develop Discussion CNS dysfunction received lorazepam on the day prior to dysfunction (13/21 vs 6/21, P = 0.06) or on the day of Changes in mental status (defined as changes in the Folstein development of organ dysfunction (11/21 vs 4/21, P = 0.05) mini-mental status examination) are a relatively frequent (Table 3). However, since the patients with dysfunction occurrence after high-dose therapy and stem cell rescue. In received less total dose on that day than did patients with- our series, these changes occurred as the first organ dys- out dysfunction, the relevance of this is unclear. There were function in 11% of patients. Nonetheless, occurrence of this no statistically significant differences in the proportion of dysfunction carried an increased risk of transplant-related patients receiving morphine or diphenhydramine. mortality. More than 50% progressed to second organ dysfunction (either pulmonary or hepatic), and only 36% sur- Outcome of patients with CNS dysfunction vived to day 100. Neurologic complications of high-dose therapy and stem Although the transplant-related mortality was low overall cell transplantation have been reported previously.9–14 Our in this patient population, patients who developed CNS dys- report differs in several important ways from these previous function were more likely to die before day 28 than were series. Encephalopathy has been a frequent finding in earl- those with no organ dysfunction (P Ͻ 0.02). Furthermore, ier reports, occurring in 30–40% of patients. However, patients who developed CNS dysfunction as their first dys- these studies have defined neither the mechanism for detec- function had a similar mortality to patients who developed tion of an altered mental status nor the threshold for con- a different dysfunction (P = 0.68). sidering the altered mental status abnormal. It is also Patients with CNS dysfunction who did not develop unclear from these studies if patients were examined for second organ dysfunction were significantly more likely to alterations in mental status prospectively and in a uniform survive to day 100 than were those who did develop second manner, raising the possibility of under-diagnosing the dis- organ dysfunction. Of the 21 patients who developed CNS order. Our study used a tool for detection of alterations in

Table 3 Relationship between use of CNS active medications and development of CNS dysfunction

Dose (mg) t-test Proportion of patients ␹2 receiving drug

No dfxn CNS dfxn No dfxn CNS dfxn day prior to CNS dfxn morphine 31 ± 27 25 ± 17 NS 10/21 15/21 NS lorazepam 2 ± 1.5 1 ± 0.4 P = 0.03 6/21 13/21 P = 0.06 diphenhydramine 20 ± 750± 35 NS 5/21 2/21 NS day of CNS dfxn morphine 30 ± 23 24 ± 16 NS 9/21 14/21 NS lorazepam 3.5 ± 3.8 2.3 ± 1.8 NS 4/21 11/21 P = 0.05 diphenhydramine 19 ± 925± 1 NS 2/21 4/21 NS

Total daily dose (in mg; mean ± s.d.) of CNS active medications, and proportion of patients receiving medication for patients who developed CNS dysfunction (dfxn) vs patients who did not develop CNS dysfunction. There were too few patients receiving meperidine for statistically relevant compari- son.

