Brain, Vol. 124, No. 5, 1043-1051,
May 2001
© 2001 Oxford University Press
Stroke after bone marrow transplantation
Frequency, aetiology and outcome
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1 Division of Pulmonary and Critical Care Medicine and the 2 Departments of Neurology and Neurological Surgery, University of Washington, Seattle, Washington, 3 Department of Neurology, Wayne State University, Detroit, MI and 4 Division of Pulmonary and Critical Care Medicine, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
Correspondence to:
William M. Coplin, MD, Departments of Neurology and Neurological Surgery, Wayne State University School of Medicine, 4201 St Antoine 8D-UHC, Detroit, MI 48201, USA E-mail: wcoplin@med.wayne.edu
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Abstract |
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Few data exist on the frequency, aetiology and outcome of cerebrovascular complications of bone marrow transplantation (BMT). We reviewed all patients undergoing BMT at the Fred Hutchinson Cancer Research Center, Seattle, Wash., USA (a large referral institution) over 3 years. We reviewed ICD-9 (International Classification of Diseases) codes for ischaemic stroke, seizure, intracranial haemorrhage and brain infection. Using standardized forms, we paid detailed attention to clinical features and demographics, oncological diagnosis, conditioning regimens, neurological history, comorbidities, time from BMT to ictus, stroke subtype, radiological and pathological features, and outcomes. We identified 36 patients with stroke from 1245 patients who had BMT (2.9%) over 3 years. These patients' median age was 35 (range 5–60, interquartile range 25–45) years. The most common causes of stroke were intracranial haemorrhage related to thrombocytopenia (38.9%) and infarction or haemorrhage secondary to fungal infection (30.6%). Twenty-five patients (69.4%) died from their stroke; none survived without disability. Using a logistic regression model, we found that neither demographic (e.g. age, gender) nor clinical (e.g. oncological diagnosis, type of BMT, time of stroke after BMT) factors predicted outcome. Stroke occurs relatively frequently (incidence almost 3%) after BMT, has a relatively high frequency of infection-triggered events, has a neurological outcome not easily predicted from available data and is often fatal.
stroke; cerebrovascular disease; bone marrow transplant; infection; epidemiology
BMT = bone marrow transplantation; FHCRC = Fred Hutchinson Cancer Research Center; GOS = Glasgow Outcome Scale; TBI = total body irradiation
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Introduction |
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A variety of neurological complications after bone marrow transplantation (BMT) have been reported (Wiznitzer et al., 1984
; Patchell et al., 1985; Davis and Patchell, 1988; Mohrmann et al., 1990; Diener et al., 1991; Gordon et al., 1991, 1993; Reece et al., 1991; Nakamura et al., 1992; Furlong and Gallucci, 1994; Patchell, 1994; Snider et al., 1994; Yuh et al., 1994; Ferster et al., 1995; Abboud et al., 1996; Gallardo et al., 1996; Graus et al., 1996; Moore et al., 1997; Walters et al., 1995). Neurological complications are an important contribution to the morbidity and mortality after BMT. Stroke has been noted anecdotally following BMT and several of the above-referenced series reported relatively small numbers of cerebrovascular complications. These series have not explored systematically the occurrence of strokes and their aetiology, diagnosis and prognosis after BMT. We therefore evaluated the frequency, causal factors and outcome after stroke complicating BMT to further clarify their clinical, radiological, laboratory and prognostic features. We hypothesized that BMT patients, because of thrombocytopenia and leukopenia, would have more haemorrhagic and infectious strokes and that stroke would prove to be a more frequently fatal diagnosis than stroke in the general population. |
Design and methods |
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Patients
We reviewed complete medical records of consecutive patients undergoing BMT at the Fred Hutchinson Cancer Research Center (FHCRC), Seattle, Wash., USA, over a 3-year period. Patients were identified from ICD-9 (International Classification of Diseases) diagnosis codes for stroke, cerebrovascular accident, cerebral artery occlusion, cerebrovascular disease, transient cerebral ischaemia, cerebral arteritis, intracerebral or intracranial haemorrhage, subdural or subarachnoid haemorrhage, hemiplegia, seizure, meningitis and intracranial abscess. These diagnoses were reviewed to overcome possible miscoding and ensure case detection. This review was sanctioned by a confidentiality agreement signed with the FHCRC Institutional Review Board.
