moyamoya syndrome following childhood acute lymphoblastic leukemia
TRANSCRIPT
Pediatr Blood Cancer 2007;48:268–272
Moyamoya Syndrome Following Childhood AcuteLymphoblastic Leukemia
Akira Kikuchi, MD, PhD,* Miho Maeda, MD, Ryoji Hanada, MD, Yuri Okimoto, MD, PhD, Koichi Ishimoto, MD, PhD,Takashi Kaneko, MD, PhD, Koichiro Ikuta, MD, and Masahiro Tsuchida, MD, PhD
On behalf of the Tokyo Children’s Cancer Study Group (TCCSG)
INTRODUCTION
To date, the prognosis of childhood acute lymphoblastic
leukemia (ALL) has improved considerably [1–3]. However,
as the number of long-term survivors has been increasing,
adverse sequelae have emerged as serious problems for the
quality of life (QOL) of these patients [4].
Moyamoya disease is characterized by stenotic and
occlusive changes in the bilateral internal carotid arteries
and their rich arterial collaterals at the base of the brain.
Diagnostic criteria of Moyamoya disease are shown in
Table I [5]. It predominantly occurs in Asians and in children,
although the cause of genetic susceptibility to Moyamoya
disease in Asian is totally unknown. Signs and symptoms
include mental and physical deterioration such as conscious-
ness disturbance or convulsions as the result of brain
hypoperfusion. In some cases, it may be fatal. If the patients
have a known systemic disease or a history of cranial insults,
these cases are referred as moyamoya syndrome (MoS) or
quasi-moyamoya disease.
The Tokyo Children’s Cancer Study Group (TCCSG)
conducted four consecutive ALL treatment protocols (L84-
11, L89-12, L92-13, and L95-14) between 1984 and 1999,
and follow-up studies of long-term survivors [6–9]. In this
series, we identified six MoS patients who had experienced
childhood ALL. Here we report the clinical course of MoS
and the prognosis of these patients in relation to the primary
disease and ALL treatment.
PATIENTS AND METHODS
A total of 1,846 ALL patients were treated with four
consecutive TCCSG ALL protocols (L84-11, L89-12, L92-
13, and L95-14) between 1984 and 1999. Briefly, these
protocols consisted of remission induction therapy using
prednisolone or dexamethasone, vincristine and L-asparagi-
nase with or without cyclophosphamide and anthracyclines,
consolidation therapy, BFM (Berlin-Frankfurt-Munster)-
style reinduction therapy and maintenance therapy. The
duration of each protocol ranged from 1 year (L92-13) to 3½
years (L84-11). For prophylaxis of central nervous system
(CNS) leukemia, cranial irradiation or high dose methotrex-
ate (HD-MTX) with intrathecal injections were used
according to the criteria of each protocol. Table II shows
the number of patients who were treated with each protocol
and who received prophylactic cranial irradiation. Patient
age ranged from 1 to 15 years at diagnosis of ALL. All
treatments were performed with informed consent from the
patients’ guardians.
To evaluate the QOL of long-term survivors, information
about late complications was collected at annual follow-up
investigation. The median follow-up period for these patients
was 8 years and 8 months.
For statistical analysis, Chi-square tests were used
to analyze the relationships between MoS and clinical data.
Background. Long-term survivors of childhood acute lympho-blastic leukemia (ALL) sometimes suffer from adverse long-termsequelae. We analyzed the incidence, clinical course and prognosisof moyamoya syndrome (MoS) following childhood ALL. Procedure.A total of 1,846 ALL patients were treated with four consecutiveTCCSG ALL protocols (L84-11, L89-12, L92-13, and L95-14)between 1984 and 1999. We surveyed the MoS cases among thesepatients in the follow-up studies. Results. Six patients with MoS wereidentified: four boys and two girls whose ages ranged from 2 yearsand 1 month (abbreviated as ‘‘2y1m’’) to 14y 1m at diagnosis of ALL.None of the patients had central nervous system (CNS) leukemia. Allsix patients received prophylactic cranial irradiation with a dosage of
18 or 24 Gy. Although one patient died of brain infarction due toMoS, no leukemic relapse was observed in the group. Thecumulative incidence of MoS in our series was 0.46�0.02% at8 years. Among several clinical characteristics, use of cranialirradiation was the only factor that appeared to be significantlyrelated to the development of MoS. Conclusions. MoS occurs withincreased frequency in children treated for ALL, and might be asso-ciated with cranial irradiation. Prophylactic cranial irradiationshould be used cautiously in ALL patients who can be cured byother CNS-directed therapies. Pediatr Blood Cancer 2007;48:268–272. � 2006 Wiley-Liss, Inc.