Bone Marrow Transplantation CNS dysfunction and MODS after HSCT B Gordon et al 82 mental status that is standardized and whose validity and tion5 and hepatic VOD.5,16 CNS dysfunction is also associa- limitations have been established.15 The definition of the ted with increased platelet transfusion requirement, as are degree of alteration of mental status that was considered pulmonary and renal dysfunctions,17 and hepatic abnormal was also precisely and prospectively defined in VOD.4,17,18 Furthermore, in this and other series addressing our patient population. The tool for detection of encepha- organ dysfunction in general,5 isolated CNS dysfunction lopathy was applied prospectively on a daily basis, minim- has outcomes identical to those seen in patients’ pulmonary izing the likelihood that patients with mild alterations or hepatic dysfunctions: an increased risk of subsequent would be missed. This mechanism of defining and detecting development of other organ dysfunctions, and death. In the alterations in mental status minimizes the likelihood of series focusing on neurologic complications of transplan- underdiagnosis and provides a basis for duplication in other tation, encephalopathies are most often said to occur along transplant centers. with pulmonary, renal or hepatic dysfunction.10–13 Further, Previous descriptions of neurologic complications of development of ‘CNS complications’ was often followed marrow transplantation have taken into consideration all by multiorgan failure and death. Antonini and coworkers12 neurologic complications seen in all patients, including found a significant decrease in probability of survival at day those with concurrent liver, renal and/or lung disease. In 90 among patients with ‘significant CNS complications’. many of these patients a diagnosis of metabolic encepha- Because CNS, pulmonary and hepatic dysfunctions during lopathy due to these organ dysfunctions was made. transplantation all have the same correlates (lower levels Unfortunately, a precise link between the liver, lung or of antithrombin III and protein C, and a higher number of kidney dysfunction and the altered mental status is diffi- platelet transfusions) and the same outcomes (higher inci- cult to establish with certainty in an individual patient. dence of subsequent development of the other organ dys- The prognosis of these individuals obviously includes the functions and death) and generally have no alternative outcome of their underlying organ dysfunctions, as well as their neurologic status. Our study describes the out- explanation we postulate that these organ dysfunctions are come of patients whose CNS dysfunction was their first individual components of a larger disorder, similar to that detected organ dysfunction. These patients were free of seen in other populations of critically ill patients where it evidence of significant renal, hepatic or pulmonary dys- is termed the multiple organ dysfunction syndrome 19,20 function at the time the altered mental status was (MODS). This syndrome of gradual and sequential fail- detected. Consequently, the patients described in our ure of virtually all organ systems is felt to be a systemic study provide a more accurate depiction of the clinical disorder, not confined to a one organ system, that is the outcome of patients with isolated CNS dysfunction in end result of an incompletely understood interplay between whom no other coexistent organ dysfunction can be numerous cytokines, the complement cascade, the hemo- foundtocontributetoanadverseclinicaloutcome. static system, the kinin-generating pathways, vascular Finally, no previous analysis of CNS dysfunction during endothelial cells and other unrecognized elements induced transplantation has considered the effect of CNS-active by a wide spectrum of noxious stimuli from infections to medication. Clinically, isolated alterations in mental status thermal burns. In marrow and blood transplantation, the in patients without other organ dysfunction are often preparative regimen is felt to be the initial stimulus to the ascribed to medication effects. Our analysis suggests this development of this syndrome,21 with the possibility of is unlikely for two reasons. The first is the analysis of the non-bacteremic infections and other phenomena (such as use of CNS depressants during and prior to the develop- platelet transfusion) adding to the intensity of the original ment of CNS dysfunction. On the day prior to the detection stimulus. As a component of this systemic and highly lethal of CNS dysfunction, the patients destined to develop this syndrome, the subsequent development of other compli- complication used a mean of 1 mg less lorazepam, but 30 cations and high mortality of isolated CNS dysfunction can mg more diphenhydramine. On the day that CNS dysfunc- be readily understood. tion was detected, there was no difference in the doses of The implications of this data to the clinical practice of these medications used by patients with and without this blood and marrow transplantation are potentially signifi- complication. The second is the high likelihood of death cant. The Folstein MMSE is an easy instrument to use with conferred by the detection of CNS dysfunction. It is minimal training, has good intra- and interobserver repro- unlikely that the alteration of mental status induced by these ducibility,6,15 does not require unusual technology to per- medications can account for a 64% mortality over the sub- form, and is not expensive to use. It is a good tool to use sequent 3 months, a mortality rate significantly higher than for the purpose of early identification of patients at risk for that of patients without detectable CNS dysfunction. other complications and death. At the very least, patients Rather than a medication effect, we postulate that iso- developing CNS dysfunction are not candidates for cess- lated CNS dysfunction occurring in patients after high-dose ation of close, active clinical monitoring and intense sup- therapy and HSCT represents the initial manifestation of a portive care. At most, these patients may then be candidates systemic disorder (MODS), which is a risk factor for sub- for interventions designed to alter the progression of single sequent morbidity and mortality. Isolated CNS dysfunction organ dysfunction to MODS, such as use of antithrombin has similar systemic correlates to other isolated organ dys- III concentrate.22–25 Such studies need to be conducted, as functions. We have previously shown that development of well as studies designed to detect patients at risk for devel- CNS dysfunction is associated with decreases in circulating anticoagulants protein C and antithrombin, in a manner opment of CNS dysfunction and MODS prior to its actual identical to that seen in patients with pulmonary dysfunc- recognition clinically.

