Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 88

Neurologic complications of bone marrow transplantation TULIO E. RODRIGUEZ* Bone Marrow Transplantation Program, Loyola University Medical Center and Department of Medicine, Loyola University Chicago, Stritch School of Medicine, Chicago, IL, USA

HISTORICAL BACKGROUND Although the detrimental effects of ionizing radiation exposure to humans have been known since the early part of the 20th century, the major advances in the field of bone marrow transplantation originated shortly after the detonation of the first atomic bombs at the conclusion of World War II. It became clear that human bone marrow is very sensitive to radiation exposure (Takeshima, 1953). Analysis of peripheral blood from survivors revealed the presence of leukopenia and, in some instances, even neutropenia. Fevers and a variety of infections were observed as well. In what could be considered seminal reports in the development of the bone marrow transplantation technique, Jacobson et al. (1949) demonstrated that shielding the spleen of a mouse could prevent death. Lorenz et al. (1951) went further by showing in animal models that protection against radiation could be accomplished by infusing bone marrow intravenously. The existence of self-renewing cells in the bone marrow of mice was demonstrated some years later (Till and McCulloch, 1963). The evidence suggested that the benefit of bone marrow transplantation was mediated by the transfer of hematopoietic stem cells from one individual to another. Initial attempts at performing bone marrow transplantation in humans were reported in the 1950s. However, effectiveness was poor and survival was short-lasting. Two young girls with refractory acute leukemia received a myeloablative preparative regimen consisting of total body irradiation (TBI) followed by syngeneic bone marrow infusion. Prior to the bone marrow transplantation, one of the patients developed generalized convulsions during her salvage chemotherapy requiring intubation to protect her airways and phenytoin for control of convulsions. Her cerebrospinal fluid

(CSF) was normal. After transplantation, a brief period of improvement was observed in both patients; however, both patients died from relapsed disease a few weeks later. It was not until the late 1960s that the first successful allogeneic transplantation was performed. Subsequently, Thomas et al. (1977) reported on 100 patients with acute leukemia. He demonstrated that some patients could achieve long-term survival after TBI and high-dose chemotherapy, followed by marrow graft from an HLA-identical sibling. Sources of marrow grafts from donors other than HLA-matched identical siblings, including nonrelated donors and autologous bone marrows, have been found to be acceptable alternatives for selected diseases (Speck et al., 1973; Dicke et al., 1979; Hansen et al., 1981). The increasing success of hematopoietic stem cell transplantation (HSCT) led to its acceptance as a standard therapeutic option for several malignant as well as nonmalignant disorders. Preparative regimens for HSCT evolved from single dose TBI and fractionated TBI with high-dose chemotherapy, to reduced-intensity regimens consisting of moderate doses of radiation and chemotherapy, to nonmyeloablative regimens in which the intention is to provide an aggressive immunosuppressive therapy that allows the engraftment of hematopoietic stem cells with minimal cytotoxicity to the bone marrow of the recipient. The number of autologous hematopoietic stem cell transplantations in the US has steadily increased since 2000. Allogeneic transplants from unrelated donors surpassed the number of allogeneic transplants from related donors after 2006 (Pasquini and Wang, 2011). The major contributing factors to this trend are the growth of unrelated donor databases and improvements in the management of unrelated donor transplant recipients. The most common indications for hematopoietic

*Correspondence to: Tulio E. Rodriguez, M.D., Cardinal Bernardin Cancer Center, 2160 S. First Avenue, Maywood, IL 60153, USA. Tel: þ1-708-327-3157, Fax: þ1-708-327-3219, E-mail: [email protected]

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stem cell transplantation in the US are multiple myeloma and lymphoma, accounting for 60% of all hematopoietic stem cell transplantations. Multiple myeloma continues to be the most common indication for autologous and acute myeloid leukemia for allogeneic transplantation. Other indications for hematopoietic stem cell transplantation include acute lymphoid leukemia, myelodysplasia, and myeloproliferative disorders, chronic leukemias, and nonmalignant blood disorders such as aplastic anemia and immunodeficiencies.

