Journal of Neuro-Oncology 27: 241-250,1996.
© 1996KluwerAcademic Publishers. Printedin the Netherlands.
Clinical Study

Delayed, transient encephalopathy after marrow transplantation: case
reports and MRI findings in four patients

H.I. Tahsildar, 1B.E Remler, 2'3 R.J. Creger, 1B.W. Cooper, 1S.M. Snodgrass, 2 R.W. Tarr 4 and H.M. Lazarus 1
The Ireland Cancer Center, Departments o f 1 Medicine, 2 Neurology, ~ Ophthalmology, and 4 Radiology, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, Ohio 44106, USA

Key words: encephalopathy, marrow transplantation, seizures, magnetic resonance imaging, computed tomographic scanning

Summary
Subacute encephalopathy developed in four patients within one to two months after undergoing high-dose
chemotherapy and bone marrow transplantation or peripheral blood progenitor (stem) cell transplantation
for breast cancer, acute myeloid leukemia, and non-Hodgkin's lymphoma. None of the patients had previously known neurologic disorders, central nervous tumor or infection. Two patients presented with generalized
tonic, clonic seizures, and two with confusion and lethargy. In all patients lumbar puncture and CT scans of the
brain were normal, while magnetic resonance imaging (MRI) demonstrated multifocal predominantly white
matter lesions. Phenytoin therapy was given to the two patients with seizures and all four patients improved
without specific therapeutic intervention. Repeat MRIs became normal within three months. We report a
delayed and transient encephalopathy which appears to be a unique complication of high-dose cytotoxic
chemotherapy. The corresponding brain lesions may not be appreciated on CT scans, suggesting an expanded
role for MRI studies in patients who develop neurologic findings while undergoing high-dose cytotoxic therapy.

Introduction
Patients who have systemic cancer are at high risk
of developing neurologic complications due to both
metastatic involvement of the central nervous system as well as non-cancerous conditions including
metabolic disturbances, thromboembolism, and infections [1, 2]. In addition, cancer therapy may be
neurotoxic. Chemotherapeutic agents administered in conventional (non-myeloablative) doses
have been reported to cause both central and peripheral nervous system dysfunction [3-11]. The
risk of neurotoxicity, as well as systemic toxicity, is
increased with dose-escalated regimens, such as
those used in conjunction with bone marrow trans-

plantation. Despite the increased potential for injury, neurologic dysfunction attributable to these
agents is infrequently reported in this situation [913].
We describe the development of a subacute encephalopathy in four patients within one to two
months after undergoing bone marrow or peripheral blood progenitor (stem) cell transplantation.
Computed tomography (CT) on these patients was
normal, but magnetic resonance imaging [MRI]
showed prominent white matter abnormalities. All
patients recovered with supportive therapy only,
and the neuroradiologic abnormalities resolved
within weeks to several months.

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Table I. S u m m a r y of clinical data on four patients
UPN

A g e (yr)/
Gender

Dx

BCNU
mg/m 2

5045
1179
5054

64/M
41/F
38/F

600

1224

31/F

NHL
AML
breast
cancer
AML

Busulfan
mg/kg

Carboplatin Cisplatin
mg/m 2
mg/m 2

Cyclophosphamide
mg/kg

Ifosfamide
g/m 2

200
16

2400
200

1800
16

VP-16 m g / m 2

19.1

2400

200

U P N = unique patient number; D x = diagnosis; N H L = n o n - H o d g k i n ' s lymphoma; A M L = acute myeloid leukemia; B C N U = carmustine; VP-16 = etoposide.

Case reports
Patients were treated from July 1992 to April 1993 at
the Ireland Cancer Center, University Hospitals of
Cleveland, Case Western Reserve University, Cleveland, Ohio. The treatment protocols were approved by the Institutional Review Board for Human Investigation and all patients gave written informed consent. The patient characteristics, including age, gender, diagnosis, and preparative
high-dose cytotoxic drug regimen, are shown in Table 1. CT examinations were performed on a Seimens Somatome Plus unit (Seimens, Ehrlangen,
Germany). MRI examinations were performed on
either a 1.0 or 1.5 Tesla Seimens Magnet.