Bone Marrow Transplantation CNS dysfunction and MODS after HSCT B Gordon et al 83 References 14 Furlong TG, Gallucci BB. Patterns of occurrence and clinical presentation of neurological complications in bone marrow 1 Knaus WA, Draper EA, Wagner DP, Zimmerman JE. Prog- transplant patients. Cancer Res 1994; 17: 27–36. nosis in acute organ-system failure. Ann Surg 1985; 202: 15 Anthony RC, LeResche L, Niaz U et al. Limits of the ‘Mini- 685–693. Mental State’ as a screening test for dementia and delirium 2 Faist FN, Baue AE, Dittmer H, Heberer G. Multiple organ among hospital patients. Psychol Med 1982; 12: 397–408. failure in polytrauma patients. J Trauma 1983; 9: 775–787. 16 Faioni EM, Krachmalnicoff A, Bearman SI et al. Naturally 3 Goris RJ, te Boekhorst TP, Nuytinck JK, Gimbrere JS. Mul- occurring anticoagulants and bone marrow transplantation: tiple-organ failure. Arch Surg 1985; 20: 1109–1115. plasma protein C predicts the development of venocclusive 4 McDonald GB, Hinds MS, Fisher LD et al. Veno-occlusive disease of the liver. Blood 1993; 81: 3458–3462. disease of the liver and multiorgan failure after bone marrow 17 Gordon BG, Tarantolo SR, Ruby EI et al. Increased platelet transplantation: a cohort study of 355 patients. Ann Int Med transfusion requirement is associated with multiple organ dys- 1993; 118: 255–267. functions in patients undergoing hematopoietic stem cell trans- 5 Haire WD, Ruby EI, Gordon BG et al. Multiple organ dys- plantation. Bone Marrow Transplant 1998; 22: 999–1003. function syndrome in bone marrow transplantation. J Am Med 18 Rio B, Andreu G, Nicod A et al. Thrombocytopenia in veno- Assoc 1995; 274: 1289–1295. occlusive disease after bone marrow transplantation or chemo- 6 Folstein MF, Folstein SE, McHugh PR. ‘Mini-mental state’. therapy. Blood 1986; 67: 1773–1776. A practical method for grading the cognitive state of patients 19 Bone RC. Immunologic dissonance: a continuing evolution in for the clinician. J Psychiatr Res 1975; 12: 189–198. our understanding of the systemic inﬂammatory response syn- 7 McDonald GB, Sharma P, Matthews DE et al. Veno-occlusive drome (SIRS) and the multiple organ dysfunction syndrome. disease of the liver after bone marrow transplantation. Diag- Ann Int Med 1996; 125: 680–687. nosis, incidence and predisposing factors. Hepatology 1984; 20 Haire WD. The multiple organ dysfunction syndrome in can- 4: 116–122. cer patients undergoing hematopoietic stem cell transplan- 8 Jones RJ, Lee KS, Beschorner WE et al. Venocclusive disease tation. Semin Thromb Hemost 1999; 25: 223–237. of the liver following bone marrow transplantation. Transpl 21 Haire WD, Stephens LC, Ruby EI. Systemic inﬂammatory 1987; 44: 778–783. response syndrome (SIRS), sepsis and organ dysfunction in 9 Wiznitzer M, Packer RJ, August CS, Burkey ED. Neurologic bone marrow transplantation (BMT). Blood 1996; 88 (Suppl. complications of bone marrow transplantation in childhood. 1): 255b (3748). Ann Neurol 1984; 16: 569–576. 22 Dickniete G, Paques EP. Reduction of mortality with 10 Patchell RA, White CL, Clark AW et al. Neurologic compli- antithrombin III in septicemic rats: a study of Klebsiella pneu- cations of bone marrow transplantation. Neurol 1985; 35: moniae induced sepsis. Thromb Haemost 1993; 69: 98–102. 300–306. 23 Phillips TF, Staricco A, Assarian GS et al. Antithrombin 11 Graus F, Saiz A, Sierra J et al. Neurologic complications of administration protects from experimental DIC. Blood 1983; autologous and allogeneic bone marrow transplantation in 62 (Suppl. 1): 308a. patients with leukemia: a comparative study. Neurol 1996; 46: 24 Haire WD, Stephens LC, Ruby EI. Antithrombin III (AT3) 1004–1009. treatment of organ dysfunction during bone marrow transplan- 12 Antonini G, Ceschin V, Morino S et al. Early neurologic com- tation (BMT): results of a pilot study. Blood 1996; 88 (Suppl. plications following allogeneic bone marrow transplant for 1): 458a. leukemia: a prospective study. Neurol 1998; 50: 1441–1445. 25 Morris J, Harris RE, Hashmi R et al. Antithrombin-III for the 13 Snider S, Bashir R, Bierman P. Neurologic complications after treatment of chemotherapy-induced organ dysfunction follow- high-dose chemotherapy and autologous bone marrow trans- ing bone marrow transplantation. Bone Marrow Transplant plantation for Hodgkin’s disease. Neurol 1994; 44: 681–684. 1997; 20: 871–878.

Bone Marrow Transplantation