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Cerebellar degeneration caused by high-dose cytosine arabinoside A clinicopathological study.

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Cerebellar Degeneration Caused by
High-Dose Cytosine Arabinoside:
A Clinicopathologcd Study
Marc D. Winkelman, MD," and John D. Hines, MD-;
~~
~
Twenty-four patients with leukemia or lymphoma refractory to conventional chemotherapy were given a course of
systemic, high-dose cytosine arabinoside ( 3 gmim' every 12 hours for twelve doses). Four patients developed cerebellar
degeneration during treatment. Ataxia of gait and limb movements, dysarthria, and nystagmus appeared five to seven
days after the first dose, worsened over the next two to three days, and then remained stable for two to six days.
Incomplete improvement occurred over the following one to two weeks. Postmortem examination disclosed loss of
Purkinje cells in the depths of cortical sulci with relative preservation of those at the crests of folia and those in the most
posterior inferior portions of the cerebellum. Other patients developed a mild, reversible cerebellar syndrome over the
same time course as that of the irreversible disorder. Manifestations ranged from nystagmus alone to dysarthria and
unsteadiness of gait without limb ataxia. We conclude that cytosine arabinoside at this dosage causes a cerebellar
degeneration with characteristic clinical and pathological features. Among the present patients with refractory
hematological malignancies, such degeneration occurred with an incidence of 16.7%, more than twice that reported in
previous series.
Winkelman MD, Hines JD: Cerebellar degeneration caused by high-dose cytosine arabinoside:
a clinicopathological study. Ann Neurol 14:520-527, 1983
Cytosine arabinoside ( Ara-C), in systemic daily doses
of 100 to 200 mgim', has been used widely in the
treatment of acute nonlymphocytic leukemia (ANLL)
for at least fifteen years, with no reports of neurological
toxicity [20, 4 2 , 471.Since 1979 several studies have
shown that high-dose Ara-C (HDARAC; up to thirty
times the usual dose) can induce remissions in patients
with ANLL {13-15, 21, 31, 431 and malignant lymphoma [ 131 refractory to conventional treatment. In
the earliest of these clinical trials, signs of neurological
toxicity, including somnolence [3 11 and transient confusion 1211, were noted. Subsequently, reversible cerebellar ataxia [13, 15, 231 and cerebellar degeneration
[ 2 3 , 33, 45) were reported. The incidence of this cerebellar degeneration is still unclear, and the clinical and
pathological features heretofore have been described
only incompletely.
Methods
Between 1979 and 1982, 25 patients, 15 males and 10 females, were given d course of HDARAC The patients
ranged in age from 18 to 69 years (mean, 4 2 , median, 4 2 ,
standard deviation, 16 years) Twenty-three patients had
From rhe Departments of "Pathology ; i d Neurology and -I.Medicine,
Cleveland Metropoliran General Hospiral, and Case Western Reserve University School of Medicine, Cleveland, OH 441(!9.
520
hematological malignancies refractory to conventional therapy: 9 had ANLL in relapse; 2 had ANLL that developed
after eight and ten years, respectively, of chemotherapy and
irradiation for Hodgkin's disease; 2 had myeloproliferarive
disorders terminating in ANLL; 1 had acute myelosclerosis
in a leukemic phase; 2 had acute lymphocytic leukemia in
relapse; and 7 had malignant lymphoma. One patient had
newly diagnosed ANLL, and 1 had osteosarcoma of the orbit
unresponsive to conventional treatment. Informed consent,
approved by the hospital's human investigation committee,
was obtained from all patients after the expected toxicities
and the investigational nature of the therapy were explained.
The drug regimen consisted of Ara-C dissolved in sterile
5 p dextrose in water and administered intravenously in a
dose of 5 gm per square meter of body surface area over
1 hour every 1 2 hours for six days. Ten patients were
also treated with 4'-(9-acridinylamino)-methane-sulfon-manisidine (AMSA), 2 with doxorubicin, and 3 with daunorubicin o n days 7, 8, and 9.
Baseline neurological examinations were performed the
day before treatment was begun. Patients were examined
daily during treatment and throughout hospitalization.