NEUROLOGIC COMPLICATIONS IN HEMATOPOIETIC STEM CELL TRANSPLANTATION Although bone marrow transplantation has been recognized as an effective therapy for malignant and nonmalignant blood disorders, the modality has also been associated with side-effects and complications. Among these adverse events, neurologic complications emerged as an important and frequent source of treatmentrelated morbidity and mortality. Neurologic complications have been described in approximately 11–59% of patients undergoing all types of HSCT, contributing to morbidity or mortality in 60% of the recipients of allogeneic transplantation, and are the principal cause of death in 10–15% (Garrick, 2000; Uckan et al., 2005). Moreover, neuropathologic findings have been reported in more than 90% of autopsies studied. The most frequent findings are subarachnoid hemorrhage, intraparenchymal hemorrhages, fungal infections, Wernicke’s encephalopathy, microglial nodular encephalopathy, and neurotoxoplasmosis (Bleggi-Torres et al., 2000). The survival of patients who died from complications related to central nervous system (CNS) abnormalities appears to be shorter compared to those who died from nonneurologic complications. Fungal infections and toxoplasmosis are also more frequently observed in patients who died from neurologic complications after HSCT.

Neurologic complications in allogeneic HLA-matched transplantation Among allogeneic transplant recipients, organ failure and infections are higher after HLA-matched unrelated donor transplants (Pasquini and Wang, 2011). The incidence of neurologic complications appears to correlate with the degree of HLA disparity and the risk status of the underlying disease. A retrospective analysis compared 39 patients who were recipients of HLA-matched unrelated marrow to 102 patients who were recipients of HLA-matched sibling marrow (49 with high-risk leukemia, myelodysplastic syndromes, or aplastic anemia and 53 with standard risk leukemia, myelodysplastic syndromes, or aplastic anemia) demonstrated an incidence

of neurologic complications of 44%, 27%, and 11%, respectively (p < 0.005) (de Brabander et al., 2000). The most frequent complication was metabolic encephalopathy occurring in 18% of patients. Infections of the CNS developed in 9% of patients and cerebrovascular lesions in 3%. Another retrospective study analyzed 165 pediatric patients who underwent HSCT (Weber et al., 2008). Some 67% of the patients underwent an allogeneic transplantation and 33% received autologous transplants. Neurologic complications were observed in 24% of the patients. Among the 40 patients with neurologic symptoms, six patients were recipients of autologous transplants, 11 had an HLA-matched sibling transplant, and 23 received an unrelated HLA-matched marrow graft. The majority of the patients who were recipients of autologous HSCT and who developed neurologic complications showed mainly nonrepetitive symptoms lasting less than 24 hours. However, 58% of those patients with progressive neurologic symptomatology, abnormal magnetic resonance imaging (MRI) findings, and/or abnormal CSF results were recipient of unrelated HLA-matched HSCT. The main complications observed were related to infections, drug toxicity, cerebrovascular events, and relapse of the underlying disease. The higher incidence of neurologic complications in recipients of unrelated HLA-matched grafts is most likely associated with the higher frequency of morbidity and prolonged immune reconstitution in comparison to HLA-matched sibling HSCT and the recipients of autologous HSCT.

Neurologic complications in reducedintensity allogeneic hematopoietic stem cell transplantation For many years, the terms myeloablative, nonmyeloablative, and reduced-intensity conditioning regimens have been a source of confusion in the bone marrow transplant community. In preparation for allogeneic hematopoietic stem cell transplantation, most patients receive chemotherapy alone or in combination with radiotherapy with the intention of reducing tumor burden and to suppress the immune system in order to allow engraftment of the stem cells (Vriesendorp, 2003). The term myeloablation applies to the administration of conditioning regimens at doses which will not allow autologous hematologic recovery (Bacigalupo et al., 2009). There is a direct correlation between transplant-related mortality after myeloablative regimens and increasing patient age. Therefore, in order to reduce toxicity and allow older patients to undergo allogeneic hematopoietic stem cell transplantation, less intense regimens known as nonmyeloablative have been developed.