Key words: childhood acute lymphoblastic leukemia; Moyamoya syndrome; prophylactic cranial irradiation; vasculopathy
� 2006 Wiley-Liss, Inc.DOI 10.1002/pbc.20837
——————Division of Hematology/Oncology, Saitama Children’s Medical
Center, Saitama, Japan
*Correspondence to: Akira Kikuchi, Division of Hematology/
Oncology, Saitama Children’s Medical Center, 2100 Magome
Iwatsuki-ku Saitama-shi, Saitama 339-8551, Japan.
E-mail: [email protected]
Received 25 September 2005; Accepted 14 February 2006
RESULTS
We identified six MoS patients in the follow-up studies.
The clinical background of these six patients who developed
MoS following ALL is shown in Table III. Four Japanese
boys and two Japanese girls whose ages ranged from 2 years
and 1 month (abbreviated as ‘‘2y1m’’) to 14y 1m at diagnosis
of ALL were studied. Initial white blood cell (WBC) counts
were between 2,300 and 84,000/mm3. The immunopheno-
type was B precursor in all six patients. The treatment
regimen was L84-11 in four cases, L92-13 in one case, and
L95-14 in one case. Two patients were categorized as
standard risk and four as intermediate risk. No patient had
CNS leukemia at diagnosis or at any point during the clinical
course. All six patients experienced complete remission after
remission induction therapy and they received prophylactic
cranial irradiation with a dosage of 18 or 24 Gy. No leukemic
relapse was observed in these patients.
The age at diagnosis of MoS ranged from 3y2m to 20y 11m,
between 1y6m and 6y10m after diagnosis of ALL. The
interval between the onset of neurological symptoms and
diagnosis of MoS ranged from 1m to 3y9m. MoS was screened
by computed tomography (CT) (Fig. 1A), magnetic resonance
imaging (MRI) and MR angiography (MRA) and confirmed
by cerebral angiography (CAG) (Fig. 1B). In four of the
six patients, encephalo-duro-arterio-synangiosis (EDAS) or
encephalo-duro-arterio-myo-synangiosis (EDAMS) was per-
formed for MoS. These procedures are indirect revasculariza-
tion techniques for MoS in which vascularly rich tissues such
as dura mater(DM) and superficial temporal artery (STA) in
EDAS or temporal muscle in addition to DM and STA in
EDAMS are placed on the surface of the brain to induce
neovascularization to the ischemic part of the brain. All four
patients who received EDAS or EDAMS obtained improve-
ment of cerebral vascularity and neurological symptoms. In
one case (Case 6), a surgical procedure was not indicated
because the case was less severe. In another case (Case 3),
MoS was diagnosed by CAG after two transient ischemic
attacks (TIA). An EDAS operation was planned, but the
patient again suffered a severe ischemic attack and died due to
brain infarction resulting cerebral edema. The cumulative
incidence of MoS in our series was calculated as 0.46� 0.02%
at 8 years. We analyzed the relationship between MoS and
several clinical characteristics of the ALL patient (age, gender,
initial WBC, immunophenotype, treatment protocol and use
of cranial irradiation). Among these characteristics, use of
cranial irradiation was the only factor that was significantly
related to the development of MoS (6/1,105 vs. 0/741, Chi
square test, P¼ 0.045).