Complete postmortem examinations were performcd on
13 patients. Small blocks of cerebellar cortex from the vermis
(declive) and hemisphere (ansiform lobule, crus 11) were
Received Jan 24,1981, and in revised form Mar 18, 1983. Accepted
for publication Mar 21, 1983.
Address reprint requests ro Dr Winkelman, Deparnnenr of Pathology, Cleveland Metropolitan General I3ospital. 3 3% Scranton Kd,
Cleveland, OH 44109.
Tuhle 1. Clirzicul Feutures of 7 Fatienti
ulith
Cerebellar Ataxia Caused by High-Dose Cytosine AruhinoJide
Time of Appearance of Crrcbrllar Signs'
Patient
No.
Sex:
Age
Oculomotor Abnormalities
Ataxia
Stance,
Gait
Arms,
Legs
Dysarthria
...
6
Hodgkin's disease
-ANLL
i
6
6
Myelohhrosis
-ANLL
ANLL, relapse
5
6
6
7
(yr)
Diagnosis
1"
M: 69
Acute myelosclerosis,
leukemic phase
2"
F; 29
3"
M; 59
31,
F, 49
5
F; 32
6'
-'
8
8
-,
7
M: 2 1
Hodgkin's disease
+ANLL
Malignant lymphoma
...
.
M ; 16
Malignant lymphoma
5
"Indicated as number of days &r
"Irreversible araxia
'Reversible ataxla.
.
..
...
6
Nystagmus
Ci>gwheel Hypometric
Pursuits
Saccades
Ocular
Dysmerria
5
7
Ex rrxerc be llrir
9
12
\ wk
Left medial rectus 4 wk
muscle palsy:
verrigo
C<infusion
6 mil
I2
C;iinfusion
11
6
...
8
6
. .
5
...
Signs, Svmptoma
4 wk
3 wk
8
6
Duration CIC
Surwviil afrer
Treatment
Improvemrnr
...
10
...
9
...
Drowsiness
5 mo (alivc)
3 mi
the first dose of cytosine ardhinoside.
+ = terminating in; ANLL = acute nonlymphocytic leukemia; ellipses in columns indicate that the cerehellar sign was not present.
fixed in 4% buffered glutaraldehyde, postfixed in 2 % osmium tetroxide, and embedded in plastic, and semithin (1.5
I*.)sections were examined by phase contrast microscopy.
The rest of the brain and spinal cord was fixed in 2057 formalin. The cerebellum was split sagittally. One half was studied
in six to eight parasagittal sections, and the other in horizontal
section. These and representative blocks from the rest of the
central nervous system were embedded in paraffin, and sections were stained for cells (cresyl violet), myelin (Woelke's
stain), nerve fibers (Bodian method), and glial fibers (Holzer's
stain), and with hematoxylin and eosin.
Between 1977 and 1982, 10 patients with ANLL treated
only with conventional doses of Ara-C (200 mdm', continuous intravenous infusion, daily for five days) and 5 patients
with ANLL not treated with Ara-C were examined postmortem. Ataxia during treatment was not noted in their charts.
Representative slides of the central nervous system of these
patients were reviewed as pathological controls.
Results
Clinical Obsewations
Four of the 25 patients developed irreversible cerebellar ataxia during treatment with HDARAC (Table I).
A fifth patient (Table 1, patient 5 ) developed ataxia but
became debilitated by sepsis and unable to cooperate
with daily neurological examinations, so it was not possible to determine whether ataxia was irreversible. For
this reason the case was excluded from statistical andyses. Thus, the clinically observed incidence of irreversible ataxia was 16.7%).The temporal evolution of
ataxia was similar in all patients. The onset was marked
by subtle signs, such as a mildly unsteady tandem gait,
nystagmus, or cogwheel (saccadic) ocular pursuit movements. These signs were detected five to seven days
after the first dose of Ara-C and preceded symptoms
by about 24 hours. Other cerebellar signs appeared
(see Table l), and the severity of ataxia reached a peak
over the next two to three days, after which the clinical picture remained stable for two to six days. Improvement began four to seven days after the onset of
signs and continued for one to two weeks, but after two
weeks no further improvement was observed, and no
patient recovered completely. The degree of recovery
varied inversely with the severity and anatomical extent
of the ataxia. Most patients (Table 1, patients 2 to 5 )
were so ataxic that they could not walk or feed themselves, and so dysarthric that their speech was unintelligible; they showed little recovery. One patient (Table
1, patient l),whose gait ataxia and dysarthria were less
disabling and who lacked limb ataxia, recovered almost
completely .