Lumbar puncture, cerebrospinal fluid cultures, and
uncontrasted CT of the brain (Fig. 1), were normal.
A TR-weighted MRI of the brain, however, showed
areas of increased signal intensity within the midbrain (Fig. 2). There was no evidence of enhancement with Gadolinium DTPA. The patient received
phenytoin therapy and had no evidence of recurrent seizures. His mental state returned to normal
within two weeks, and he had no relapses of neurologic dysfunction. A repeat MRI two months later
showed no structural abnormalities (Fig. 3). Fifteen
months after transplant there has been no recurrence of lymphoma.

U P N # 5045

A 64-year-old man with recurrent follicular smallcell cleaved non-Hodgkin's lymphoma received cisplatin 200 mg/m 2, BCNU (carmustine) 600 mg/m 2,
and VP-16 (etoposide) 2400 mg/m 2, followed by peripheral blood progenitor cell reinfusion [14]. Peripheral blood neutrophil count > 500/btl and platelet count > 20,000/gl (transfusion independence)
occured 21 and 29 days after progenitor cell reinfusion, respectively. Four weeks after progenitor
cell infusion, he became increasingly lethargic. One
day later he developed several short lasting generalized tonic, clonic seizures in rapid succession. The
E E G obtained within six hours after seizure onset
showed diffuse theta slowing without epileptiform
discharges or other evidence for seizure activity.

Fig. 1. Normal uncontrasted CT of the head after the developm e n t of neurologic syndrome.

243

Fig. 2. Axial T2-weightedMRI (TE = 90 msec;TR = 2500 msec)

Fig. 3. T2-weightedMRI (TE = 90 msec; TR = 2500 msec) ob-

showing an increasedT2signal within the brain stem after development of neurologicsyndrome.

tained two months after transplant which shows resolution of
previouslynoted abnormal T2signal in the midbrain.

U P N #1179

showed multiple areas of increased signal in the
deep white matter of the hemispheres, and symmetrical lesions in the occipital lobes involving gray and
white matter. There was minimal enhancement of
the right occipital lesion after Gadolinium D T P A
administration. The patient had no significant visual deficit on formal examination one week after
the onset of neurologic symptoms. Followup MRI
three weeks later showed nearly complete resolution of the white matter abnormalities and progressive volume loss of the occipital lobes. The patient
remains in complete remission 14 months after
transplant and has a normal neurological examination.

A 41-year-old woman with acute myelogenous leukemia French-American-British (FAB) type M 4 in
first complete remission, was admitted to undergo
an autologous bone marrow transplant. She received a short course of phenytoin for busulfan-induced seizure prophylaxis, then busulfan 16 mg/kg,
cyclophosphamide 200 mg/kg, and purged autologous marrow [15, 16]. Peripheral blood neutrophil
count > 500/gl and platelet count > 20,000/gl (transfusion independence) occured 48 and 72 days after
progenitor cell reinfusion, respectively. Five weeks
after bone marrow infusion, she developed two unheralded generalized tonic clonic seizures, followed
by a mild confusional state of several days duration.
An E E G obtained after the seizures showed diffuse
slowing in the 6-7 Hz range compatible with an encephalopathic process. No evidence of epileptiform
activity was seen. After phenytoin therapy was administered, a CT scan of the head, lumbar puncture,
and cerebrospinal fluid cultures were performed
with normal results. A T2-weighted MRI, however,

U P N #5054

A 38-year-old woman with refractory advanced
breast cancer was given ifosfamide 19.1 g/m 2, carboplatin 1800 mg/m 2, etoposide 2400 mg/m 2, and autologous peripheral blood progenitor cell infusion
[17]. Peripheral blood neutrophil count > 500/gl and

244

Fig. 5. T2-weightedMRI (TE = 90 msec;TR = 2500 msec) showFig. 4. T2-weightedMRI (TE = 90 msec;TR = 2500 msec) showing patchy areas of increased signal intensity within the internal
capsules bilaterally.