NEUROLOGIC COMPLICATIONS OF BONE MARROW TRANSPLANTATION Understanding and defining the intensity of conditioning regimens becomes critically important for an adequate interpretation of published data and for the development of prospective trials. The Center for International Blood and Marrow Transplant Research proposed defining conditioning regimens in three categories: myeloablative conditioning, reduced-intensity conditioning, and nonmyeloablative conditioning. Myeloablative conditioning regimens are combinations of agents which are expected to produce profound pancytopenia and myeloablation within 1–3 weeks from administration; pancytopenia is long-lasting, usually irreversible, and in most instances fatal, unless hematopoiesis is restored by hemopoietic stem cell infusion. Nonmyeloablative, on the other hand, is a regimen which will cause minimal cytopenia and does not require stem cell support. Finally, reduced-intensity conditioning is a regimen that does not fall into either category. Therefore, it may cause profound cytopenias which may be prolonged. It does require stem cell support and, although an autologous recovery is possible, the prolonged recuperation time will significantly increase transplant-related morbidity and mortality. Nonrelapse mortality associated with reduced-intensity regimens is lower compared to myeloablative conditioning regimens (Valca´rcel et al., 2005). However, this should not lead to a false sense of security since reduced-intensity regimens are still associated with significant incidence of complications, including graft-versus-host disease, opportunistic infections, organ toxicity, and neurologic complications. Some 191 consecutive patients who underwent a fludarabine-based reduced-intensity regimen were analyzed to determine the incidence and characteristics of neurologic complications after reduced-intensity regimen (Barba et al., 2009). Patients received fludarabine 150 mg/m2 in combination with busulfan 8–10 mg/kg for myelogenous malignancies; with melphalan 70– 140 mg/m2 for multiple myeloma and lymphoid malignancies; with cyclophosphamide 120 mg/kg for solid tumors; or with cyclophosphamide 120 mg/kg combined with low-dose TBI 2 Gy for chronic myelogenous leukemia. The determination to utilize a reduced-intensity regimen was based on age older than 50 years, severe comorbidities, or prior heavy pretreatment. Phenytoin prophylaxis was given to all patients receiving busulfan-based conditioning at a starting loading dose of 300 mg every 6 hours the day before, followed by 300 mg/day until 24 hours from the last dose of busulfan. Twenty-seven patients developed a total of 31 neurologic complications. The CNS was involved in 74% of the cases, whereas 26% involved the peripheral nervous system (PNS). Patients were receiving immunosuppressive drugs such as ciclosporin, prednisone, mycophenolate mofetil, and sirolimus

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in 81% of 31 neurologic events. No correlation between neurologic complications and type of conditioning, type of donor, graft-versus-host prophylaxis regimens, previous autologous HSCT, underlying disease or patients’ comorbidities was identified. Toxic-metabolic encephalopathy was the main type of CNS complication followed by infectious meningoencephalitis. Drug-related toxicity was directly responsible for 35% of the CNS complications. Neurologic complications more often presented as a focal syndrome, as, for example, dysarthria and hemiparesis. Neurologic complications manifesting as CNS abnormalities more often presented within the first 100 days after transplantation in contrast to PNS abnormalities, where 87% were observed after that period. Overall survival was lower in patients who developed CNS complications compared to those who did not.

ENCEPHALOPATHIES AND HEMATOPOIETIC STEM CELL TRANSPLANTATION Usually, encephaloathy does not refer to a specific disease, but rather to a syndrome of global brain dysfunction that is initiated by a disease process extrinsic to the brain. Depending upon the etiology and severity of the triggering factor, the presentation may range from mild mental confusion to severe and potentially fatal manifestations such as dementia, seizures, and coma.

Metabolic encephalopathy in hematopoietic stem cell transplantation Frequent causes of metabolic encephalopathy affecting recipients of hematopoietic stem cell transplantation are sepsis and the use of sedative-hypnotic drugs (Openshaw and Slatkin, 1999). A correlation between sepsis and brain dysfunction has been recognized for centuries. Encephalopathy related to sepsis can be classified into early encephalopathy or late encephalopthy (Papadopoulos et al., 2000). Early encephalopathy characteristically presents prior to multiorgan failure and cannot be explained by hypoxia, hypotension, renal or hepatic dysfunction. This is in contrast to late septic encephalitis in which the presence of multiple organ failure, hypotension, and other systemic phenomena characterize the syndrome. The syndrome is most likely mediated by inflammatory mediators affecting the brain or by cytotoxic response by the brain cells to those inflammatory mediators (Papadopoulos et al., 2000). The incidence of septic encephalitis is difficult to estimate. Patients who develop sepsis are commonly under sedative hypnotic drugs, neuromuscular blocking agents, or requiring mechanical ventilation, making the assessment of encephalopathy difficult. The incidence