DISCUSSION
MoS is characterized by bilateral stenotic and occlusive
changes in the internal carotid arteries and their rich arterial
Pediatr Blood Cancer DOI 10.1002/pbc
TABLE I. Diagnostic Criteria for Moyamoya Disease
1. Cerebral angiography is indispensable for the diagnosis and should present the following findings as a minimum:
a. Stenosis or occlusion at the terminal portion of the internal carotid artery or at the proximal portion of the anterior or the middle cerebral
arteries.
b. Abnormal vascular networks demonstrated in the arterial phase in the vicinity of the occlusive or stenotic lesions.
c. These findings should be present bilaterally.
2. When magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) clearly demonstrated all the following findings,
conventional cerebral angiography is not mandatory:
a. Stenosis or occlusion at the terminal portion of the internal carotid artery or at the proximal portion of the anterior and the middle cerebral
arteries on MRA and an abnormal vascular network in the basal ganglia on MRA.
b. An abnormal vascular network can also be diagnosed when more than two apparent flow voids are seen by MRI in the basal ganglia on the
same side.
c. Findings a. and b. above are seen bilaterally.
3. Because the etiology of moyamoya disease is unknown, cerebrovascular disease associated with (and most likely caused by) the following
diseases should not be diagnosed as moyamoya disease: arteriosclerosis, autoimmune disease, meningitis, brain neoplasm, Down syndrome,
Recklinghausen’s disease, head trauma, irradiation to the head, or other known disease.
4. Instructive pathological findings are as follows:
a. Intimal thickening and consequent stenosis or occlusion of the lumen are observed in and around the terminal portion of the internal carotid
artery, usually on both sides. Lipid deposits occasionally are seen in the proliferating intima.
b. Arteries constituting the circle of Willis, such as the anterior and middle cerebral and posterior communicating arteries, often show stenosis
of various degrees or occlusion associated with fibrocellular thickening of the intima, a waving of the internal elastic lamina, and
attenuation of the media.
c. Numerous small vascular channels (perforators and anastomotic branches) are observed around the circle of Willis.
d. Reticular conglomerates of small vessels frequently seen in the pia mater.
TABLE II. The Numbers of Patients who Were Enrolled and whoReceived Prophylactic Cranial Irradiation in Each Protocol
Protocol
Patient
number
Cranial
irradiation
No cranial
irradiation
L84–11 484 484 0
L89–12 418 335 83
L92–13 347 152 195
L95–14 597 134 463
Total 1846 1105 741
Moyamoya Syndrome Following Childhood ALL 269
collaterals at the base of the brain, and with known systemic
disease or a history of cranial insults. MoS associated with
hematological disease is mainly reported in hemoglobino-
pathy (sickle cell anemia) [10], coagulopathy such as protein
C deficiency [11] or protein S deficiency [12] and congenital
hemolytic anemia (hereditary spherocytosis) [13]. In
these disorders, obstruction of major arteries probably occurs
secondary to the increased cerebral blood flow caused
by anemia, hypercoagulability or poor microcirculation
resulting from spherical red blood cells. This leads to the
development of Moyamoya vessels as arterial collaterals. On
the other hand, MoS in malignant disease is mainly reported
in patients with brain tumor as a late effect of cranial
irradiation [14–16].
It is well-known that Moyamoya disease occurs pre-
dominantly in Asian people and in children, and its incidence
is estimated to be about 3.5/1,000,000 persons per year in
Japan [17]. About two thirds of patients are under the age of
15 and as about 15% of the total population of Japan is under
this age, the incidence of Moyamoya disease under the age of
15 in Japan is estimated to be about 1.5/100,000 person per
year. Our patients were almost exclusively Japanese children
and the incidence of six cases among 1,846 patients
with median follow-up period of nearly 9 years is apparently
20-fold higher than observed in the general pediatric
population. We suspected a causative relationship between
MoS and ALL or its treatment, and cranial irradiation
appeared to be the only factor significantly related to the
development of MoS. Recently, Kondoh et al. [18] reported
on MoS patient who had experienced ALL, and their case
also received cranial irradiation. They commented on the
possibility of co-existence of MoS and ALL. We have
extended their observations in a large series of patients with
Pediatr Blood Cancer DOI 10.1002/pbc
TABLEIII.