platelet count > 20,000/gl (transfusion independence) occured 20 and 24 days after progenitor cell
reinfusion, respectively. Two months after transplant, she developed a moderately severe global
aphasia and a mild confusional state. E E G showed
a poorly sustained background rhythm of 7-8 Hz
and a single sharp wave originating from the right
frontal head region. There was no corresponding
clinical or electrographical seizure activity. Chemical and cellular spinal fluid profiles and cultures as
well as a CT of the head with contrast were normal.
The patient underwent an MRI three days into her
illness which showed patchy areas of increased T 2
signal intensity within both internal capsules (Fig.
4). There was no enhancement after Gadolinium
D T P A administration. No specific therapy was instituted. A repeat MRI obtained seven weeks later
showed resolution of these abnormalities (Fig. 5).
The patient recovered without neurologic sequalae
but developed recurrent breast cancer six months
after transplant. She expired 11 months after trans-

ing resolution of abnormal signals seven weeks after bone marrow transplant.
plant. Permission for post-mortem examination
was withheld.

U P N #1224

A 31-year-old woman with acute myelogenous leukemia FAB M 2 in first complete remission was admitted for allogeneic bone marrow transplantation
using her HLA-identical sister. She was given a
short course of phenytoin for busulfan-induced seizure prophylaxis, then busulfan 16 mg/kg, cyclophosphamide 200 mg/kg, allogeneic bone marrow,
and cyclosporine 3 mg/kg in conjunction with methylprednisolone for graft-versus-host disease prophylaxis [16,18]. Peripheral blood neutrophil count
> 500/gl and platelet count > 20,000/gl (transfusion
independence) occured 22 and 28 days after progenitor cell reinfusion, respectively. Three weeks
after marrow infusion she developed headaches
and a rapidly evolving confusional state. H e r evaluation, including metabolic and microbiologic stud-

245
ies as well as a C T of the h e a d and l u m b a r p u n c t u r e
cellular profiles and cultures were unrevealing. T 2weighted M R I of the brain d e m o n s t r a t e d increased
T 2 signal intensities in b o t h cerebellar hemispheres.
T h e r e was no e n h a n c e m e n t after G a d o l i n i u m
D T P A administration. Several days later the neurologic abnormalities s p o n t a n e o u s l y resolved. A repeat M R I o b t a i n e d three m o n t h s later s h o w e d resolution of these abnormalities. Four m o n t h s after
the b o n e m a r r o w transplant the patient developed
sepsis and expired. Disseminated toxoplasmosis
was the p r e d o m i n a n t finding at p o s t - m o r t e m examination, but permission for p o s t - m o r t e m examination of the brain was denied.

Discussion
We describe a delayed, reversible e n c e p h a l o p a t h y

in four patients with s y m p t o m onset one to two
m o n t h s after undergoing b o n e m a r r o w or peripheral blood p r o g e n i t o r (stem) cell transplantation.
T2-weighted M R I of the brain revealed white matter abnormalities while C T scans and l u m b a r puncture were unrevealing. T h e patients r e p o r t e d herein received drugs that penetrate into brain parenc h y m a and can cause severe central nervous system
dysfunction [3, 10, 19-26]. C h e m o t h e r a p y - r e l a t e d
e n c e p h a l o p a t h y occurs with n u m e r o u s agents (Table 2) and can range in severity f r o m very mild brain
dysfunction to severe and p e r m a n e n t neurologic
d a m a g e [10, 27, 28]. In a review of the neurotoxicity
of antineoplastic agents, neurologic s y n d r o m e s
such as acute e n c e p h a l o p a t h y and chronic reactions
were n o t e d but n o t a delayed yet reversible encephalopathy as experienced by our patients [29]. T h e
pyrimidine analogues 5-fluorouracil and cytarabine
m a y p r o d u c e acute encephalopathies in a dose-de-