1298 T.E. RODRIGUEZ of sepsis increases in patients who receive mechanical infection and guide an effective antimicrobial therapy. ventilation for 1 week or longer (Bolton and Young, However, pursuing a microbiological diagnosis must 2007). Frequently, the complications of sepsis-related not delay the administration of antibiotics and resuscitaencephalopathy in mechanically ventilated patients are tion of a patient with septic shock. Frequently, the cause either overlooked or misdiagnosed. Stupor is attributed of infection may not be obvious. Nevertheless, timely to sedation, weaning difficulties to diaphragmatic debridement of infected tissues is associated with fatigue, and limb weakness to catabolic myopathy. Other improved outcomes. Therefore, the identification of common concomitant complications such as hypoxemia, occult sources of infection becomes critically important. hypotension, renal or hepatic failure, and metabolic Hemodynamic stability should be pursued aggressively abnormalities manifested as hyperglycemia or electroand fluid replacement to correct hypovolemia should lyte disturbances might complicate even further the recnot be delayed. Hematology patients with septic shock ognition of sepsis-related brain dysfunction. If are at high risk of respiratory failure even in the absence successful weaning is accomplished, further subsequent of a primary respiratory infection. Restoration of oxysymptoms might be unmasked, as, for example, gen delivery is of paramount importance. The goal of impaired cognition, difficulty dressing, eating, and risrespiratory management should be to maintain the airing from the bed or toilet seat, difficulty standing and way patency, correct hypoxia, and ensure adequate venwalking, shortness of breath, and fatigue. This clinical tilation. A trial of noninvasive respiratory ventilation picture is sometimes attributed to “deconditioning” through bilevel positive airway pressure mask is an and a prolonged stay in a rehabilitation center may be acceptable intervention. Intubation and mechanical vennecessary. tilation should be avoided unless respiratory failure is The clinical presentation of sepsis-related encephaimminent. For patients requiring more than 48 hours lopathy usually includes impaired attention, orientation, of mechanical ventilation, sedation with propofol results concentration, and writing (Young et al., 1990). In severe in significantly fewer ventilator days compared with cases, the patient might develop delirium and coma. benzodiazepines (Carson et al., 2006). It is also advisable Focal findings like those found in structural abnormalito adopt “the least sedation” method of briefly discontities of the brain are usually absent. Asterixis, tremors, nuing sedation each day and determining the level of and multifocal myoclonus found in encephalopathy alertness. The importance of prompt establishment of resulting from liver, kidney, or endocrine gland failures antibiotic therapy, even if empirically directed, cannot are also infrequent in sepsis. The diagnosis of sepsisbe overemphasized. There is a clear correlation between related encephalopathy requires the exclusion of other initiation of antibiotic therapy and patient outcome. possible etiologies such as drug-induced encephalopaKumar et al. (2006) demonstrated that the administrathy, hypoxemia, hypotension, withdrawal of sedatives tion of an antimicrobial therapy against a suspected or or opioids, electrolyte disturbances, uremia, alcohol proven cause of infection within the first hour of docuwithdrawal, and Wernicke encephalopathy (Iacobone mented hypotension in critical care patients, including et al., 2009). The development of Wernicke encephalop6.8% with neutropenia, was associated with a survival athy, which may result from long fasting, hyperemesis, rate of 79.9%. After 6 hours, each additional delayed and total parenteral nutrition, all of which are common hour was associated with an average decrease in survival in hematopoietic stem cell transplant patients, might be of 7.6%. Delaying antibiotic therapy is particularly detdifficult for clinicians to recognize. rimental for patients with neutropenia. Another retroWernicke encephalopathy is a disorder affecting prispective analysis of patients with monomicrobial marily the alcoholic population; however, autopsy study bloodstream infections demonstrated that delayed antihas shown that approximately 23% of patients with the biotic therapy among patient with neutropenia was assocondition are nonalcoholics (Lindboe and Loberg, 1989). ciated with significant increased mortality when Computed tomography (CT) head scans and CSF compared to non-neutropenic patients (Lin et al., 2008). examination are unremarkable in septic encephalopathy, Encephalopathy related to liver dysfunction, renal but the EEG shows abnormalities consistent with a difinsufficiency, metabolic disturbances, respiratory failfuse encephalopathy (Bolton and Young, 2007). ure, drug overdose, hypnotic drugs or sedative withEvidence-based guidelines for the management of drawal, Wernicke encephalopathy, and alcohol sepsis in recipients of hematopoietic stem cell transplanwithdrawal are the main differential diagnoses of tation are limited. Nevertheless, advances in the treatsepsis-related encephalopathy. The management of ment of severe sepsis have improved mortality rates these patients should be based mainly on controlling (Cohen and Drage, 2011). Obtaining a microbiological probable infections with prompt initiation of antibiotic diagnosis through body fluid cultures or tissue identifitherapy, managing organ system failure through ventilacation is important in order to identify the source of tion support while avoiding, as far as possible, invasive