Inclusion and exclusion criteria
Before conducting the review, we defined stroke as rapidly developing, new, unremitting focal or global loss of cerebral function lasting >24 h, with no apparent cause other than vascular origin (Hatano, 1976; Bamford et al., 1991). Haemorrhagic stroke was diagnosed if there was evidence of haemorrhage on radiography or pathology examination; otherwise the stroke was defined as ischaemic.
Exclusion criteria were meningoencephalitis or abscess without coexisting cerebral infarction or haemorrhage, traumatic subdural or epidural haematoma, seizure with Todd's paralysis and transient ischaemic attack.
Data collection
During the study period, 1245 patients underwent BMT at FHCRC. There were 181 patients with one of our initial diagnosis codes whose charts were reviewed. We identified 36 patients meeting our definition for having had a stroke while in the hospital after BMT (Fig. 1).
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We collected data on standardized abstraction forms, paying specific detailed attention to abstracting systematic and standardized clinical data (where available): demographic data; dates of BMT, ictus and hospital discharge or death (whichever came first); neurological history and examination; haematological diagnosis prompting BMT; comorbidities; conditioning regimen; microbiology results; stroke subtype (Adams et al., 1993
); results of ultrasonographic (e.g. carotid duplex, echocardiography) studies and pathology/autopsy results; and neurological outcome. Laboratory results included complete blood and platelet counts, prothrombin time and partial thromboplastin time. Abnormal values were defined by our laboratory normal values, as follows: white blood cell count <3500/mm3; neutrophil count <500/mm3; platelet count <100 000/mm3; prothrombin time >15 s; and partial thromboplastin time >45 s. These data (e.g. blood pressure, platelet count) were recorded categorically according to these threshold values; the exact values were not recorded per se.
Neuroradiological investigations
We reviewed CT and MRI reports systematically and one of the authors, with knowledge of the clinical features, reviewed the actual films when available. Cerebral angiography results were also systematically reviewed.
Clinical assessment
We assigned the ordinal Glasgow Outcome Scale (GOS) score (Jennett and Bond, 1975) retrospectively to all patients. Rather than use other widely used simple scales to judge outcome in retrospect (e.g. the Rankin scale), we chose to use the GOS because it includes death as a possible outcome and because it was not always possible from the chart review to determine a patient's ability to cope with his or her deficit in activities of daily living. A single investigator performed the data abstraction and determined the GOS. Outcome was defined as the GOS score at hospital discharge or death, whichever came first. The study defined a good outcome (GOS 4–5) as being able to follow commands, having comprehensible speech and being able to walk and feed oneself and a poor outcome (GOS 1–3) as being severely disabled, vegetative or dead.
The protocol for BMT at FHCRC involves having all out-of-town patients remain locally in the Seattle metropolitan area during the initial post-BMT outpatient period for follow-up; thus, if they require rehospitalization in the immediate post-BMT period, this is likely to occur at FHCRC.
Statistical analysis
Clinical ordinal data are presented as medians and ranges. We used descriptive statistics to analyse our cohort and non-parametric methods to assess the relationship of outcome with potential factors related to outcome. We used the 
2 test for heterogeneity (corrected for small numbers) to assess the association between the stroke rate with the oncological diagnosis or type of BMT. A logistic regression model was used to assess the contribution of specific demographic or clinical variables to neurological outcome.
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Results |
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Frequency, epidemiology, demographics and haematological diagnoses
For the 36 patients (2.9% of 1245), the median age was 35 years (range 5–60 years) and 20 (55.6%) were female. The diagnoses prompting BMT were varied (Table 1
), as were the types of BMT (Table 2). Most patients in the cohort received a conditioning regimen (pretransplant antineoplastic chemotherapy) of standard doses of cyclophosphamide (cyclophosphamide) and total body irradiation (TBI) (Table 3). Table 1 shows highly statistically significant differences in the stroke rate between the different oncological diagnoses (P < 0.001). Similarly, there was significant heterogeneity according to type of BMT in Table 2 (P = 0.02).
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Clinical features
Among the 36 patients, 28 (77.8%) had no prior neurological history. The other eight patients' histories included seizure (n = 3, 8.3%), headaches (n = 3, 8.3%) and a history of stroke predating the present hospitalization (n = 2, 5.6%). Other prior neurological disorders included symptomatic central nervous system, leukaemia relapse, meningoencephalitis from an Ommaya reservoir-related infection and a subdural hygroma (n = 1 each, 2.8% each). Two patients had more than one of the above neurological conditions.