Table 2. Cytotoxic agents associated with the development of encephalopathy

Agent and Citation(s)
Cytosine arabinoside
[4, 3O, 5O, 511
Carmustine (BCNU) [10]
Busulfan [16, 19-21]
Carboplatin [22]
Cisplatin [39]
Chlorambucil [52]
Cyclosporine [13, 40, 42, 43]
Etoposide (VP-16) [24, 53]
FK506 [44]
Fludarabine [34, 54]
5-fluorouracil [55, 56]
Ifosfamide [23, 28, 32, 33]
L-asparaginase [57]
Thiotepa [25, 26]
Methotrexate [6, 12, 58]
Pentostatin [59, 60]
Nitrogen mustard [61]
Paclitaxel [taxol] [62-67]

Comments
10% prevalence of encephalopathy in adult leukemics; progressive optic atrophy and anosmia after
recovery in one patient
Delayed onset encephalopathy (25-47 days after treatment); lesions in basis pontis, corpus
callosum, spinal cord, cerebrispheres
Seizures are common, but readily prevented by phenytoin prophylaxis
Microangiopathic hemolytic anemia with secondary cerebral ischemia and focal/diffuse neurologic
dysfunction
Rare focal encephalopathies (blindness, aphasia, seizures)
Rare seizure occurence in children; EEG patterns resemble 3 ttz spike and wave discharges of
abscence seizures
Predeliction for posterior hemispheric areas with cerebral blindness; onset after short latency;
occasionally permanent structural changes
Sudden onset severe encephalopathy in glioma patients 1-2 weeks after therapy; reversible with
dexamethasone
Predeliction for posterior white matter involvement and central visual disturbance; short latency to
symptom onset
Reversible encephalopathies after conventional therapy; high-doses can cause delayed, severe
encephalopathy
When given with levamisole, late onset (15-19 weeks) ataxia & mental status changes: white matter
abnormalities on MRI correlate with perivascular lymphocytic infiltrates
Early onset severe encephalopathy and seizures
Delayed onset cerebral vein and dural sinus thrombosis; focal/generalized neurological deficits
Short latency encephalopathy in patients given extremely high-dose thiotepa
Severe additive neurotoxicity with cranial irradiation; reversible encephalopathy within 1 week
after treatment onset
Lethargy, seizures, and rarely coma if given in setting of renal failure; if renal function normal,
frequent dose-scheduling results in same toxic effects
Early transient central nervous system toxic effects followed by late (6 months) permanent deficits
Rapid onset, cumulative sensory neuropathy; optic nerve disturbances

246
pendent fashion; these usually evolve within several
days of chemotherapy infusion yet resolve, for the
most part, over several weeks [3, 30, 31]. Ifosfamide
may cause a transient, subacute encephalopathy
which has been successfully prevented and treated
with methylene blue [23, 28, 32, 33]. Metabolic derangements could account for a subacute dose-dependent reversible toxicity due to ifosfamide, but a
similar metabolic derangement causing a delayed
toxicity is unlikely in our patients. The purine analogues fludarabine, cladribine, and pentostatin, also
are known to produce dose-limiting encephalopathy
that can be delayed and accompanied by white matter changes on MRI and spinal fluid protein elevations [34]. Though delayed and reversible, these toxicities are not typical. Dose is a strong predictive factor for toxicity, but it is not clear if dose, intensity,
length of exposure, or cumulative dose is the most
important predictive factor for toxicity [34].
E E G recordings were obtained within hours to
days after the ictal events from both patients (UPN
#5045 and #1179) who suffered seizures. Aside from
non-specific mild to moderate slowing, the EEGs
did not show any epileptiform activity. In a prospective EEG study of busulfan neurotoxicity, this 'epileptogenic' chemotherapeutic agent elicited generalized spike-and-waves and polyspike-and-wave
discharges in 21 of 34 subjects within 8-10 hours after drug administration [35]. These abnormalities
were still present in 5 subjects up to two months afterwards indicating a possible long term epilepto-

