key: cord-0005601-kqnlcqpt
authors: Woodard, P; Helton, K; McDaniel, H; Khan, R B; Thompson, S; Hale, G; Benaim, E; Kasow, K; Leung, W; Horwitz, E; Srivastava, D K; Tong, X; Yusuf, U; Cunningham, J M; Handgretinger, R
title: Encephalopathy in pediatric patients after allogeneic hematopoietic stem cell transplantation is associated with a poor prognosis
date: 2004-04-12
journal: Bone Marrow Transplant
DOI: 10.1038/sj.bmt.1704480
sha: d64a92fc3c649b01b132f2dec2e817680792d84c
doc_id: 5601
cord_uid: kqnlcqpt

Encephalopathy is a poorly characterized complication of hematopoietic stem cell transplantation (HSCT). No comprehensive report of encephalopathy exists for children, and the literature contains only a few for adults. We analyzed a large cohort of 405 pediatric patients who underwent allogeneic HSCT during a 10-year period and identified 26 patients (6.4%) who experienced encephalopathy. Identifiable causes of encephalopathy included infection (n=5), single or multiorgan failure (n=4), medication-related complications (n=3), nonconvulsive seizures (n=4), acute disseminated encephalomyelitis (n=2), thrombotic thrombocytopenic purpura (n=2), and stroke (n=1). We were unable to identify the etiology of encephalopathy in five (19%) patients. The prognosis for pediatric patients with encephalopathy was poor: only four (15%) experienced complete neurologic recovery, and 10 (38%) patients experienced partial recovery with residual neurologic deficits. Nine (35%) patients with complete or partial recovery survive long term. A total of 17 patients died; one died of progressive encephalopathy, and 16 died of either relapse of primary disease or toxicity. MRI, CSF analysis including molecular testing for infectious pathogens, and brain biopsy were helpful in obtaining a diagnosis in most of our patients. However, a standardized approach to accurate and timely diagnosis and treatment is needed to improve outcome in these patients.

Encephalopathy after hematopoietic stem cell transplantation (HSCT) is a poorly described complication. Case reports have identified infectious causes of encephalopathy: JC virus, 1,2 central nervous system (CNS) toxoplasmosis, [3] [4] [5] [6] human herpes virus-6 (HHV-6), [7] [8] [9] and a variety of fungal agents. 4, 5 Noninfectious causes of encephalopathy included hypertension, 10 reversible posterior leukoencephalopathy syndrome, 11 and parkinsonism. 12 Encephalopathy can also be caused by cyclosporine, tacrolimus, ganciclovir, dimethyl sulfoxide, and amphotericin, 11 among other medications.

There are few comprehensive reports of encephalopathy in the literature. In one series, 25% of 115 adults with leukemia who underwent HSCT experienced major neurologic complications, including metabolic encephalopathy, seizures, psychiatric symptoms, or a combination of these conditions. 13 The incidence of neurologic complications may be higher after receiving bone marrow from a matched unrelated donor rather than from a matched sibling donor. In another series of 141 adult patients, the most frequently described complication was metabolic encephalopathy, which occurred in 18% of the patients. 14 In another review of neurologic complications of autologous and allogeneic HSCT, 11% of adult patients developed CNS or peripheral nervous system complications due to metabolic encephalopathy, electrolyte disturbances, or hypoxia. 15 Little is known about encephalopathy after allogeneic HSCT in pediatric patients.

All patients were treated in the Hematopoietic Stem Cell Transplant Program at St Jude Children's Research Hospital on treatment protocols approved by the Institutional Review Board between November 1991 and January 2000, inclusive.

HSCT and supportive treatment Following HSCT, neutrophil engraftment was defined as the first occurrence of three consecutive days in which the patient's absolute neutrophil count was X500/mm 3 . Platelet engraftment was defined as the first day the patient's platelet count was X20 000/mm 3 

Patients who received unmanipulated bone marrow grafts from a matched sibling donor also received graftvs-host disease (GVHD) prophylaxis with cyclosporine and short-course methotrexate. Grafts from unrelated donors or partially matched family members were partially T-cell depleted using anti-CD6/CD8 antibodies and complement; patients who received these types of transplants also received GVHD prophylaxis with cyclosporine.

