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Encephalopathy with parkinsonian features in children following bone marrow transplantations and high-dose amphotericin B.

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Encephalopathy with
Parkinsonian Features in
Children Following Bone
Marrow Transplantations
and High-Dose
Amphotericin B
Stephen H. Mott, MD,"? Roger J. Packer, MD,V
L. Gilbert Vezina, MD,"$ Sudesh Kapur, MD,"Q
Patricia A. Dinndorf, MD,"Il Joan A. Conry, MD,V
Michael R. Pranzatelli, MD,"?
and Ralph R. Quinones, MD"11
Encephalopathy, leukoencephalopathy, and secondary
parkinsonism occurred in 3 children with refractory leukemia undergoing allogenic bone marrow transplantation (BMT) who were treated with high-dose amphotericin B for pulmonary aspergillosis or sinus aspergillosis
that did not involve the nervous system. Treatment included high-dose cytosine arabinoside, cyclophosphamide, and total body irradiation prior to the BMT. The
children developed a progressively worsening encephalopathy and parkinsonian features, characterized by resting tremor, cogwheel rigidity, and masklike facies. Neuroimaging studies showed cerebellar, cerebral, and basal
ganglia atrophy, as well as frontal and temporal lobe
white matter involvement. Two of the 3 patients recovered, although 1 has residual intellectual impairment.
The third succumbed to non-central nervous system Epstein-Barr virus-lymphoproliferative disease and had
autopsy-confirmed leukoenephalopathy .
Mott SH, Packer RJ, Vezina LG, Kapur S,
Dinndorf PA, Conry JA, Pranzatelli MR,
Quinones RR. Encephalopathy with parkinsonian
features in children following bone marrow
transplantations and high-dose amphotericine B.
Ann Neurol 1995;37%10-8 14
Leukemic patients undergoing bone marrow transplantation (BMT) are often exposed to potentially
neurotoxic agents, including high-dose chemotherapy,
focal cranial and total body radiation therapy, and intensive antibiotic therapy 11]. Neurologic complications of therapy are often difficult to separate from the
effects of systemic illness or the cancer itself. In one
From the Departments of "Pediatrics, $Neurology, $Radiology, $Pathology, and llHematology/Oncology, Children's National Medical
Center and The George Washington University, Washington, DC.
Received Aug 17, 1994, and in revised form Dec 27. Accepted for
publication Feb 23, 1995.
Address correspondence to Dr Mott, Department of Neurology,
Children's National Medical Center, 111 Michigan Avenue, NW,
Washington, DC 20010.
Copyright 0 1995 by the American Neurological Association
study, 59% of children undergoing BMT developed
acute neurologic complications and children with leukemia were at highest risk for these sequelae 12). Comm o n acute central nervous system (CNS) complications included seizures, infections, encephalopathies,
and cerebrovascular accidents. Most encephalopathies
were n o t associated with focal neurologic dysfunction.
I n this report, 3 children with leukemia are described
with a unique syndrome of encephalopathy and parkinsonian features associated with leukoencephalopathy
that developed while receiving high-dose amphotericin
B ( H D A m B ) treatment and slowly resolved after cessation of HDAmB. Each child previously received
high-dose ( H D ) chemotherapy, total body irradiation
(TBI), and allogenic BMT.
Case 1
A 12-year-old Romanian boy with acute myelocytic leukemia
(AML) in second complete remission received myeloblative
doses of cyclophosphamide and TBI followed by BMT for
hematopoietic rescue, from his HLA-identical, mixed lymphocyte culture (MLC) nonreactive sister. Prior treatment
and the pretransplant regimen are outlined in the Table.
Prior to transplant he had suffered transient cytosine arabinoside (ARA-C)-related cerebellar ataxia, which had completely
resolved. He was being treated for pulmonary aspergillosis
(0.5 mg/kg/day) during transplant. Low-dose intravenous
methotrexate was given for graft versus host disease
(GVHD) prophylaxis [3, 41. Twelve days following transplant, because of persistent high fevers and recent history
of Aspergillus pneumonia, the intravenous AmB dose was
empirically increased to HDAmB 1.5 mg/kg/day (single
dose). He engrafted by 29 days and was diagnosed as having
acute G V H D and was started on prednisone 49 days following transplant.