Strokes occurred a median of 28 days after BMT (range 3–470 days, interquartile range 15–83 days). Fifteen patients (41.7%) had seizures as part of the clinical presentation of their cerebrovascular disease. Twenty-five of the 36 patients died in hospital (69.4%). The other GOS scores were severe disability for seven patients (19.4%) and independent with mild or moderate disability in four (11.1%). There were no patients with GOS 5 (no disability) or 2 (vegetative); patients either survived with disability or died. Factors related to outcome were analysed. Outcome (GOS) was not significantly related to age, gender, diagnosis prompting BMT, type of transplant or timing of the stroke after BMT.
Four vignettes are presented to represent the spectrum of cerebrovascular disease; other cases are summarized in Table 3
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Vignette 1
A 47-year-old woman, who had refractory anaemia with excess myelogenous blasts, received a matched-related BMT from her sister. She had a history of treatment-related hypertension. Having engrafted (normal platelet and other blood counts), on day 23 after BMT she developed lethargy with global aphasia and right-sided hemiparesis with hemianopia. Her CT showed a left internal capsular haemorrhage with drainage into the ventricle and hydrocephalus. She received 15 days of external ventricular drainage; thereafter, she had a CSF leak for 6 days which resolved. She was discharged alert with right-sided hemiparesis and hemianopia. She had predominantly non-fluent dysphasia. Her hydrocephalus had resolved.
Vignette 2
A 45-year-old woman had a 12-year history of Hodgkin's disease (stage IVB). Her bone marrow had been harvested 2 years previously. She underwent an autologous BMT after preparation with busulfan, cyclophosphamide and TBI. She had refractory thrombocytopenia but not disseminated intravascular coagulation or other disorder of platelet consumption. On day 24 after BMT, she had rapid progression to coma followed by cardiopulmonary arrest. CT showed a right temporo-parieto-occipital subarachnoid haemorrhage with falcine and tentorial blood. On day 29 she worsened and her CT showed hypodensity within the right middle cerebral artery territory. The echocardiogram was unremarkable. She died on day 33 from malignant cerebral oedema resulting from the infarction. Necropsy additionally revealed midline cerebral and cerebellar haemorrhages, without evidence of aneurysm, infection or malignancy.
Vignette 3
A 26-year-old man underwent BMT for acute myelocytic leukaemia, after conditioning with cyclophosphamide/TBI. On day 98 after BMT he developed severe right temporal headache with the onset of left hemiparesis a day later. Platelet count was normal (in accordance with our previously set threshold value.) His CT showed a right parieto-occipital infarction. Echocardiogram and carotid duplex were both normal. He underwent brain biopsy on post-BMT day 101 and died the next day. The biopsy agreed with the necropsy findings of disseminated Aspergillus fumigatus in the brain, kidneys and prostate.
Vignette 4
A 37-year-old man underwent BMT, from an unrelated donor, for chronic myelogenous leukaemia after cyclophosphamide/TBI conditioning. On day 14 after BMT, he developed fever, dysarthria and dyscoordination. His CT showed bilateral inferior cerebellar haemorrhages. Examination and cultures diagnosed an oral source of Torulopsis glabrata, for which he was treated. Echocardiogram was normal. He was discharged home on day 32 with residual dysarthria and dyscoordination.
Radiological features
Thirty-two out of 36 patients (88.9%) had brain imaging after the index event. All four patients who did not have brain indexing died quickly after their ictus, presumably before imaging could be performed. Thirty-one of the 32 patients received a CT scan as their initial diagnostic investigation. This scan was diagnostic for all but two of the patients with an intracranial haemorrhage. One patient, who had an intracranial haemorrhage, presented with seizures and underwent MRI as the initial diagnostic study of choice. In three patients, the initial CT scan was non-diagnostic and subsequent MRI revealed the index stroke. A total of eight patients underwent MRI. For two of these patients, the diagnosis of stroke was based on the MRI when the CT did not show changes indicative of stroke (von Kummer, 1995, 1996).
Aetiology
The aetiologies of stroke are shown in Table 4. The three most common stroke mechanisms were, in descending order of frequency: non-infectious intracranial haemorrhage (predominantly intracerebral, secondary to thrombocytopenia), infectious infarction (predominantly fungal) and non-infectious infarction (usually supratentorial).
