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Moyamoya disease in children

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Childs Nerv Syst (2010) 26:12971308
DOI 10.1007/s00381-010-1209-8
SPECIAL ANNUAL ISSUE
Moyamoya disease in children
David M. Ibrahimi & Rafael J. Tamargo &
Edward S. Ahn
Received: 8 June 2010 / Accepted: 12 June 2010 / Published online: 4 July 2010
# Springer-Verlag 2010
Abstract
Purpose Moyamoya disease, a rare cause of pediatric
stroke, is a cerebrovascular occlusive disorder resulting
from progressive stenosis of the distal intracranial carotid
arteries and their proximal branches. In response to brain
ischemia, there is the development of basal collateral
vessels, which give rise to the characteristic angiographic
appearance of moyamoya. If left untreated, the disease can
result in overwhelming permanent neurological and cogni-
tive deficits.
Methods Whereas moyamoya disease refers to the idio-
pathic form, moyamoya syndrome refers to the condition in
which children with moyamoya also have a recognized
clinical disorder. As opposed to adults who typically
present in the setting of intracranial hemorrhage, the classic
pediatric presentation is recurrent transient ischemic attacks
and/or completed ischemic strokes.
Results Surgical revascularization, including direct and
indirect techniques, remains the mainstay of treatment,
and has been shown to improve long-term outcome in
children with moyamoya.
Conclusion The authors discuss the diagnosis and treat-
ment of moyamoya disease in the pediatric population.
D. M. Ibrahimi : R. J. Tamargo : E. S. Ahn
Department of Neurosurgery, Johns Hopkins School of Medicine,
Baltimore, MD, USA
D. M. Ibrahimi
Department of Neurosurgery,
University of Maryland School of Medicine,
Baltimore, MD, USA
E. S. Ahn (*)
Division of Pediatric Neurosurgery, The Johns Hopkins Hospital,
600 N. Wolfe St., Harvey 811,
Baltimore, MD 21287, USA
e-mail: eahn4@jhmi.edu
Keywords Moyamoya disease . Stroke .
Cerebral revascularization . Pial synangiosis . Pediatric
Introduction
Moyamoya disease is a cerebrovascular arteriopathy of
unknown origin characterized by progressive stenosis and,
ultimately, occlusion of the distal intracranial internal
carotid arteries (ICA) and the proximal branches of the
anterior and middle cerebral arteries. To perfuse the
ischemic brain distal to the occlusion, there is parallel
development of collateral vessels from the leptomeninges
as well as both the external and intracranial ICAs. It is the
dilated basal collateral vessels arising from the intracranial
ICAs, which normally supply the optic nerves, pituitary
gland, anterior perforated substance, dura, and other skull
base structures [1], that lead to the characteristic angio-
graphic appearance likened to a puff of smoke.
Moyamoya disease was first described in the Japanese
literature in 1957 by Takeuchi and Shimizu [2] as a case of
hypoplasia of the bilateral internal carotid arteries.
However, it was not until 1969 when Suzuki and Takaku
[3] coined the term moyamoya signifying something
hazy, like a puff of cigarette smoke to describe the
angiographic appearance that would both describe and
define the illness.
Epidemiology
Though initial descriptions and studies initially centered on
Japanese populations, presently, moyamoya disease is
observed throughout the world, affecting children and
adults of various ethnic backgrounds [4, 5]. With this
observation, moyamoya disease is becoming more widely
1298
recognized, and currently accounts for approximately 6% of
all causes of pediatric ischemic stroke [6, 7]. There are
striking differences between the incidences of moyamoya
disease among pediatric populations based upon ethnic and
geographic background. For example, moyamoya remains
the most common cause of pediatric cerebrovascular events
in Japan, and in a recent European study by Yonekawa et
al. [79], the incidence of moyamoya disease in Europe
was 0.3 patients per center per year, nearly one tenth that of
the incidence found in Japan. The reported incidence in the
USA is approximately 0.086 per 100,000 patients, as
compared to 0.35 per 100,000 found in the Japanese
literature [10, 11]. In the past, moyamoya disease was an
under-recognized cause of pediatric stroke within the USA,
as evidenced by a review published by Numaguchi et al.