Limb ataxia was bilateral but more marked on one
side in 2 patients. In 2 patients, the upper and lower
limbs were affected equally, but in 2 others, ataxia was
worse in the arms than the legs. In most cases the
abnormalities of ocular movement were more marked
with gaze in some directions than in others. Nystagmus
was of the gaze-evoked type; vertical nystagrnus was
not observed. The dysarthria was both scanning and
slurring in nature. In 3 patients (see Table I), extracerebellar symptoms or signs formed part of the initial clinical picture but resolved in one to two days and
were overshadowed by the cerebellar disorder. Spinal
fluid and computed tomographic scans of the head
were normal.
In other patients reversible cerebellar abnormalities
evolved and resolved over the same time course as the
irreversible disorder (see Table 1). Only fragments of
the full cerebellar syndrome were observed (see Table
l), and the symptoms were mild. Several patients developed only nystagmus or cogwheel ocular pursuit
Winkelman and Hines: HDARAC Cerebellar Degeneration
52 1
Table 2. Patholojiical Findin@ in Cerebellums of Patients Receiciing High-Dosr Cjtosine Arabinoside
and Control Patients. uiith Clinical Correlations
No. of Patients
Cortical Degeneration
~~
~
Focal: All
Layers
Diffuse: Purkinje
Cell Layer
Group
Nuclear
Degeneration
Patients receiving HDARAC
With irreversible ataxia (n = 4 )
Without ataxia (n
8)
Control patients
Receiving only CDARAC (n = 10)
Not receivin,g Ara-C (n = 5 )
Ara-C
= cyrosinm:
arabinoside; CDARAC
=
convenrional-dose Ara-C; H D A R A C
movements. In only 1 of these (Table 1, patient 6 ) was
it possible to be certain of the cause, because many
drugs can produce these nonspecific signs. For this reason the incidmce of a mild, reversible cerebellar disorder caused by HDARAC could not be determined.
Before receiving HDARAC the ataxic patients
showed n o neurological abnormalities. Malnourishment, alcoholism, known cerebellar toxins, hypoglycemia, anoxia, shock, peripheral eosinophilia, hyperthermia (above 4OoC), and hypothyroidism were absent.
Patients 2 and 4 (see Table 1) were given AMSA and
patient 6 received doxorubicin, but only after cerebellar signs had been noted.
Pathological Obserilatiom
Neuropathological findings are summarized in Table 2.
The cerebellums of the patients with irreversible ataxia
522 Annals of Neurology
Vol 14
No 5
=
high-dose Ara-C
and of patient 5 (see Table 1) were normal on gross
examination. Microscopically, the principal abnormidity of the cortex was a loss of Purkinje cells with two
topographic patterns (Figs 1 and 2). Purkinje cells in
the most posterior inferior portions of the cortex were
relatively preserved. In the vermis these portions included the nodulus and to a lesser degree the uvula and
part of the pyramis; in the hemisphere they included
the ffocculus and to a lesser extent the tonsil. Purkinje
cells in the depths of primary and secondary sulci
throughout the cerebellum were lost, but those at the
1 . (Patient 41 Cerebellar iavtex depleted of Purkinje cells. The
numerous small nuclei in the Purkiwje i-rll layer (short arrow)
are of Bevgmann glia: tho.re in the molecular ku>er (arrowhead)
are of microglia and astrocytes. The ~variulecell Layer (long ar-.
row) is normal. (Cresyl violet; x 8O.t
Fig
November 1981
VERMIS
HEMISPHERE
Fix 2. Topography of Purkinje cell loss in
ca.res of cerebellar
degeneration caused by high-dose cytosine arahinoside. Dots indicate area.r of cortex depleted of Purkinje cells and indicate involvement of deep nuclei (d). The inset represents the cerebellar tonsil
(t). (1" = primav rorticalsulrus; 2" = secondary cortical sulcus;
n = n o d u h : u = u z d a : p = pyranis: f = jocculus.)