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Discussion |
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Stroke occurs more frequently in patients who have undergone BMT than in the general population, with an incidence of ~3% in the present study. Haemorrhagic and infectious causes of stroke were over-represented in our cohort, and the outcome of stroke after BMT was worse (69.4% mortality) than that seen in the general population. The age-matched incidence of stroke in the State of Washington is ~1% (Price et al., 1993
; Toole et al., 1993). Until relatively recently, BMT was reserved as a `last-ditch' treatment for haematological and some solid malignancies, but it is now being employed more frequently and earlier in the course of treatment, particularly for the leukaemias and preleukaemic states. Cerebral dysfunction occurs for a variety of reasons after BMT, including, but not limited to, the following: as a sequela of antineoplastic drugs and radiation used to treat the index malignancy (Diener et al., 1991); as an adverse event after the chemoprophylaxis or treatment of graft-versus-host disease (with e.g. cyclosporin A or methotrexate) (Irle et al., 1985; Lind et al., 1989; Gallardo et al., 1996); metabolic (e.g. hepatic veno-occlusive disease) or infectious causes (Kay et al., 1983; Wiznitzer et al., 1984; Graus et al., 1996), seizures (Walters et al., 1995); recurrence of the index malignancy (Wiznitzer et al., 1984; Furlong and Gallucci, 1994). Being extra-axial (and so not a stroke per se), acute subdural haemorrhage has also been noted as a complicating central neurological event that may be treated conservatively despite its apparent gravity (Nakamura et al., 1992; Graus et al., 1996).
Other investigators have described the occurrence of stroke after BMT (Wiznitzer et al., 1984; Gordon et al., 1991, 1993; Furlong and Gallucci, 1994; Gallardo et al., 1996) and noted (compared with stroke in the general population) the over-representation of haemorrhages (Walters et al., 1995; Gallardo et al., 1996; Graus et al., 1996). Mechanisms postulated to explain stroke after BMT include not only the conditions noted above. An association of BMT with protein C deficiency may contribute to a hypercoagulable state after BMT (Gordon et al., 1991, 1993). This may explain not only stroke but also the occurrence of such entities as hepatic veno-occlusive disease after BMT.
While the incidence of stroke from infectious causes was relatively high (compared with infectious causes of stroke in the general population), it was not the most common cause. However, there was a higher incidence of unusual infectious causes of stroke than is seen in the general population. Others have reported nocardial infection of the craniospinal axis in association with malignancy or after BMT, but the organism has formed abscesses and not caused stroke per se (Choucino et al., 1996; van Burik et al., 1997; Bhave et al., 1999; Freedman and Nielsen, 1999). Invasive fungal infections are reportedly increasing in incidence, affecting as many as 50% of neutropenic BMT patients (Denning et al., 1997). Maschke and colleagues have reported a 4% incidence of CNS infections after allogeneic BMT (Maschke et al., 1999). In their series, the second most common CNS infection was aspergillosis (18% of all infections). In the present study, nine out of 12 infectious strokes were related to aspergillosis. Previous series examining CNS aspergillosis, like ours, have been retrospective (Beal et al., 1982; Hooper et al., 1982; Walsh et al., 1985; Ashdown et al., 1994; Hagensee et al., 1994; Patchell, 1994; Yuh et al., 1994). Our patients had the features commonly associated with this angioinvasive infection (e.g. leukaemia, lymphoma, aplastic anaemia, transplantation, receiving cytotoxic drugs and granulocytopenia). Focal neurological deficits have been seen in 
33% of patients and seizures in 30% (Walsh et al., 1985; Hagensee et al., 1994) (they were present in two of our patients with proven aspergillosis). Because of unperformed biopsy or necropsy, it is possible that the incidence of aspergillosis was higher and was undetected as the cause of some of the other intraparenchymal haemorrhages in our series.