The clinical database of the Stem Cell Transplant Service and International Classification of Disease-Ninth Revision (ICD9) codes were reviewed to identify patients with neurologic complications, encephalopathy, or both after HSCT. Encephalopathy was defined as altered mental status or sensorium persisting 24 h or longer that was not caused by narcotic or sedative medications. Patient medical records were reviewed in detail to assess comorbid conditions, prior neurologic status, pretransplantation conditioning, and donor source. Additionally, relevant diagnostic imaging, laboratory studies, and neurologic examinations were carefully reviewed. All diagnostic testing was performed using standardized laboratory methods. All CNS diagnostic images were reviewed by a single neuroradiologist (KH).

Computed tomography (CT) and magnetic resonance imaging (MRI) of the brains of patients with encephalopathy were reviewed and compared. In most cases, MRIs included T1-and T2-weighted images, diffusionweighted and fluid-attenuated inversion recovery (FLAIR) images. Electroencephalograms (EEGs) were reviewed by one of two neurologists (RBK or ST) Brain biopsy was performed in some patients when imaging revealed focal or biopsy-accessible lesions, when cerebral spinal fluid (CSF) tests were inconclusive, when the patient's status did not improve or worsened, or a combination of these events. Encephalopathy was attributed to Amphotericin B or Cyclosporine when a compatible MRI picture was seen, other diagnostic possibilities were excluded, and/or resolution of symptoms was seen after withdrawal of the medication. Patients were considered to have viral encephalopathy despite negative cultures if brain biopsy material, other site cultures, EEG, or MRI findings were most consistent with viral encephalitis and other causes were excluded.

The Fisher's exact test, Chi-square test, or both were used to determine statistically significant differences between patients with encephalopathy and those without in terms of sex, race, primary diagnosis, donor type, degree of HLA match, and presence of GVHD. The Student's t-test was used to determine whether there was a statistically significant difference in age at the time of HSCT between the two groups.

Encephalopathy developed in 26 of 405 (6.4%) pediatric patients who had received allogeneic HSCT ( Table 1 ). The onset of encephalopathy occurred at a median of 64.5 days after transplantation (range, 0-203 days). The median age at the time of HSCT was 11 years (range, 1-21 years). Four donors were matched siblings, 16 were matched unrelated donors, and six were partially matched family donors. In general, the patients had complex medical problems, with a number of comorbid conditions noted at the onset of encephalopathy (Table 1 ). There was a trend toward older age at the time HSCT being associated with encephalopathy; the median age at HSCT of those who experienced subsequent encephalopathy was 11.2 years, and that of patients who did not was 8.8 years (P ¼ 0.078). There was no significant difference in sex, race, primary diagnosis, donor type, degree of HLA match, or presence or absence of GVHD between patients with or without encephalopathy.

MRI was performed in 22 of the 26 (85%) patients ( Table 2) ; MRI assessment in only one (4.5%) patient was normal. The most frequently seen abnormality was leukoencephalopathy (LE), which occurred in 12 (54.5%) patients ( Figure 1 ). Other abnormalities included the presence of both cerebral atrophy and a subdural hemorrhage (SDH) (n ¼ 1, 4.5%), infarctions (n ¼ 2, 9%), and focal lesions (n ¼ 3, 14%) ( Figure 2 ). Images from three patients showed an unusual pattern of hyperintensity of the pituitary on T1-weighted, T2-weighted, or both MRIs ( Figure 3 ). This pattern has not been previously described. Diagnoses in these patients included parkinsonism caused by Amphotericin B treatment, thrombotic thrombocytopenic purpura (TTP), and uremia.

A total of 17 (65%) patients had an EEG performed; only one (5.9%) study revealed no abnormalities. EEG revealed diffuse slowing in 11 (65%) patients, bilateral frontal slowing in one patient, and combinations of frontal or diffuse slowing and epileptiform discharges in four (24%) patients.

Lumbar punctures were performed on 17 (65%) patients ( Table 2 ). Seven (41%) patients had normal cell counts and levels of glucose and protein. Other CSF studies revealed elevated protein only in four (24%) patients, elevated WBC count only in two (12%) patients, and elevations in both WBC count and protein in three (18%) patients. No patient had a positive CSF culture for bacteria, viruses, or fungi. PCR analysis of the CSF was performed in only five (23%) patients; the studies were negative for Epstein-Barr virus (EBV) (n ¼ 4), herpes simplex virus (HSV) (n ¼ 4), cytomegalovirus (CMV) (n ¼ 3), HHV-6 (n ¼ 3), enteroviruses (n ¼ 2), varicella-zoster virus (VZV) (n ¼ 1), adenovirus (n ¼ 1), and BK virus (n ¼ 1).