NEUROLOGIC COMPLICATIONS OF BONE MARROW TRANSPLANTATION ventilator interventions, and aggressive maintenance of metabolic homeostasis, while avoiding neurotoxic drugs.

Treatment-induced encephalopathy in hematopoietic stem cell transplantation TOTAL BODY IRRADIATION Several chemotherapy agents and TBI utilized as part of the conditioning regimen for hematopoietic stem cell transplantation have been implicated in the development of encephalopathy. The analysis of the clinical course of 302 consecutive patients who underwent allogeneic HSCT for malignant and nonmalignant hematologic disorders demonstrated that TBI at a dose of 1200 cGy was an independent risk factor for the development of CNS complications within the first 100 days posttransplantation (Siegal et al., 2007). Other risk factors identified were the use of imatinib prior to transplantation, myeloablative therapy, receiving methotrexate and ciclosporin as graft-versus-host disease prophylaxis, and female gender. Mortality due to graft-versus-host disease was more frequently observed in patients who developed CNS complications within 100 days post-transplantation compared to those who did not. No correlation between CNS complications and TBI or increased mortality was observed after 100 days post-transplant. Posterior reversible encephalopathy syndrome (PRES) was observed in 23% of the patients analyzed in this study. The development of PRES was also associated with a shorter survival at day 100 post-transplantation (Fig. 88.1).

BUSULFAN Busulfan is a bifunctional alkylating agent frequently used in myeloablative and reduced-intensity conditioning regimens. Systemic exposure to busulfan is typically expressed as area under the plasma concentration-time curve or average concentration at steady state. Several investigators have identified relationships between busulfan concentration at steady state and outcome of patients undergoing hematopoietic stem cell transplantation (McCune et al., 2000; Andersson et al., 2002). Traditionally, the drug was administered every 6 hours for a total of 16 doses. With the availability of the intravenous formulation, several investigators have adopted twice daily and once daily dosing. Busulfan readily crosses the blood–brain barrier (BBB) and has been implicated in the development of neurotoxicity in hematopoietic stem cell transplant patients. Seizures and electroencephalographic changes as diffuse polyspikes and spike-and-wave discharges followed by slowing of background activity intermixed with diffuse slow waves and isolated d and y bursts have

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been described (La Morgia, 2004). Neurotoxicity does not appear to be increased by once daily administration when the drug is infused over a 3 hour period. Wernicke-like encephlopathy after autologous bone marrow transplantation has been described with the use of busulfan (Majolino et al., 1990). Other compounds with similar structure to busulfan have been associated with CNS complications including encephalopathy. Hepsulfam is a bisulfamic ester which is similar in structure to busulfan and is believed to act as a bifunctional alkylator inducing both DNA-DNA and DNA-protein cross-links (Larson et al., 1995). The dose-limiting toxicity is CNS toxicity with increasingly severe encephalopathy. Uncomfortable paresthesias were avoided by infusing the drug over a longer period of time. Busulfan might cause encephalopathy by an indirect mechanism. The drug has been implicated in a higher incidence of hepatic veno-occlusive disease and centrilobular hepatic degeneration following bone marrow transplantation compared to nonbusulfancontaining regimens. Some investigators believe that therapeutic drug monitoring of busulfan should be performed to maximize the likelihood of engraftment and minimize the risk of toxicity and relapse in HSCT patients receiving the busulfan-based preparative regimens (McCune et al., 2000). Busulfan has been also implicated in the development of seizures during the conditioning regimen. The seizures are generally tonic-clonic in character. For many years, phenytoin was frequently used to prevent and treat busulfan-induced seizures. However, there are concerns over possible pharmacokinetic interactions between both drugs that might accelerate the metabolism of busulfan. The use of benzodiazepines to prevent busulfan-induced seizures does have clinical data support, especially clonazepam and lorazepam (Eberly et al., 2008). Obviously, the sedative property of these drugs with the potential for confusion and disorientation should be kept in mind. The second-generation antiepileptic drug levetiracetam possesses the characteristics of optimal prophylaxis for busulfan-induced seizures, and early data of its efficacy are promising. However, myelosuppression is a characteristic of this drug that might not be suitable for some selected hematopoietic stem cell transplant recipients.