firle
crests of the folia were relatively preserved in patients
I and 2; in patients 3, 4 , and 5 , most Purkinje cells
were lost, but those that remained were found at the
crests of folia. Peri-Purkinje cell baskets were lost in
the same distribution as Purkinje cells but to a lesser
degree. Surviving Purkinje cells appeared normal. In
the patients who survived for three to four weeks after
receiving HDARAC (see Table l ) , there was an increase in the number of Bergmann glial nuclei (see Fig
11, and in the patient who lived for six months (see
Table 1), there was an increase in radial Bergmann glial
fibers. In all cases the molecular layer showed an increase in astrocytes and microglia but no reduction in
width, and stellate and basket cells appeared to be present in normal numbers (see Fig 1).
In addition to the diffuse change in the Purkinje cell
layer, there were several focal areas of degeneration of
all three cortical layers. Segments of cortex measuring
40 to 100 showed thinning of the molecular layer to
half its normal thickness, loss of steliate and basket
cells, and loss of Purkinje and granule cells, with an
astroglial reaction (Fig 3). Such foci were randomly
distributed; depths of sulci were not affected selectively. In the patients with the greatest loss of Purkinje
cells (Fig 2, cases 3, 4 , and 5 ) , the deep cerebeiiar
nuclei showed a mild focal loss of nerve cells, with
clusters of pleomorphic microglia in their place and a
diffuse gemistocytic astrocytosis (Fig 4).
In the longest-surviving patient (Table 1, patient 3),
examination revealed loss of axons and an isomorphic
astrogliosis in the laminae albae and central white matter of the cerebellum and in the amiculum and hilurn of
the dentate nucleus. There was also degeneration of
the inferior olivary complex, with generalized loss of
neurons, increased astrocytes, and gliosis of amiculum
and hilum.
The inferior, middle, and superior cerebellar peduncles and the spinocerebellar tracts were normal in all
Winkelman and Hines: HDARAC Cerebellar Degeneration
523
Fig 3. (Patient 4)Focal cerebellar degeneration, usith sharpb
r,
of
limited neuronul loss in all three cortii-ul f u ~ j e ~thinninK
molecular luyer, and Kliosis. The large circn1avj;irms (arrowhead) are corpora umjlacea. an uprefated L-hunge. 1Cresyl zmiolet:
x 80.)
Fig 4. (Patient 3 ) Degeneration of dentrktr nurleu. uith f;irb*lreplacement of nerve trlls bii nests of mzcroxfirk (arrow) and u &/fuse increase in atrorytes (arrowhead). (Cre.yl zmiolet: x .j15 ,i
524 Annals of Neurology
Vol 14
No 5
November 1981
patients. The rest of the central nervous system, including Ammon’s horn, was without significant abnormality. No lesions were found to account for the transient
extracerebellar signs and symptoms.
None of the patients with reversible ataxia (see
Table 1) was examined postmortem. The lesions of
focal cortical degeneration in the HDARAC patients
without ataxia and in the control patients (see Table 2)
were similar in appearance, size, number, and distribution to those observed in the ataxic patients (see Fig 3).
A comparison of the patients who developed irreversible ataxia and those who did not disclosed no statistically significant differences in age or in duration of
malignant disease before or survival after treatment
with HDARAC (Mann-Whitney U test). No positive
or negative correlation was found between cerebellar
degeneration and the following: simultaneous [28, 3 5 )
or prior { 131 cranial irradiation, prior intrathecal chemotherapy [I 31, prophylaxis with pyridoxine, type of
previous systemic chemotherapy, other drugs given
with HDARAC, history of meningeal leukemia or
lymphoma, hematological response to HDARAC,
liver disease or infection, other adverse effects of
HDARAC, or general postmortem findings.
Discussion
Development of ataxia in a stereotyped, close temporal
relationship to treatment with HDARAC, and improvement following cessation of therapy, indicated
that the cerebellar degeneration was a direct toxic effect of the drug. The diluent supplied by the manufacturer could not be incriminated {32],because it was not
used. Nor could the chemotherapeutic agents AMSA
and doxorubicin be implicated, because ataxia was
noted before these were given. The rapid evolution
and partial resolution of the ataxia differed from the
slower, steadily progressive course of paraneoplastic
cerebellar degeneration {40]. The topography of the
pathological changes in the cerebellum differed from
that found in nutritional degeneration [21, which the
setting of far-advanced malignancy might have suggested as a cause.