genic potential. Patients UPN #1124 and #1179 received phenytoin seizure prophylaxis for one week
which did not prevent encephalopathy. Additionally patient UPN #1179, who developed seizures, did
not exhibit changes on EEG noted by Meloni et al.
[351.
Several studies have addressed the frequency of
neurologic complications and chemotherapy-related encephalopathies in bone marrow transplantation. Atkinson et al. [12] recognized cerebral white
matter damage as a treatment complication in 1.7 %
of patients related to the use of intrathecal methotrexate and cranial irradiation. Snider and associates [36] reported neurologic complications in 39 %
of autologous bone marrow transplant patients but
did not attribute any complications to cytotoxic
therapy. Similarly, Patchell and co-workers [9] observed a high rate of central nervous system complications (55 of 78 patients) with only two therapyrelated cases. Reversible encephalopathies occured
in 4.2% of patients treated with cyclosporine after
allogeneic bone marrow transplantation [13]; preparatory treatment with intrathecal methotrexate
and cranial irradiation increased the post-transplant risk of leukoencephalopathy to 7% [37]. Even
in these published series, when other identifiable
causes were excluded, the number of cases which
potentially could be attributed to chemotherapy
was low. During the period in question at our center, 81 patients underwent bone marrow transplantation (autologous and allogeneic) and four (5%)

Table 3. MRI and cerebrospinal fluid (CSF) findings in patients with central nervous system (CNS) complications of cancer

Acute findings using MRI
Chemotherapy
neurotoxicity
CNS ischemia

PML
CNS infection
Limbic encephalitis

Chronic findings using MRI

Normal, or minor pleocytosis and
protein elevation
Shrinkage of lesions, chronic scar Normal, or mild pleocytosis
formation
+ hemorrhage, usually normal
glucose and protein
Multiple lesions in varied locations Progressive lesion formation
Non-specific elevation of WBC
count and protein
Bacterial, fungal, toxoplasmosis
Resolution or residual but smaller Positive bacterial, fungal,
abscesses
lesions after appropriate therapy
toxoplasmosis cultures
Predominantly temporal or
Chronic scar formation
Hemorrhage, mild to moderate
frontotemporal lesions
pleocytosis
Symmetrical lesions, posterior
cortex, basal ganglia
One or more lesions in vascular
distribution, + hemorrhage

Improvement or full resolution

Acute findings in CSF

PML = progressive multifocal leukoencephalopathy; WBC = white blood cell.

247
developed chemotherapy-related brain dysfunction.
Chemotherapeutic agents produce central nervous system toxic effects through a variety of mechanisms including microvascular damage, alteration
of neurotransmitter concentrations, disruption of
the blood-brain barrier, electrolyte disturbances,
and deleterious effects on cerebral glucose and protein metabolism [3, 38-41]. Highly lipophilic drugs
such as cyclosporine and FK506 may bind to myelin
inducing local toxicity [42-44]. Cyclosporine also
has been shown to augment thromboxane A 2generation which may result in vasoconstriction and focal
hypoperfusion [45]. Our patients did not have gross
metabolic disturbances, a history of brain irradiation, or other conditions which may have contributed to the central nervous system toxicity of their
chemotherapeutic regimens.
Many patients undergoing hematopoietic stem
cell transplantation have advanced malignant disease, and neurological findings could be secondary
to metastatic central nervous system involvement,
infectious and ischemic complications, or a paraneoplastic syndrome. Normal cerebrospinal fluid profiles and the spontaneous reversibility of neurologic
symptoms in our patients make these possibilities
low probability. In recent years innovative testing
procedures have become available to improve the
speed and certainty of diagnosis. While the value of
SPECT and PET scanning still is under investigation in a variety of situations, these tests have been
shown to be of benefit in brain imaging in some patients who experienced chemotherapy- related central nervous system injury [46]. Patient UPN #1224
developed disseminated toxoplasmosis affecting
the brain months after the initial encephalopathy
occured. There is, however, only a remote likelihood that this infection could have accounted for
the initial central nervous system symptomatology.
Our patients had normal renal and hepatic function
at the start of high-dose cytotoxic therapy and
should have been able to eliminate these agents
readily; the high doses of chemotherapy employed,
however, may have resulted in sufficiently elevated
serum concentrations to account for the central
nervous system damage.
The abnormalities on MRI in our patients largely