Approximately 7 weeks following the BMT, he had slow
concurrent deterioration in motor, cognitive, and cerebellar
functions. He became encephalopathic, and had marked oromotor dysfunction, masklike facies, a coarse resting tremor,
cogwheel rigidity, brady- and hypokinesia, marked weakness,
dysmetria, diffuse hyperreflexia, and a wide-based shuffling
gait. By this time, he had received approximately 51 mg/kg
total AmB post BMT. A head computed tomographic (CT)
scan showed severe cerebellar hemispheric and markedly
worse vermian atrophy when compared with his pretrans-
plant CT. Cerebral spinal fluid (CSF) analysis revealed a total
protein of 76 and a normal cell count. All cultures were
negative. An electroencephalogram demonstrated generalized slowing consistent with diffuse encephalopathy. The
magnetic resonance imaging (MRI) performed approximately
3 weeks after onset of neurologic symptoms (Fig 1A) revealed abnormalities primarily involving the basal ganglia,
adjacent white matter and cortex of the temporal and frontal
lobes, and cerebellum.
An empiric trial of I-dopa/carbidopa resulted in a decrease
of rigidity and overall improvement in motor abilities. Selegiline was added with further neurologic improvement. By 3
months, the patient’s parkinsonian symptoms resolved and
the child no longer was on antiparkinsonian treatment. During this time, the HDAmB, the methotrexate for GVHD,
and acyclovir for herpes virus prophylaxis had been discontinued, and the prednisone had been decreased. A follow-up
MRI (see Fig 1B) revealed severe cerebellar atrophy, most
evident in the inferior vermis, moderate atrophy of the basal
ganglion, although their gray matter signal abnormalities had
resolved, and persistent T2 high-intensity signal in the affected white matter. Currently, he is fully ambulatory, communicative, and functioning near his pre-BMT level. (This
case was previously cited by Pranzatelli and colleagues 171.)
Case 2
An 8-year-old black male with AML, in second complete
remission, with prior treatment as outlined in the Table, received TBI, HDARA-C, and cyclophosphamide followed by
T cell-depleted marrow from his HLA disparate mother 141.
During the transplant procedure, he received HD prednisolone and antithymocyte globulin. He engrafted within 2
weeks of transplant.
Thirty-four days following transplant, he began treatment
with HDAmB (1.5 mgikglday) for Aspergillus sinusitis. MRI
of head demonstrated mild sulcal enlargement. Approximately 2 weeks following the HDAmB, he developed a
coarse resting tremor that coincided with AmB infusion and
fever spikes. His total AmB dose at this time was approximately 24 mg/kg. Because of failure to control his fungal
sinusitis, 7 weeks following the BMT he began treatment
with AmB lipid complex (ABLC, Liposome Company, obtained on a compassionate use protocol) at a single dosing of
5 mg/kg/day [b]. Following 3 weeks of ABLC, he developed
a moderate encephalopathy characterized by poor memory
and psychomotor retardation. He had slightly dysarthic
Treatment of Patients Reported
Tumor Type
Prior Treatment
Pretransplant Regimen
Posttransplant Regimen
TBI (1,200 cGy);
H D C T X (120 mg/kg)
TBI (1,200 cGy);
HDARA-C (18 g/m2)
TBI (1,200 cGY)
HDARA C (18 g/m*)
HDCTX (90 mg/kg)
Prednisone; ATG
AML = acute myelogenous leukemia; CML = chronic myelogenous ieukemia; TBI = total body irradiation; HDARAC
cytosine arabinoside; MTX = methotrexate; ATG = antithymocyte globulin; HDAmB = high-dose amphotericin; HDCTX
Brief Communication: Mott et al: Amphotericin B Parkinsonian Encephalopathy 811
speech, masklike facies, brady- and hypokinesia, and mild
cogwheel rigidity in the left arm and leg (compared with the
right), bilateral finger-to-nose dysmetria, slow rapid alternating movements, and a slightly wide-based, mildly ataxic gait.
An MRI obtained at this time revealed further sulcal and
ventricular enlargement and abnormal T2 bright signal in the
frontal white matter.
Following stoppage of the amphotericin, the parkinsonian
features improved, though he was left with a mild cerebellar tremor and intellectual impairment. Follow-up MRI 4
months later revealed marked ventriculomegaly and sulcal
enlargement, diffuse cerebellar atrophy, and mild white matter changes, primarily frontally. The basal ganglia were
spared. Presently, he has recovered with respect to speech,
reflexes, and gait, with a mild persistent neurocognitive difficulty. His cognitive impairment may also be, in part, secondary to varicella-zoster encephalitis occurring 5 months post
Case 3
Fig 1. (A)Brain magnetic resonance imaging (MRI) scan, 3
weeks after neurologic symptom onset in Patient 1 , revealing abnomzal signal intensity on the proton density images involving
the basal ganglia (black arrow) and adjacent white matter
and cortex of the insular and frontal lobe>(small arrows).