[12] that showed there were only 46 definitive and 52
presumptive cases of moyamoya disease published in the
American literature prior to 1997. More recently, there have
been considerably more reports on both cases of and
surgical treatment for moyamoya disease in the USA, as it
is now considered in the differential diagnosis for any child
with ischemic cerebrovascular disease [13, 14]. There is a
bimodal age distribution of moyamoya disease, with the
first peak occurring in the pediatric population, typically in
the first decade of life, and a second peak between 30 and
40 years of age [8]. Moyamoya is found in both females
and males; however, there is a clear female preponderance,
with affected females outnumbering males nearly 2:1 [15].
Lastly, familial occurrence has been reported in Japan to
range from 7% to 12%, and similarly, approximately 6% in
the USA [1, 16, 17].
Clinical presentation
There are a multitude of symptoms associated with
moyamoya disease, including TIAs, ischemic strokes,
intracranial hemorrhages, seizures, headaches, choreiform
movements, and cognitive deficits. In contrast to adults
who often present within the setting of intracranial
hemorrhage (46%) [18], children affected with moyamoya
disease typically exhibit signs and symptoms of cerebral
ischemia secondary to TIAs and/or cerebral infarctions.
Ischemia to the frontal, parietal, and temporal lobes are
associated with hemiplegia or paresis, sensory loss or
parasthesias, aphasia, and/or cognitive impairments [19].
Following a TIA, children have a much higher rate of
completed infarcts when compared to their adult counter-
parts. This tendency is likely due to immature verbal skills
in younger children making it difficult to communicate
symptoms associated with TIAs, delaying the diagnosis of
moyamoya and increasing likelihood of completed stroke
upon presentation [20]. Moyamoya disease should be
Childs Nerv Syst (2010) 26:12971308
suspected in children who present with ischemic symptoms
prompted by common childhood behaviors including,
hyperventilation, crying, coughing, or blowing. Ischemia
in the setting of these activities results from hypocapnia-
induced cerebral vasoconstriction of already maximally
dilated cerebral blood vessels (in the face of chronic
ischemia), further reducing cerebral blood flow and prompting
worsening ischemia [21]. Though rare, visual symptoms
related to posterior circulation stenosis and ischemia have
been well documented and include temporary and permanent
blindness, visual field deficits, homonymous hemianopsia,
quadrantanopsia, scintillating scotomata, blurred vision, and
amaurosis fuguax [22]. Disturbances in the visual pathway
are more likely to occur in children as opposed to adults. For
example, in a study by Miyamoto et al. [22], visual
abnormalities attributed to moyamoya disease were found
in 43 of 178 patients reviewed, and 79.1% of these cases
were in children.
Intracranial hemorrhage associated with moyamoya is
infrequently encountered in the pediatric population. More
commonly seen in adults, the hemorrhage can be located
within the intracerebral, intraventricular, and/or subarach-
noid spaces. Specifically, 40% are within the basal ganglia,
30% are intraventricular, and 15% are thalamic with
intraventricular extension [23]. Traditionally, hemorrhage
associated with moyamoya disease has been attributed to
rupture of the fragile intracranial ICA collaterals that
develop to perfuse the ischemic brain distal to the occluded
vessels [19]. However, more recently, there have been
reports of intracerebral and subarachnoid hemorrhage
related to moyamoya-induced aneurysms and arteriovenous
malformations [2426]. Aneurysms associated with moya-
moya are likely induced from the increased flow and
subsequent shear stress on the fragile basal collateral
vessels, and are likely to be found at the basilar apex and
posterior communicating artery [25, 26]. It is also thought
that the hyperangiogenic state of moyamoya induces the
formation of arteriovenous shunts that mimic traditional
arteriovenous malformations [27]. There has even been a
case report of a non-traumatic subdural hematoma resulting
from spontaneous rupture of a transdural collateral vessel
[8].
Headache is a common presenting symptom of moya-
moya, although its etiology remains unclear. It is postulated
that headaches arise from hypoperfusion-induced activation
of pain-sensitive structures such as both intracranial and
extracranial vasculature, dura, orbital contents, and mucous
membranes of the oral and nasal cavities [28]. Concomi-
tantly, other mechanisms such as dilation of the meningeal
collaterals stimulating dural nociceptors and ischemia
induced lowering of the migraine threshold have also been
suggested [8, 29]. Seizures, both focal and generalized,
have been associated with moyamoya and are likely related
Childs Nerv Syst (2010) 26:12971308
to hypoperfusion. Choreiform movements have been
associated with moyamoya disease, occurring in 36% of
patients, and are attributed to any dysfunction of the basal
ganglia-thalamocortical circuits, including infarctions and
mechanical compression by traversing dilated collateral
vessels [30].