Usually, the organism enters the body through the lungs by inhalation of Aspergillus conidia (Schwartz and Thiel, 1997) [as described in 87–88% of biopsy or necropsy-proven cases of CNS aspergillosis (Walsh et al., 1985; Hagensee et al., 1994)] and it travels to the brain haematogenously. Neurological symptoms are reported to be present in 27% of Aspergillus-infected BMT patients and many patients have advanced infection at the time of diagnosis. The infection is reportedly diagnosed most commonly a median of 131 days after BMT (compared with a median 95 days in our cohort) and may not be diagnosed until post-mortem in as many as 27% of patients (compared with 3% in our series) (Jantunen et al., 2000). The fungus has a predilection for blood vessels and causes thrombosis and angionecrosis of the vascular wall, with subsequent haemorrhage. In previous series, 33–59% of patients presented with focal findings, usually hemiparesis, and headache was rare (6% of patients). The infection often develops gradually (Meyers, 1990; Hagensee et al., 1994). CT and MRI often show infarcts with haemorrhage, often not in one vascular territory, and the infarcts grow contiguously over a period of days. In the present series, we concerned ourselves not with slow-growing infection but with the acute onset of cerebrovascular occlusions.
Enhancement on neuroimaging is minimal or absent in most cases. Gross haemorrhage is reported in up to 44% of initial radiographic studies (78% in the present cohort) and the most common sites appear to be in perforating artery territories rather than at the grey–white junction (DeLone et al., 1999). Others have reported a radiographic incidence of cerebral aspergillosis after BMT of 0.5%, representing 18% of radiographically apparent CNS infections after BMT (Coley et al., 1999). Aspergillosis of the CNS is reported to carry a uniformly poor prognosis in BMT recipients (Khoury et al., 1997). The mortality of patients with opportunistic CNS infection is reported to be 67% (Maschke et al., 1999). There was 89% mortality in patients with aspergillosis in the present cohort.
Study limitations
As with any retrospective study, this chart review may have underestimated the true frequency of stroke after BMT. Patients were identified by ICD-9 codes. From our clinical experience, a seizure was not an uncommon presentation of cerebrovascular disease in these patients. We therefore attempted to improve our capture rate by reviewing the charts not only of patients with a diagnosis of stroke or intracranial haemorrhage but also those of patients having seizure as one of their diagnoses during the index hospitalization for BMT or any subsequent readmission during the study period. Patients were identified at various stages in their disease processes (e.g. some received a transplant after relapse of the index malignancy) but they had all undergone BMT recently.
It is possible that we may have missed some patients who may have been lost to follow-up and suffered a stroke after BMT during the study period (or thereafter). Patients leaving the Seattle metropolitan area after engraftment might have had strokes after BMT, but this was likely to have been beyond the acute post-transplant period, which was the time-frame of interest in the present study.
In general, retrospective series may miss minor strokes. This may explain, in part, the relatively high frequency of haemorrhagic strokes (which tend to be more severe) and the very high case fatality and disability rates we observed. We cannot comment on exactly how accurate is the coding of diagnoses in the hospital where the study was carried out. There are published data for the USA on the sensitivity (0.81) and specificity (0.90) of hospital coding for the diagnosis of stroke (ICD-9 codes 430–8) (Benesch et al., 1997; Goldstein, 1998). None of these studies reflects something we did, which was to try to find stroke patients coded with other diagnoses (e.g. seizure, infection).
One other limitation of the study design is that we cannot comment on the absolute values of certain laboratory analyses (i.e. platelet counts) that were associated with stroke, because we recorded whether patients met laboratory threshold values for measures such as thrombocytopenia and leukopenia and not the absolute blood cell counts themselves.
In summary, strokes occur relatively often after BMT, have a relatively high frequency of infection-triggered events, have a neurological outcome not easily predicted from the data available, and are frequently fatal. This retrospective study, despite our best efforts, may have suffered from problems of case ascertainment. On the basis of our data, the frequency, aetiology and outcome of stroke after BMT deserve further, prospective evaluation.
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Notes |
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* Present address: Departments of Neurology and Neurological Surgery, Wayne State University, Detroit, Michigan, USA
Present address: Division of Pulmonary and Critical Care Medicine, University of California, San Diego, San Diego, California, USA
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Acknowledgments |
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We wish to thank Dr Louis R. Caplan for providing critical review of the manuscript, Drs Douglas J. Lanska and Robert G. Holloway for supplying information pertinent to the investigation and Dr Bradley S. Jacobs for statistical assistance. This work was supported in part by NIH grants NS-30305 (W.M.C.), NS-38905 (W.M.C.) and NS-30896 (S.R.L.).
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Received August 18, 2000. Revised December 26, 2000. Accepted January 22, 2001.
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