Brain biopsies were performed on six (23%) patients. In one patient who had TTP, the brain biopsy was nondiagnostic. In two patients, both histology and culture were positive for Aspergillus species. In two patients, morphologic findings were consistent with acute disseminated encephalomyelitis (ADEM). In one patient, perivascular inflammation and cuffing were detected, which suggested a viral etiology. One biopsy was nondiagnostic.

A definitive diagnosis was made in 21 (81%) patients. Diagnoses included TTP (n ¼ 2), parkinsonism with or without akinetic-mutism caused by Amphotericin B (n ¼ 2), seizures or nonconvulsive status epilepticus (n ¼ 4), viral encephalitis (n ¼ 3), ADEM (n ¼ 2), hyperammonemia/ hepatic failure (n ¼ 2), uremia (n ¼ 1), CNS aspergillosis (n ¼ 2), stroke (n ¼ 1), cyclosporine neurotoxicity (n ¼ 1), and multisystem organ dysfunction (n ¼ 1). These diagnoses were made by characteristic pathologic findings on blood smear, brain biopsy, EEG, or MRI. Viral encephalitis was diagnosed by brain histology in conjunction with isolation of adenovirus in blood and stool cultures, by EEG and MRI findings, and by presence of BK viuria in conjunction with a progressive multifocal leukoencephalopathy-like picture on MRI.

Four of 26 (15%) patients experienced a full neurologic recovery ( Table 2) . Diagnoses associated with complete recovery included ADEM (n ¼ 1), seizures (n ¼ 1), stroke (n ¼ 1), and viral encephalitis (n ¼ 1). Three of these patients are alive and well; one subsequently died of relapse. In total, 10 (38%) patients experienced partial recovery but had residual neurologic sequelae. Diagnoses associated with partial recovery included ADEM (n ¼ 1), CSA toxicity (n ¼ 1), idiopathic causes (n ¼ 2), parkinsonism with TTP (n ¼ 1), CNS Aspergillosis (n ¼ 1), nonconvulsive seizures (n ¼ 3), and uremia (n ¼ 1). Six of these patients survive and three died of other causes. Patients with seizures were treated with anticonvulsants, and patients with idiopathic causes were treated empirically with antivirals, anticonvulsants, and intravenous immunoglobulin. Residual neurologic sequelae included seizures, cognitive impairment, behavior problems, language disorder, and residual confusion. In all, 17 (65%) patients died, 12 (46%) of whom died with no resolution of encephalopathy. The etiology of encephalopathy in these patients was organ failure (hepatic, n ¼ 2; multisystem, n ¼ 1), infection (CNS aspergillosis, n ¼ 2; viral encephalitis, n ¼ 2), TTP (n ¼ 2), parkinsonism (n ¼ 1), or idiopathic causes (n ¼ 3). In all cases but one of viral etiology, death was due to other causes.

Encephalopathy after allogeneic HSCT is associated with a grim prognosis. In our experience, only four of 26 pediatric patients experienced a complete recovery, and only three of those are long-term survivors. A total of 10 patients experienced partial recovery, and six of those remain longterm survivors with residual neurologic sequelae such as learning disabilities or seizures. Nonconvulsive seizures were the most frequently identified cause of encephalopathy in our patients. Four patients in our cohort had ongoing nonconvulsive seizures at the time of EEG; anticonvulsant therapy was either initiated or augmented as a result. EEG assessment is a necessary part of the evaluation of patients with encephalopathy after HSCT as such seizures may not be clinically apparent.