Moyamoya disease refers to the idiopathic variant,
whereas moyamoya syndrome refers a condition in which
children with a recognized clinical disorder also have
moyamoya. There are multiple documented clinical syn-
dromes and conditions that have been associated with
moyamoya. These entities include: prior radiotherapy to the
head or neck for tumors, including craniopharyngiomas,
pituitary tumors, optic gliomas; genetic disorders including
Down syndrome, neurofibromatosis type 1 (with or without
hypothalamic-optic pathway tumors), tuberous sclerosis,
primordial dwarfism, large facial hemangiomas, Fanconis
anemia, sickle cell disease, and other hemoglobinopathies;
autoimmune disorders including Graves disease; collagen
vascular disorders including Marfans syndrome; congenital
cardiac anomalies; renal artery stenosis; infections includ-
ing tuberculous meningitis and leptospirosis; and fibromus-
cular dysplasia [15, 19]. These clinical associations and
syndromes represent a risk factor for both the development
and progression of moyamoya.
Natural history and progression
The natural history of untreated moyamoya ranges from
a slow progression with intermittent events, to rapid
neurological and cognitive decline, with overall mortality
rates in the Japanese literature as high as 4.3% [1]. The
long-term outcome of moyamoya disease is poor, as
inevitable progression occurs in the majority of patients,
with up to 66% having symptomatic progression over a
5-year period following diagnosis [19, 31]. However,
various studies have shown a significant impact on long-
term outcome in those patients undergoing surgical
revascularization. Fung et al. [70] conducted a literature
review of all cases of reported pediatric moyamoya from
1966 to 2004, and found a total of 1,156 symptomatic
patients treated surgically. Post-operatively, 592 (51.2%)
were completely asymptomatic, 411 (35.5%) had defini-
tive improvement (defined as decreased frequency and/or
severity of symptoms), and 122 (10.5%) remained static.
Only 31 (2.7%) of 1,156 patients had definitive deterio-
ration following surgical revascularization. As far as
clinical indicators for favorable long-term prognosis in
children undergoing surgical revascularization, it is appar-
ent that neurological status at the time of surgery holds the
most prognostic value (as opposed to age at time of
surgery) [19].
1299
There have been several reports of children presenting
with unilateral moyamoya, and the obvious concern in
these cases becomes contralateral progression of disease.
The rate of progression of contralateral disease is variable.
For example, Smith and Scott [8] report that of 16 children
with unilateral disease, nine developed contralateral steno-
sis over a 6-month to 4-year follow-up period, whereas the
remainder of children were disease free up to 7 years after
initial angiogram. In a single-center review of 157 patients
by Kelly et al. [32], there were 28 patients with unilateral
moyamoya, 18 of which had clinical follow up of greater
than 5 months. Seven went on to develop contralateral
findings of moyamoya, and the authors noted that equivocal
or mild stenosis in the contralateral hemisphere was a good
predictor for the development of contralateral moyamoya.
Mean time to development of contralateral disease varies
by study, and has been reported as 12.7 months (range of
5-22 months) to 3.1 years (0.5-7 years) [32, 33].
Pathology and pathophysiology
Pathologically, the stenosis associated with moyamoya
arises in the supraclinoid ICA, extends distally to the
bifurcation, and in the latter stages, involves the proximal
branches of both the anterior and middle cerebral arteries.
In rare cases, stenosis has also been observed in vessels of
the posterior circulation, most commonly affecting the
proximal portion of the posterior cerebral arteries or the
basilar artery [22]. Histologically, vascular changes involve
endothelial hyperplasia, fibrocellular thickening of the
intima, and torturosity and duplication of the internal elastic
lamina [15, 19, 34, 35]. There is neither evidence of an
inflammatory infiltrate nor atheromatous plaque within the
vascular walls [34]. Rather, occlusion results from progres-
sive narrowing of vessel diameter from a combination of
smooth muscle cell hyperplasia and the formation of an
intraluminal thrombus [19, 35].
Collateral vessels form in moyamoya disease in response
to brain ischemia distal to the ICA stenosis. They originate
from various perforating vessels including the lateral and
medial lenticulostriate, anterior and posterior choroidal,
thalamoperforating, and thalamogeniculate arteries [22, 36].