TheClinicalBackgroundoftheSix
Patients
whoDeveloped
MoSFollowingALL
Pat
ien
tN
um
ber
12
34
56
Ag
eat
AL
L2
y7
m1
0y
4m
2y
8m
14
y1
m2
y1
m2
y4
m
Gen
der
mm
fm
fm
Init
ial
WB
C(/
mm
3)
3,9
00
8,7
00
2,3
00
9,7
00
57
,60
08
4,0
00
Tre
atm
ent
regim
enL
84
-11
S1
L8
4-1
1H
1L
84
-11
S1
L8
4-1
1H
2L
92
-13
HR
18
L9
5-1
4H
R1
8
Cra
nia
lir
rad
iati
on
do
se1
8G
y2
4G
y1
8G
y2
4G
y1
8G
y1
8G
y
CN
Sle
uk
emia
(�)
(�)
(�)
(�)
(�)
(�)
Ag
eat
Mo
S9
y4
m1
2y
8y
1m
20
y1
1m
4y
8m
3y
10
m
Neu
rolo
gic
alsy
mp
tom
sT
IA
sud
den
mo
tor
wea
kn
ess
Su
dd
enm
oto
rw
eak
nes
s
spee
chd
istu
rban
ce
hem
iple
gia
Ep
ilep
sy
gai
td
istu
rban
ce
sud
den
mo
tor
wea
kn
ess
Dip
leg
ia
wo
rsen
ing
of
tran
sver
sem
yel
itis
Su
dd
enm
oto
rw
eak
nes
s
gai
td
istu
rban
ce
Su
dd
enm
oto
rw
eak
nes
s
Inte
rval
bet
wee
no
nse
to
fsy
mp
tom
s
and
Mo
Sd
iag
no
sis
3y
9m
6m
2y
11
m1
m1
y2
m3
m
Tre
atm
ent
for
Mo
SE
DA
SE
DA
S,
ED
AM
SE
DA
SE
DA
SA
spir
in
Su
rviv
alst
atu
sN
ED
(24
0mþ
)*N
ED
(20
6mþ
)D
ied
of
bra
inin
farc
tio
n
(66
m)
NE
D(2
00
mþ
)N
ED
(14
8mþ
)N
ED
(71
mþ
)
NE
D,
no
evid
ence
of
dis
ease
.
*In
the
par
enth
esis
,su
rviv
ald
ura
tio
nis
show
nin
mo
nth
s.A
plu
ssi
gn
ind
icat
esth
atth
ep
atie
nt
isst
ill
aliv
e.
Fig. 1. Brain imaging of a patient with MoS (Case 2). A: Brain
computed tomography (CT) findings of Case 2. Bilateral strokes are
seen in the watershed distribution, indicating brain hypoperfusion.
B: Cerebral angiography (CAG) of the same patient. Stenotic portion of
internal carotid artery is indicated by black arrow and arterial collaterals
perfused by external carotid artery, so-called ‘‘Moyamoya vessels,’’ are
indicated by white arrows.
270 Kikuchi et al.
ALL and found a significant correlation between these two
disorders, with a much higher incidence of MoS among ALL
patients than in the general pediatric population. Further-
more, we showed that MoS among ALL patients also
correlated with prophylactic cranial irradiation. Radiation-
induced MoS is mainly reported in brain tumor patients and
they usually receive high dose cranial irradiation (40–50 Gy)
for the treatment of tumors [14–16]. MoS after cranial
irradiation is a form of radiation-induced vasculopathy and
this is possibly why MoS is more than 20 times higher in our
ALL patients than in the general pediatric population.
Among our six MoS patients, two received prophylactic
cranial radiation at doses as low as 18 Gy: This is probably the
lowest dose of cranial irradiation among post-irradiation
MoS. Intrathecal injection and CNS-directed methotrexate
therapy were also performed on these patients and such
cranial insults might have influenced the development of
MoS. MoS associated with coagulation disorder has been
reported [12,13]. All of our patients received L-asparaginase
during the therapy and transient coagulopathy may also have
been present. However, our six MoS patients never
experienced clotting problems and we do not think L-
asparaginase related coagulopathy influenced the develop-
ment of MoS in our series.