Some clinical features of this toxic ataxia were conscant; others were variable. The course, including the
time of onset and the temporal evolution and resolution of the signs, was similar in all patients. However,
in some patients the disorder was irreversible and in
others reversible, and the anatomical extent and severity of ataxia ranged from nystagmus alone to mild dysarthria and unsteadiness of gait to disabling ataxia affecting the entire musculature.
Among central nervous system structures, an order
of vulnerability to the toxic effect of HDARAC was
apparent. The presence of transient extracerebellar
symptoms and signs without fixed pathological lesions
accounting for them indicated that structures other
than the cerebellum were mildly and reversibly affected. The deep cerebellar nuclei seemed less liable to
injury than did the cortex, because they were damaged
only in those cases with the greatest Purkinje cell loss.
Neurons in the molecular and granule cell layers of the
cortex were lost only focally and in relatively small
numbers and so seemed relatively resistant. Purkinje
cells were the most vulnerable, as they were lost diffusely and extensively.
All Purkinje cells were not equally vulnerable, however. The characteristic topography of Purkin je cell
loss (see Fig 2 ) indicated a regional variation in the
vulnerability of these neurons. In several diffuse cerebellar disorders, such as organic mercury poisoning
CIS, 381, postmortem necrosis of the granule cell layer
(conglutination) [17), and some cases of anoxic encephaloparhy {lo, 24, 261, cortical damage is greater in
the depths of sulci than at the cresrs of folia, as in
HDARAC toxicity. And in nutritional { 2 ) and some
familial cerebellar degenerations [17, 29,411and some
cases of anoxic encephalopathy { I , 261, the most posterior inferior portions of the cortex are also relatively
spared, as in HDARAC toxicity. Vascular factors {S,
391 do not account for nor do phylogenetic divisions of
the cerebellum 1271 coincide with these patterns of
injury. The responsible factors are not known; in particular, there is no known regional variation in the metabolic composition of the cerebellar cortex. A recent
study [I61 showed that the nodulus contains both a
greater percentage of Purkinje cells with more than
one primary dendrite and a lesser content of norepinephrine than other regions of the cerebellum, but
whether these anatomical and biochemical factors have
any relation to the resistance of the nodulus to toxic,
metabolic, and nutritional insults is unknown.
Most of the other neuropathological changes can be
explained as secondary to death of Purkinje cells. The
diffuse microglial reaction in the molecular layer without loss of stellate or basket cells probably was elicited
by the presence of dead Purkinje cell dendrites. Loss of
axons in the laminae albae of the cerebellar folia and in
the amiculum of the dentate nucleus probably represented anterograde degeneration of the cerebeiiar corticonuclear projection following loss of Purkin je cell
bodies. The changes in the olivary complex were consistent with degeneration secondary to a diffuse lesion
of the cerebellar cortex.
The mechanism by which HDARAC caused the
death of Purkinje cells is unknown. In neoplastic and
normal cells undergoing mitosis, cytotoxicity is effected by interference with deoxyribonucleic acid
(DNA) synthesis through inhibition of D N A polymerase activity 1121. Although Purkinje cells are postmitotic, some synthesis of nuclear D N A persists (in
adult mice), possibly for gene amplification, turnover,
Winkelman and Hines: HDARAC Cerebellar Degencration
525
or repair [9]. In rabbits, systemically administered AraC is taken up and phosphorylated to its active metabolite by brain cells [37]. Therefore, it is conceivable
that Purkinje cells are injured by h a - C through its
only known pharmacological action: interference with
D N A synthesis. But it is also possible that injury occurs through another, unknown action of the drug.