(B) Brain MRI scan, 3 months later in Patient 1, reneahg
very severe shrinkage of the inferior cerebellar flermis,severe cerebellar atrophy, and moderate atrophy.
812 Annals of Neurology
Vol 37
No 6 June 1995
A 17-year-old white male with chronic myelocytic leukemia
in chronic phase underwent T cell-depleted HLA disparate
bone marrow transplantation following fractionated total
body irradiation (1,200 cGy), HDARA-C (18 gm/M*), HD
cyclophosphamide (90 mg/kg). He received HD corticosteroids and antithymocyte globulin to prevent rejection. One
week following BMT he was begun on HDAmB (1.5 mg/
kgiday) for biopsy proven invasive pulmonary aspergillosis.
Seven weeks following BMT, and after receiving a cumulative AmB dosage of 53 mg/kg, he developed bilateral resting
tremors of the upper extremities. The tremors worsened with
intentional movements. The tremor became progressively
more generalized paralleling a marked decline in his mental status. He had brady- and hypokinesia, diffuse resting
tremor, marked cog wheel rigidity in all extremities and neck,
and diffuse hyperreflexia with bilateral Babinski signs. A head
C T scan demonstrated sulcal enlargement. His CSF protein
was 61, a normal cell count, and cultures were negative.
An MRI 14 days later demonstrated new low attenuation
changes in the cerebral white matter diffusely (worse frontally) and further ventricular enlargement. An MRI 4 weeks
later (Fig 2A) revealed diffuse abnormal T2 bright signal in
the cerebral white matter (sparing the central white matter
tracts) consistent with a leukoencephalopathy. Two sequential CSF analyses during this time period showed a rising
protein 77 to 182, normal cell count, and a normal myelin
base protein. All viral studies were negative.
He subsequently developed akinetic mutism and respirator dependence for airway protection. He had no improvement with a cogentin challenge. H e developed severe hypotension and succumbed to a rapidly progressive non-CNS
Epstein Barr virus (EBV)-mediated lymphoproliferative disease 14 weeks following the BMT.
Brain examination at autopsy showed minimal changes
with focal grayish lesions in the white matter. Microscopic
examination of the brain showed vacuolar degeneration of
the striatum, the globus pallidus, and perivencricular white
matter with proliferation of gemistocytic astrocytes with irregular nuclei, microglial cells, and focal loss of myelin as
shown by luxol fast blue stain. Minimal mononuclear perivas-
Fig 2. (A) Magnetic resonance imaging (MRI) scan, 4 weeks following initial MRI in Patient 3, revealing dgfuse T2 high signal in the cerebral white matter (asterisk), sparing the internal
crrpsule and carpus callosum f black arrow). (Bi Phoiomicrograph in Patient 3, obtained at autopy, of globus pallidus
showing gliosis, focal vacuolar change with perivascular mononuclear infiltrates. Few foamy macrophages are also present. (Hematoxyline and eosin, x 255 before 5 1% reduction.)
cular infiltrates were also present. Nuclei of the oligodendrocytes showed no inclusions (see Fig 2B). Tracts in the midbrain were also involved; however, neurons in the substantia
nigra were normal. In situ hybridization studies showed no
evidence of EBV virus in the brain.
The 3 children in this series developed strikingly
similar neurologic dysfunction including parkinsonian
symptoms of brady- and hypokinesia, cogwheel rigid-
ity, masklike facies, coarse resting tremor, and, in Case
1, a shuffling gait. Although all had MRI evidence of
leukoencephalopathy, symptoms of basal ganglia dysfunction overshadowed the common symptoms of
white matter damage, such as spasticity. The parkinsonian symptoms in our patients were most likely related
to neostriatal damage in the basal ganglia and frontal
lobe white matter as evidenced by MRI [71. Case 1,
with the most flagrant parkinsonian manifestations, had
the most marked basal ganglia involvement with subsequent atrophy. The changes in mental status observed
have been reported with leukoencephalopathy but
might also be related to more widespread neurologic
The 3 children had received very similar treatment
including ARA-C, cyclophosphamide, and TBI prior
to their BMT and developed their encephalopathy and
parkinsonian features while receiving HDAmB. All
had received more than 45 mg/kg total AmB dosage
at the time of symptom onset. The children had some
evidence of neurologic damage prior to amphotericin
treatment, since all had mild sulcal prominence or ventriculomegaly on neuroimaging studies, though none
were symptomatic at the time of transplant. Their
symptoms began from 7 weeks to 4 months following
the treatment with ARA-C, approximately 7 weeks following the BMT preparatory regimen and the BMT.