The cumulative incidence of MoS in our series was
0.46� 0.02% at 8 years. However, we cannot deny the
possibility that there may be asymptomatic children with
this, or there may be children who had neurologic symptoms,
but were not evaluated for MoS. There is another possibility
that higher-than-expected incidence of MoS in our series
may be due to chance variation unrelated to cranial
irradiation. On the other hand, we might have missed
asymptomatic patients who developed MoS after treatment
because we did not perform brain MRI for all patients with
ALL at diagnosis or perform active surveillance for MoS in
the follow-up studies, so that underestimation might also
have occurred. However, as the observed incidence of
symptomatic MoS in our series was much higher than in
general population, we can conclude MoS occurs with
increased frequency in children treated for ALL, and might
be associated with cranial irradiation.
Cranial irradiation was first introduced by St. Jude
Childrens’ Research Hospital to prevent CNS leukemia. It
markedly reduced CNS leukemia and contributed to the
improvement of the prognosis of ALL. However, as the
prognosis of childhood ALL improved, the adverse effect of
prophylactic cranial irradiation became more evident and the
effort to limit the use of cranial irradiation in initial therapy
for ALL is now in progress [19–23]. Although cranial
irradiation contributed to the improvement of prognosis for
some patients in high-risk groups [24,25], unnecessary
prophylactic cranial irradiation should be avoided if possible
to prevent adverse late effects including MoS, especially in
Asian patients who might be more susceptible to Moyamoya
disease. It is noteworthy that in some cases there is a
relatively long time period between the onset of neurological
symptoms and diagnosis of MoS (more than 2 years in two
cases). Efficacy of vasoreconstructive surgery for radiation-
induced MoS has been reported sometimes [14–16,18]. As
an early surgical procedure can reduce the severity of post-
operative neurological sequelae, physicians should be alert to
neurological symptoms indicating MoS in ALL patients.
ACKNOWLEDGMENT
We thank Mrs. Kaori Itagaki for preparing and refining the
protocol data for acute lymphoblastic leukemia in the Tokyo
Children’s Cancer Study Group.
REFERENCES
1. Pui CH, Evans WE. Acute lymphoblastic leukemia. N Engl J Med
1998;339:605–615.
2. Schrappe M, Reiter A, Ludwig WD, et al. Improved outcome in
childhood acute lymphoblastic leukemia despite reduced use of
anthracyclines and cranial radiotherapy: Results of trial ALL-BFM
90. Blood 2000;95:3310–3322.
3. Silverman LB, Gelber RD, Dalton VK, et al. Improved outcome for
children with acute lymphoblastic leukemia: Results of Dana-
Farber Consortium Protocol 91-01. Blood 2001;97:1211–1218.
4. Pui CH, Cheng C, Leung W, et al. Extended follow-up of long-term
survivors of childhood acute lymphoblastic leukemia. N Engl J
Med 2003;349:640–649.
5. Ikezaki T, Loftus CM. Moyamoya disease. Rolling Meadows, IL:
American Association of Neurological Surgeons Press; 2001.
6. Tsukada M, Komiyama A, Nakazawa S, et al. Treatment of
standard risk acute lymphoblastic leukemia in children with Tokyo
Children’s Cancer Study Group (TCCSG) L84-11 protocol in
Japan. Int J Hematol 1993;57:1–7.
7. Manabe A, Tsuchida M, Hanada R, et al. Delay of the diagnostic
lumbar puncture and intrathecal chemotherapy in children with
acute lymphoblastic leukemia who undergo routine corticosteroid
testing. Tokyo Children’s Cancer Study Group (TCCSG) study
L89-12. J Clin Oncol 2001;19:3182–3187.