Several compounds that share with Ara-C a chemical
structure based on the pyrimidine ring also cause
cerebellar disease. The cerebellar syndromes caused
by HDARAC and the chemotherapeutic agent 5fluorouraci1{20,42,4?] have several clinical features in
common: the incidence is dose related [23, 471; symptoms abate when the drug is discontinued; and each
sometimes is accompanied by a transient ocular palsy
[6]. Adult cats given the pyrimidine antimetabolite 5fluoro-orotic acid became ataxic five to ten days later
[22), a delay similar to that observed in patients given
HDARAC. Cerebellar degeneration principally affecting Purkinje cells has been observed rarely in patients
treated with the antithyroid agent methylthiouracil,
which, unlike the other pyrimidines, does not interfere
with DNA synthesis (R. D. Adams, personal communication, 1082). Thus, Ara-C may be a member of a
group of pyrimidines toxic to the cerebellum and especially Purkinje cells through an action ocher than the
inhibition of D N A synthesis.
Focal degeneration of all three layers of small zones
of cerebellar cortex may be a subclinical toxic effect of
Ara-C at both conventional and high doses. The evidence for such an effect is the presence of this type
of lesion in ataxic and asymptomatic patients given
HDARAC and in patients treated only with conventional doses of the drug, and the absence of such lesions in those nor treated with Ara-C (see Table 2).
However, the histological picture is nonspecific, the
untreated group was very small, and there was no clinical evidence temporally linking the lesion and the drug
in the patients without ataxia. For these reasons, some
other cause of focal cerebellar degeneration, such as a
remote effect of malignancy [40], could not be ruled
out in these patients.
Two other forms of neurological Ara-C toxicity have
been described, but the mechanisms of injury appear
to differ from that involved in cerebellar degeneration.
In fetal rats 131 and suckling mice 14, 34, 361, systemic
doses of 30 to 50 mgikg damage the developing brain
through interference with mitosis in nerve cells. Since
1969, 7 patients who developed paraplegia after treatment with intrathecal Ara-C have been reported [ 5 , ?,
25, 32, 461.The pathological lesion in each case was
located in the white matter of the spinal cord; nerve
cells were unaffected 17,251. The rarity of this adverse
effect suggests that it is an idiosyncratic response, and
the pathological findings bear no similarity to the
neuronal cerebellar degeneration described here.
526 Annals of Neurology Vol 14 No 5
Heretofore, the dosage schedule of HDARAC used
in this study (3 g d m 2 every 12 hours for twelve doses,
the “3 x 1 2 regimen”) has been considered the OPtimum treatment of refractory ANLL; lower dosage:$
were found to be relatively ineffective [21, 30,441, and
higher dosages caused cerebellar degeneration in a high
proportion of patients [23]. Lazarus and colleagues
[23] showed that the incidence was dose related: in 40
patients with refractory hematological malignancies, irreversible ataxia developed in 2 of 6 patients given 4.5
g d m ’ every 12 hours for twelve doses but in none of
31 patients treated with 3 g d m ’ every 12 hours for
twelve or sixteen doses and none of 12 patients given
four or eight doses. Subsequently, in several other clinical trials of the 3 x 12 regimen of HDARAC, the
proportion of patients developing irreversible ataxia
ranged from 1 of 16 ( 6 . 2 5 2 ) {l3] to none of 7 5 [ 1 4 ] ,
40 {15], and 14 [43}. The results of our study, in which
4 of 24 patients developed cerebellar degeneration (or
irreversible ataxia), contrast with these findings and call
the safety of the drug at this dose into question. The
reason for the discrepancy is unclear. Possibly our
methods of detection of ataxia were more sensitive.
The number of patients in our study was small, h o w
ever, and the high incidence could have been an
anomaly caused by chance alone. Prospective observations of a large number of patients will be necessary
to determine the true incidence of this toxic effect.
The median survival period of patients with refractory acute leukemia is 2.5 months. Because of this
grave prognosis and because most evidence points to
the safety of HDARAC, we felt compelled to offer our
patients the only treatment currently proved effective
in refractory hematological malignancies.
The use of HDARAC in the treatment of refractory
hematological malignancies is increasing, and investigators are beginning to use it in newly diagnosed
ANLL, with promising results 1.113. Our observations
of the dangers of the drug prompt the following recommendations: (1) A reevaluation of the safety of the
3 X 12 regimen is necessary: all patients should be
followed prospectively by a neurologist in order to
clarify the incidence of cerebellar degeneration. (2) Patients should be fully informed of the risk of cerebellar
degeneration. (3) If a patient develops severe or progressive ataxia, the drug should be discontinued { 13,
271.
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