Five patients had encephalopathy related to CNS infection; none were caused by a bacterial pathogen. Two additional patients had encephalopathy related to ADEM, which may be associated with prior viral infection. In patients with CNS Aspergillosis, MRIs showed an area of infarction in one patient and leukoencephalopathy in another. The CSF was normal in one patient and revealed an increased number of red blood cells in the other patient. Both patients required brain biopsy for diagnosis. In three patients with presumed viral causes, two had leukoencephalopathy on MRI and one had multiple focal T2W hyperintensities. CSF was tested in two; one was normal and one showed increased total protein only. Brain biopsy was carried out in one patient and revealed perivascular cuffing, a finding most consistent with a viral process. In the two patients with ADEM, MRI showed leukoencephalopathy in one patient and focal hyperintensity of the temporal lobe in another patient. The CSF revealed elevated WBC with a lymphocytic predominance and elevated total protein in one patient and elevated RBC and total protein in another patient. Both had brain biopsy performed, which revealed perivascular inflammation in one and inclusion bodies consisting of myelin debris in another. These findings suggest that CSF differentials may not be a reliable means of assessing infection in immunocompromised HSCT patients. Further diagnostic considerations in such patients include PCR-based testing of the CSF for infectious pathogens and/or brain biopsy. Indeed, Encephalopathy in pediatric patients after HSCT P Woodard et al molecular testing for a number of viral pathogens is a relatively recent development; therefore, this crucial data is missing for most patients treated during the study period. Some of the patients with idiopathic encephalopathy may have suffered from undiagnosed viral disease. In patients with encephalopathy, CSF samples are now assayed for these pathogens as well as HSV, VZV, BK virus, and JC virus. The list of candidate pathogens for testing will continue to increase as PCR becomes available for additional agents. Six patients had brain biopsies performed with no complications, yielding a diagnosis in five. This methodology was safe and well tolerated and should be considered in the evaluation of encephalopathy after HSCT.

Medication-related encephalopathy occurred in three patients. Cyclosporine-induced encephalopathy and Amphotericin-related Parkinsonism are associated with characteristic MRI findings. MRI should be a routine part of the evaluation of encephalopathy after HSCT.

TTP-related encephalopathy occurred in two patients. This entity is well characterized after HSCT and can generally be detected by review of the peripheral blood smear and review of lactate dehydrogenase, haptoglobin, and reticulocyte count. These tests should be part of the evaluation of encephalopathy after HSCT.

Less frequent causes of encephalopathy included stroke, liver failure, uremia, and multisystem organ failure, all of which were readily apparent at the time encephalopathy developed.

Brain abnormalities were detected in 95% of the patients who had an MRI assessment. The most common abnormality was LE, which is a relatively common finding in children receiving treatment for ALL. 16 In our study, five of 12 patients who had LE also had ALL. The remaining seven patients had AML (n ¼ 3), CML (n ¼ 2), MDS (n ¼ 1), or SAA (n ¼ 1). Therefore, in our small cohort, encephalopathy did not appear to be more common in patients with ALL. At this time, a prospective study at our institution is assessing the incidence of LE and other abnormalities among pediatric patients with ALL; this study should shed more light on this phenomenon.

We detected an unusual pattern of pituitary enhancement on the MRIs of three patients. These patients had TTP, drug-related Parkinsonism, and uremia. The association between encephalopathy and pituitary changes, endocrine abnormalities, or malignant changes remains unclear, because all three patients died before more extensive endocrine or histologic evaluation could be undertaken. This is an interesting finding as this is the point in development (postadolescence) at which pituitary size is maximal. The clinical symptoms in patients are consistent with pituitary apoplexy with headache and mental status changes. Interestingly, these are common presenting symptoms for pituitary apoplexy. 17, 18 Our three patients did not report visual field deficits but were all encephalopathic at the time these symptoms may have developed. All patients were severely thrombocytopenic (platelet range 5000-23 000/mm 3 ) around the time a CNS event could have occurred. It is intriguing that one patient likely developed this in association with severe sepsis with hypotension and uremia. This clinical scenario is similar to that seen with Sheehan's syndrome with an abrupt decrease in perfusion. One patient carried a diagnosis of TTP. One patient has been reported with pituitary apoplexy and immune thrombocytopenic purpura (ITP). 19 Although the mechanism of thrombocytopenia is different with TTP and ITP, the result is severe thrombocytopenia which may predispose a patient to pituitary hemorrhage. A third patient had this MRI finding in association with drug-related Parkinsonism. In the future, the presence of this feature on the MRI of a patient who has received HSCT will indicate the need for additional diagnostic considerations, including endocrinologic evaluation. We recommend that MRIs be performed on all patients showing signs of encephalopathy. Focal lesions on MR images may lead the clinician to the appropriate diagnostic test or change in medication in Figure 4 Algorithm for standardized diagnosis of encephalopathy in pediatric patients who have undergone allogeneic HSCT. The CSF should be cultured for bacterial, fungal, and viral pathogens. PCR testing should include those available viruses such as CMV, EBV, VAV, HHV-6, and adenovirus. If the above-described measures are inconclusive, then brain biopsy for histologic analysis, pathogen culture, and PCR testing should be considered.