8. Toyoda Y, Manabe A, Tsuchida M, et al. Six months of
maintenance therapy after intensified treatment for acute lympho-
blastic leukemia of childhood. J Clin Oncol 2000;18:1508–1515.
9. Igarashi S, Manabe A, Ohara A, et al. No advantage of dex-
amethasone over prednisolone for the outcome of standard and
intermediate risk childhood acute lymphoblastic leukemia in the
Tokyo Children’s Cancer Study Group L95-14 Protocol. J Clin
Oncol 2005;23:6489–6498.
10. Dobson SR, Holden KR, Nietert PJ, et al. Moyamoya syndrome in
childhood sickle cell disease: A predictive factor for recurrent
cerebrovascular events. Blood 2002;99:3144–3150.
11. Andeejani AM, Salih MA, Kolawole T, et al. Moyamoya syndrome
with unusual angiographic findings and protein C deficiency:
Review of the literature. J Neurol Sci 1998;159:11–16.
12. Akgun D, Yilmaz S, Senbil N, et al. Moyamoya syndrome with
protein S deficiency. Eur J Pediatr Neurol 2000;4:185–188.
13. Holz A, Woldenberg R, Miller D, et al. Moyamoya disease in a
patient with hereditary spherocytosis. Pediatr Radiol 1998;28:95–
97.
14. Kestle JR, Hoffman HJ, Mock AR. Moyamoya phenomenon after
radiation for optic glioma. J Neurosurg 1993;79:32–35.
15. Nishizawa S, Ryu H, Yokoyama T, et al. Post-irradiation
vasculopathy of intracranial major arteries in children—report of
two cases. Neurol Med Chir (Tokyo) 1991;31:336–341.
Pediatr Blood Cancer DOI 10.1002/pbc
Moyamoya Syndrome Following Childhood ALL 271
16. Ishikawa T, Houkin K, Yoshimoto T, et al. Vasoreconstructive
surgery for radiation–induced vasculopathy in childhood. Surg
Neurol 1997;48:620–626.
17. Ikezaki K, Han DH, Kawano T, et al. A clinical comparison of
definite Moyamoya disease between South Korea and Japan. Stroke
1997;28:2513–2517.
18. Kondoh T, Morishita A, Kamei M, et al. Moyamoya syndrome after
prophylactic cranial irradiation for acute lymphoblastic leukemia.
Pediatr Neurosurg 2003;39:264–269.
19. Skler C, Mertens A, Walter A, et al. Final height after treatment for
childhood acute lymphoblastic leukemia: Comparison of no cranial
irradiation with 1800 and 2400 centigrays of cranial irradiation.
J Pediatr 1993;123:59–64.
20. Ankovic M, Brouwers P, Valsecchi MG, et al. Association of 1800
cGy cranial irradiation with intellectual functions in children with
acute lymphoblastic leukemia. Lancet 1994;344:224–227.
21. Butler RW, Hill JM, Steinherz PG, et al. Neuropsychologic
effects of cranial irradiation, intrathecal methotrexate and systemic
methotrexate in childhood cancer. J Clin Oncol 1994;12:2621–
2629.
22. Christie D, Leiper AD, Chessells JM, et al. Intellectual perfor-
mance after presymptomatic cranial radiation therapy for
leukemia: Effects of age and sex. Arch Dis Child 1995;73:136–
140.
23. Nachman J, Sather HN, Cherlow JM, et al. Response of children
with high-risk acute lymphoblastic leukemia treated with and
without cranial irradiation: A report from the Children’s Cancer
Group. J Clin Oncol 1998;16:920–930.
24. Conter V, Schrappe M, Arico M, et al. Role of cranial radiotherapy
for childhood T-cell acute lymphoblastic leukemia with high WBC
count and good response to prednisolone. J Clin Oncol 1997;15:
2786–2791.
25. Laver JH, Barredo JC, Amylon M, et al. Effects of cranial
irradiation in children with high risk T cell acute lymphoblastic
leukemia: A Pediatric Oncology Group report. Leukemia 2000;14:
369–373.
Pediatr Blood Cancer DOI 10.1002/pbc
272 Kikuchi et al.