IMMUNOSUPPRESSIVE DRUGS ASSOCIATED WITH NEUROTOXICITY IN HEMATOPOIETIC STEM CELL TRANSPLANTATION The utilization of immunosuppressive drugs as part of the transplant process is mainly restricted to recipients of allogeneic stem cell transplantation. The calcineurin

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Fig. 88.1. Kaplan–Meier plots of overall survival in patients with and without central nervous system complications (CNS) (within 100 days post-transplant) and posterior reversible encephalopathy syndrome (PRES). In comparison to their counterparts, survival at 1 year was significantly reduced in patients who developed CNS complications in the first 100 days post-transplant (28% versus 72%, p < 0.0001) (A), and PRES (27% versus 67%, p < 0.0001) (B). (Reproduced from Siegal et al., 2007.)

inhibitors ciclosporin and tacrolimus are immunosuppressive drugs used extensively in allograft recipients. These drugs show large interindividual pharmacokinetic variation and are associated with severe adverse effects, including nephrotoxicity and neurotoxicity (van Rossum et al., 2010). Ciclosporin-A and tacrolimus (FK506) are known as calcineurin inhibitors because of their capacity of preventing the calcineurin-mediated dephosphorilation and subsequent activation of nuclear factor of activated T cell. The activated nuclear factor of activated T cell then is not translocated into the nucleus, therefore, preventing the upregulation of the expression of interleukin 2, which, in turn, stimulates the growth and differentiation of T cell response (Yamashita et al., 2000).

Ciclosporin is a cyclic undecapeptide obtained from the fermentation of two fungi, Trichoderma polysporum and Cilindrocarpum lucidum (Laupacis et al., 1982). It is extremely lipophilic and has been used widely as an immunosuppressant drug post-transplantation of solid organs and bone marrow. Although the drug penetration into the brain is restricted by the BBB, neurotoxicity is often associated with its utilization. The data suggest that ciclosporin-A can cause disruption of the BBB by decreasing transendothelial electrical resistance leading to impairment of brain endothelial barrier function (Dohgu et al., 2010). The development of neurotoxicity associated with calcineurin inhibitors carries a dismal prognosis. It is