Encephalopathy in pediatric patients after HSCT P Woodard et al many cases. Indeed, focal MRI findings led to a brain biopsy in six patients included in this study. Positron-emission tomography (PET) or single-photon emission computed tomography (SPECT) scans were not available in this group of patients. PET or SPECT imaging may have provided additional diagnostic information. SPECT imaging has been shown to be more sensitive than CT or MRI in defining anatomic abnormalities in cases of epilepsy 20,21 and viral encephalitis. [22] [23] [24] Encephalopathy after allogeneic HSCT occurs in approximately 6% of pediatric patients. A uniform approach to diagnosis of encephalopathy is needed. We have attempted to design a diagnostic algorithm based on our experience ( Figure 4) . Although, not complete, this algorithm represents a framework for approaching the treatment of such patients. Standardized testing including MRI, EEG, and molecular studies for infectious pathogens are mandatory. The role of PET/SPECT scans requires evaluation. Brain biopsy may be required if the above measures are inconclusive or if focal lesions are seen on the MRI. Refinements will be made as data become available from prospective studies that include a full array of modern diagnostic tests. It is worth noting that nearly all of the causes of encephalopathy that we identified are treatable if diagnosed early. Therefore, early and aggressive diagnostic measures, in combination with appropriate medical therapy and intensive rehabilitation may improve the prognosis in pediatric patients who experience this devastating complication of allogeneic HSCT.

Multifocal progressive leukoencephalopathy occurring after refractory anemia and multiple infectious disorders consecutive to severe lymphopenia

Successful treatment of progressive multifocal leukoencephalopathy with low-dose interleukin-2

Disseminated toxoplasmosis following T cell-depleted related and unrelated bone marrow transplantation

Opportunistic CNS infection after bone marrow transplantation

Neuropathological findings after bone marrow transplantation: an autopsy study of 180 cases

Diagnosis of toxoplasmosis in bone marrow transplant recipients: comparison of PCR-based results and immunohistiochemistry

Successful treatment of human herpesvirus-6 encephalitis after bone marrow transplantation

Human herpesvirus-6 and -7 infections in children: agents of roseola and other syndromes

Human herpesvirus 6 reactivation and encephalitis in allogeneic bone marrow transplant recipients

Reversible posterior leukoencephalopathy during the treatment of acute lymphoblastic leukemia

Posterior leukoencephalopathy syndrome may not be reversible

Parkinsonism during cyclosporine treatment

Early neurologic complications following allogeneic bone marrow transplant for leukemia: a prospective study

Increased incidence of neurological complications in patients receiving an allogeneic bone marrow transplantation from alternative donors

Neurologic complications of autologous and allogeneic bone marrow transplantation in patients with leukemia: a comparative study

CNS late effects after ALL therapy in childhood. Part 1: Neuroradiological findings in long-term survivors of childhood ALL -an evaluation of the interferences between morphology and neuropsychological performance

Precipitating factors in pituitary apoplexy

Classical pituitary apoplexy: clinical features, management and outcome

Pituitary apoplexy with optic tract oedema and haemorrhage in a patient with idiopathic thrombocytopenic purpura

Brain single photon emission computed tomography (SPECT) in neuropediatrics

Neuroimaging and spectroscopy in children with epileptic encephalopathies

Viral infections of the brain

New onset seizures in HIV-infected patients without intracranial mass lesions or meningitis -a clinical, radiological and SPECT scan study

Reversible frontal lobe syndrome associated with influenza virus infection in children

This work was supported in part by Cancer Center Support (CORE) Grant P30 CA 21765 from the National Cancer Institute and by the American Lebanese Syrian Associated Charities (ALSAC). We express our appreciation to the nurses, nurse practitioners, and physician assistants involved in the care of these patients and to the Department of Scientific Editing for review of this manuscript.