Severe neurologic dysfunction has been described in
leukemic patients undergoing BMT [I, 2, 81. Factors
predisposing to such changes include prior neurotoxic
intrathecal and intravenous anticancer treatment, cranial irradiation, a history of CNS leukemia, pre-BMT
ablative treatment, and viral infections, as well as interactions of these factors. The known CNS toxins given
the leukemic children in this series were cytosine arabinoside, cyclophosphamide, amphotericin B, systemic
corticosteroids, and radiation therapy. The cerebellar
signs of dysmetria, ataxia, and dysarthria exhibited by
Cases 1 and 2 have been previously associated with
HD intravenous ARA-C but have been reported to
occur within a day of ARA-C infusion [9]. No such
temporal relationship was seen in our patients.
Cyclophosphamide was administered to all 3 patients
in the cytoreductive phase prior to bone marrow transplantation. This agent has been used extensively in this
setting and has rarely been associated with neurologic
dysfunction [lo, 111. The acute effects of TBI on the
nervous system have not been systematically studied;
however, it has been used extensively without associations with acute neurological dysfunction. The irradiation used may have potentiated damage by weakening
the blood-brain barrier and potentially facilitating the
passage of neurotoxic agents exposing the brain to direct effects [12).
The patients in this series received HDAmB concur-
Brief Communication: Mott et al: Amphotericin B Parkinsonian Encephalopathy 813
rent with the onset of their neurologic symptoms. Intravenous HDAmB and its methyl ester derivative
have been associated with progressive neurological decompensation, akinetic mutism, and leukoencephalopathy [2}. Ellis and colleagues 1131 reported dementia,
akinetic mutism, hyperreflexia, and tremor in 14 adult
patients treated with intravenous or intrathecal AmB
for systemic fungal illness, with or without meningeal
involvement. Neurotoxic symptoms occurred between
3 and 12 days with total intravenous AmB doses
greater than 5 gm (>70 mg/kg; estimated 70 kg adult
weight) in patients without meningitis. Symptoms occurred between 1 and 5 days in patients with meningitis given a total dose greater than 9.8 gm (>140 mg/
kg; 70 kg adult weight) with a fraction of the dose
given intrathecally. The pathology revealed diffuse
white matter involvement, predominantly frontal. Devinsky and associates 1141 reported a single case of
a 23-year-old male who developed akinetic mutism 2
months following BMT after receiving cyclophosphamide and 15 Gy TBI. This patient had received a total
AmB dose of 5.67 gm ( 4 1 mg/kg; 70 kg weight)
completed approximately 2 weeks prior to the onset
of the neurotoxicity. Autopsy revealed leukoencephalopathy primarily in the frontal lobes and adjacent temporal and parietal white matter. Walker and Rosenblum 1153 reported 2 cases of leukoencephalopathy
associated with HDAmB who had undergone BMT
and died. The common pretreatments were cyclophosphamide and TBI. The onset of neurotoxic symptoms
was concurrent with HDAmB treatment. In their first
case, symptoms followed a cumulative AmB dose of
4.33 gm (-62 mg/kg; 70 kg weight) 4 months after
BMT. The second patient had received 1.77 gm AmB
dose ( ~ 2 mg/kg;
70 kg weight) 8 weeks following
BMT. Similar autopsy findings were reported in these
2 cases as in the previous Devinsky report. Of interest
is a reported case of HDARA-C-associated parkinsonism, the patient had received an unknown quantity of
AmB prior to her symptoms for a concurrent nonCNS fungal infection [16}. More recently, Balmaceda
and colleagues [ l 71 reported a reversible encephalopathy secondary to AMB in adults.
The 3 cases presented reveal the complexity of neurologic compromise in leukemic patients undergoing
BMT requiring multimodal therapies. As all 3 patients
developed symptoms while under treatment with
AmB, it appears to be a potential causative agent. The
temporal relationship to all the other potentially neurotoxic agents given is much less clear. It is curious that
the onset of parkinsonian symptoms occurred 7 weeks
following BMT after having received greater than 45
mg/kg total AmB. The literature implies that worsening of neurologic symptoms may depend on higher
doses and intrathecal administration. Further studies
are indicated to evaluate the potential neurotoxicity of
Annals of Neurology
Vol 37
No 6 June 1995
HDAmB, especially the interaction between this drug
and other neurotoxic agents used in treating childhood
We thank Betsy Schaefer for her editorial assistance
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features, marrow, encephalopathy, dose, following, high, children, amphoteric, bones, transplantation, parkinsonism
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