NEUROLOGIC COMPLICATIONS OF BONE MARROW TRANSPLANTATION 1301 associated with significant morbidity and mortality donor transplants, and 16% of unrelated HLA-matched despite initial resolution of the symptomatology after donor transplants. Frequent clinical manifestations are discontinuation of the drug. A retrospective analysis nonspecific and include altered mental status, delirium, of 30 recipients of allogeneic HSCT for hematologic and depression of sensorium (Openshaw and Slatkin, malignancies who had radiologic and clinical findings 1999). Meningeal or lateralizing neurologic signs are compatible with calcineurin inhibitor neurotoxicity demnot necessarily present. The absence of fever does not onstrated that the initial clinical manifestations of the exclude the possibility of an infection being responsible adverse reaction consist of altered mental status for neurologic complications. (70%), seizures (50%), confusion (40%), visual changes Patterns of infections in recipients of allogeneic (30%) including cortical blindness, ataxia (20%), severe HSCT can be allocated into four stages: the pretransheadaches (16%), disorientation (13%), hemiparesis plant period; the pre-engraftment period, from day and/or aphasia (10%). Neurologic symptoms resolved 0 to day 30 post-HSCT; The post-engraftment period, promptly after discontinuation of dose adjustment of from day 31 to day 100 post-HSCT; and the late postthe calcineurin inhibitor in 70% of the patients while transplantation period, >100 days post-HSCT. 30% developed irreversible neurotoxicity despite Infections during the pretransplant period are related discontinuation of the drug. After interruption of the to the underlying disease and how competent the immune calcineurin inhibitor therapy, 54% of patients who develsystem of the patient is at that time. Patients with neoplasoped neurotoxicity before day 100 post-transplantation tic conditions associated with hypogammaglobulinemia developed graft-versus-host disease even though might develop infections due to encapsulated bacteria. alternative immunosuppressive therapy was initiated. Patients with acute myeloid leukemia might develop invaMortality was observed in 80% of the patients approxisive fungal infections due to prolonged neutropenia. Aermately 30 days after the development of neurotoxicity. obic Gram-negative bacilli, such as Klebsiella species and Most patients died of graft-versus-host disease (54%), Escherichia coli are frequently observed during this relapse disease (20%), or multiorgan failure/thrombotic period (Sable and Donowitz, 1994). However, most infecthrombocytopenic purpura (20%). The rest died from tious processes will be local infections and associated veno-occlusive disease. The majority of patients in this severity and mortality rates are low. Neurologic complicastudy achieved resolution of their symptoms after distions are not frequent during this period. continuation or dose adjustment of the drug. However, The pre-engraftment period is characterized by the half of those patients developed recurrence of their presence of neutropenia and disruption of mucosal barsymptomatology after reintroduction of the drug or an riers due to cytotoxic chemotherapy of radiation therapy. alternate calcineurin inhibitor. The high incidence of The use of central venous catheters is also a contributing graft-versus-host disease and subsequent mortality factor for the development of infections. The predomiwas not surprising considering that patients identified nant infections during this phase of transplantation are for this analysis were those with significant neurotoxicbacterial, occurring in 15–50% of recipients of bone marity and incapable of tolerating without interruption one row transplant (Sable and Donowitz, 1994). In the 1980s, of the most effective preventive therapies against graftGram-negative bacteria were a frequent source of morbidversus-host disease. Perhaps, knowing that graft-versusity and mortality in cancer patients, including recipients of host disease is one of the leading causes of mortality in HSCT. However, with the frequent use of prophylaxis patients who developed calcineurin inhibitor neurotoxicbased on quinolones and common utilization of indwelling ity, efforts should be directed at identifying alternate catheters, Gram-positive organisms became an important effective regimens for this vulnerable group of patients. source of infections during this period. Sepsis-related encephalopathy may be observed during this period. Invasive fungal infections are observed during this INFECTIONS ASSOCIATED WITH period as well and are one of the most lethal complicaNEUROTOXICITY IN HEMATOPOIETIC tions. The most common pathogens affecting recipients STEM CELL TRANSPLANTATION of HSCT are Candida species and Aspergillus species. Infections in hematopoietic stem cell transplant patients Invasive candidiasis is the most frequent mycosis affectare frequent causes of morbidity and mortality. As ing hematologic and hematopoietic stem cell transplant expected, the transplant-related mortality associated recipients. The wide use of fluconazole prophylaxis in with infections is directly proportional to the degree of HSCT patients is responsible for a higher incidence of immunosuppression and time of immune reconstitution species other than Candida albicans, as, for example, of the recipient. Infections as the main cause of mortalCandida glabrata and Candida krusei. The CNS may ity in HSCT transplant patients occur in approximately be involved by disseminated infection. The initial symp8% of autologous HSCT, 12% of HLA-matched sibling toms of meningitis secondary to Candida are