were confined to the hemispheric (patients 1, 2, 3)
and cerebellar white matter (patient 4). The lesions
were strikingly symmetric involving both internal
capsules, the posterior white matter and the cerebellar hemispheres. These findings suggest a preferential vulnerability of the involved areas in each patient but also may reflect a specific drug effect. Predominant involvement of the posterior white matter, for instance, is typically seen in cyclosporine
toxicity and with the related drug FK506 [40, 44, 47].
This pattern was observed in patient #1179 who was
the only recipient of cyclosporine. With the exception of cortical blindness, however, the correlation
between lesions seen on MRI and clinical symptoms is not precise. Global neuropsychiatric disturbances, seizures, aphasia and diffuse weakness
are not fully explained by the relatively localized
white matter lesions seen in our patients and those
reported by others. Thus, the white matter abnormalities demonstrated on MRI reflect both the sensitivity of this test as well as its limits in predicting
specific neurologic abnormalities (Table 3). Pronounced radiologic changes such as those in patient
#1179, for instance, may have no clinical correlation.
Although her examination revealed only a minimal
degree of peripheral visual field constriction, patients with similar lesions have been reported to
have severe visual disturbances [40, 44, 47].
Although CT may demonstrate white matter abnormalities related to cyclosporine, T2-weighted
MRIs are exquisitely sensitivite for detecting white
matter changes [48]. MRI was used to document
diffuse but reversible cerebral white matter abnormalities in a leukemia patient receiving high-dose
cytosine arabinoside therapy. Snider and co-workers [36] used CT to evaluate a large number of bone
marrow transplant ]patients in whom central nervous system complications developed yet found no
abnormalities. It is possible that white matter lesions related to cytotoxic agents may not have been
appreciated on their patients' scans. Paraneoplastic
diseases such as limbic encephalitis also may go undetected on CT [49]. Our four patients all had negative CTs and this imaging modality would have
been useless in monitoring the evolution of the
white matter abnormalities. Normalization of such
changes typically occurs over time but persistent

248
a b n o r m a l i t i e s can be o b s e r v e d in p a t i e n t s who suffer severe degrees of c e n t r a l n e r v o u s system toxicity [27]. T h e time of onset, M R I a p p e a r a n c e , a n d
reversibility of the s y n d r o m e s e e n in o u r p a t i e n t s is
r e m i n i s c e n t of the d e l a y e d p o s t - r a d i a t i o n syndrome. This toxic effect is d u e to d e m y e l i n a t i o n , a
n o n - s p e c i f i c r e s p o n s e to v a r i o u s types of c e n t r a l
n e r v o u s system injury, a n d m a y play a role in the
s y n d r o m e affecting o u r patients.
We o b s e r v e d a n i n c i d e n c e of 5 % of d r u g - i n d u c e d
c e n t r a l n e r v o u s system toxicity in o u r p a t i e n t s u n d e r g o i n g high dose c h e m o t h e r a p y p r i o r to b o n e
m a r r o w t r a n s p l a n t a t i o n . This c o m p l i c a t i o n m a y be
m o r e c o m m o n t h a n p r e v i o u s l y r e p o r t e d , yet was
relatively b e n i g n in o u r series. T h e etiology of the
t r a n s i e n t e n c e p h a l o p a t h y in o u r patients, w h e t h e r
due to a d e l a y e d d r u g effect, a l a t e n t viral infection,
or yet u n k n o w n cause, was t r a n s i e n t a n d left n o residua. A s a result of o u r e x p e r i e n c e we suggest
t i m e l y i n v e s t i g a t i o n of n e u r o l o g i c s y m p t o m s using
M R I as the p r e f e r r e d i m a g i n g m o d a l i t y to e l i m i n a t e
specific r e v e r s i b l e causes of n e u r o l o g i c a b n o r m a l ities.

Acknowledgements
S u p p o r t e d , in part, by g r a n t P 3 0 C A 4 3 7 0 3 f r o m the
N a t i o n a l C a n c e r Institute, the N a t i o n a l I n s t i t u t e s
for H e a l t h , a n d the U n i t e d States P u b l i c H e a l t h
Service.

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Address for offprints: Dr. H.M. Lazarus, Department of Medicine, University Hospitals of Cleveland, 11100 Euclid Avenue,
Cleveland, Ohio 44106, USA