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indistinguishable from those related to bacterial infections (Henao and Vagner, 2011). The initial symptoms of acute meningitis related to Candida are indistinguishable from those produced by bacterial infections. A negative CSF does not rule out the infection, especially in the presence of pleocytosis. Involvement of the CSF by Candida species is relatively infrequent. On the other hand, Aspergillus species account for 30–50% of CNS infections caused by an invasive fungal infection. Fluconazole has no activity against Aspergillus species and the echinocandins, such as caspofungin, mycafungin, and anidulafungin, are mainly fungistatic against this organism. Current guidelines recommend using triazoles, e.g., voriconazole, for the management of invasive fungal infections due to Aspergillus species (CDC, 2000). Infections due to Zygomycetes have emerged more frequently due to improvements in survival of transplant patients and the frequent use of fungal prophylaxis using fluconazole and voriconazole (Fig. 88.2). Zygomycosis has been found postmortem in up to 8% of patients with leukemia and 2%

of patients after allogeneic hematopoietic stem cell transplantation. Viral infections may be observed in the preengraftment period. These include human simplex virus and human simplex virus 2. The postengraftment period is characterized by resolution of the neutropenia and discontinuation of the protective isolation imposed on most patients during their conditioning regimen and pre-engraftment period. During this time, graft-versus-host disease and its therapy become important sources of morbidity and mortality. Immunosuppressive therapy increases the incidence of fungal infections and viral infections. Bacterial infections are less frequent. A significant association between pretransplant viral status, defined as a higher number of positive herpes group viral serologies in the recipient before transplantation, and the development of neurologic complications has been observed. There is also a significant association between cytomegalovirus seropositivity and the incidence of neurologic complications (Rubin et al., 2005). The late post-transplantation period is characterized by a relative immune reconstitution compared to prior transplant phases. Nevertheless, the development of graft-versus-host disease and its management may predispose patients to fungal, viral, and even bacterial infections due to the functional asplenia that characterizes the disorder.

NEUROLOGIC COMPLICATIONS ASSOCIATED WITH CHRONIC GRAFT-VERSUS-HOST DISEASE

Fig. 88.2. MRI of a central nervous system zygomycosis infection. Gadolinium ring enhancement lesion documented in the left frontal lobe. Invasive fungal infection was diagnosed by left frontal craniotomy in this 61-year-old man with a history of non-Hodgkin lymphoma and autologous hematopoietic stem cell transplantation who was requiring intermittent steroid therapy due to refractory idiopathic thrombocytopenic purpura post-transplantation.

Chronic graft-versus-host disease is a complication of allogeneic HSCT that is frequently preceded by acute graftversus-host disease. Most cases are diagnosed within the first year post-transplantation. Chronic graft-versus-host disease most often involves the skin and mouth, but almost any other organ system can be involved. Correct diagnosis is critical so that appropriate therapy can be started promptly to minimize symptoms and prevent irreversible organ damage (Lee and Flowers, 2008). First-line therapy is based on corticosteroids with or without calcineurin inhibitors (Grauer et al., 2010). The use of steroids is associated with significant morbidity and mortality including opportunistic infections, steroid-induced myopathy, and steroid-induced encephalopathy. Other neurologic complications associated with chronic graft-versus-host disease are polymyositis and immune-mediated neuropathies, such as Guillain–Barre´ syndrome (GBS) and myasthenia gravis (MG).

NEUROLOGIC COMPLICATIONS OF BONE MARROW TRANSPLANTATION

CONCLUSION Neurologic complications in hematopoietic stem cell transplant recipients are important causes of treatment-related morbidity and mortality. More than half of the patients undergoing hematopoietic stem cell transplantation will experience a neurologic complication. The incidence relates to the degree of HLA disparity and the risk status of the underlying disease. Recipients of alternate stem cell donors appear to be at a higher risk compared to recipients of HLA-matched sibling donors. The diagnosis of neurologic complications in hematopoietic stem cell transplant patients could be elusive. Patients undergoing stem cell transplantation are frequently under sedative hypnotic drugs or neuromuscular blocking agents. Other common non-neurologic complications such as hypoxemia, hypotension, renal or hepatic failure, and metabolic abnormalities, might complicate even further the recognition of neurologic dysfunction. Therefore, clinicians should keep a high level of suspicion for neurologic complications especially if the patient is the recipient of an alternate HLA-matched donor transplant. Common risk factors for the development of neurologic complications should be kept in mind. Some of the common risk factors are sepsis, TBI, or busulfan-containing regimen, the use of calcineurin inhibitors, graft-versus-host disease, prolonged immunosuppression, and infections. Prompt neurologic assessment and initiation of antibiotic therapy are of paramount importance in preventing morbidity and mortality of hematopoietic stem cell transplant recipients.

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