In the latter stages of moyamoya, transdural collaterals
derived from the external carotid arteries (ECA) including
the middle meningeal, superficial temporal, occipital, and
internal maxillary arteries, and from the ophthalmic arteries
including the anterior and posterior ethmoid, recurrent
meningeal, and anterior falx arteries are noted [36].
Histological study of postmortem collateral vessel speci-
mens reveal overall thinned walls, atrophy of the media
secondary to damaged smooth muscle cells and increased
matrix deposition with cellular debris, and torturosity,
1300
fragmentation, and thinning of the internal elastic lamina
[37]. Microaneurysm formation within the weakened
moyamoya vessels are a potential source of intracranial
hemorrhage, and have been found on both the anterior and
posterior choroidal arteries [15].
Exact pathogenesis and etiology of moyamoya disease
are currently unknown; however, several studies have
shown both environmental and genetic associations. Envi-
ronmentally, moyamoya disease has been diagnosed in
children who underwent prior head and neck irradiation for
neoplastic disease. Vascular stenosis is a documented
finding after radiation therapy. In addition, moyamoya
disease has been found in children with prior skull base
infections, including tuberculosis meningitis. Finally, in the
series from Boston Childrens Hospital, there were two sets
of identical twin, each with only one affected sibling,
indicating an environmental influence [1].
Moyamoya is most highly associated with Japanese
populations where a familial occurrence has been reported
to range from 7% to 12%, with a slightly lower occurrence
in the USA, suggesting a genetic linkage [1, 16, 17].
Furthermore, moyamoya has been associated with certain
genetic disorders including Downs syndrome, neurofibro-
matosis one, and sickle cell disease [1, 15, 19, 38]. Similar
histological changes in the extracranial vasculature, includ-
ing pulmonary, renal, and pancreatic arteries, have been
documented in patients with moyamoya disease [35]. There
have been linkages between moyamoya and genetic
markers/foci on chromosomes 3p, 6q, 8q, and 17q [39
41]. Chromosome 3p includes a locus for the Von-Hippel-
Lindau tumor suppressor gene as well as a locus for
Marfans syndrome. Though a gene product has not been
discovered from the 3p locus as of yet, in light of its
linkage to both Von-Hippel-Lindau and Marfans, it is
likely involved in the formation and maintenance of normal
vessel walls [15].
Several studies have investigated the molecular basis of
moyamoya disease, and even though a direct genetic
abnormality has not been recognized, multiple cellular
aspects of the disease have been elucidated. Basic fibroblast
growth factor (bFGF), an angiogenic substance, has been
studied in moyamoya disease. Hoshumaru et al. [39] using
immunohistochemistry examined two sections of superfi-
cial temporal artery (STA) and four samples of dura in the
postmortem study of four patients with moyamoya disease.
The vascular and meningeal cells exhibited more intense
staining for bFGF than controls, and multiple associations
were postulated [39]. First, intimal thickening, the under-
lying histology of moyamoya, may be caused by the
migration and activation of smooth muscle cells containing
abnormally large amounts of bFGF. Secondly, endogenous
production of bFGF is required for movement of vascular
endothelial cells during neovascularization. Larger amounts
Childs Nerv Syst (2010) 26:12971308
of bFGF within the STA and dura may play a role in the
development of collateral moyamoya vessels. Further-
more, Malek et al. [40] found elevations of bFGF in the
cerebrospinal fluid of children with moyamoya when
compared to matched samples in patients with hydroceph-
alus and controls, further signifying the role of bFGF in
moyamoya disease. A further link to the genetic basis of
moyamoya was revealed in a study by Minehaura et al.
[41] were a major locus for the autosomal dominant form
of moyamoya was found in the telomeric region of 17q25.
Four candidate genes were selected from this locus based
on their biological properties, including BAIAP2, which
interacts with BAI1 (brain angiogenesis inhibitor-1),
which is an inhibitor of bFGF [41]. Overall, further
studies need to be performed to elucidate both the genetic
and environmental roles in the development of moyamoya
disease.
Diagnosis
Moyamoya disease should be taken into consideration and
worked up in any child presenting with ischemic symp-
toms, especially in the setting of hyperventilation, crying,
and/or physical exertion. A suspected diagnosis of moya-
moya disease is confirmed with radiological studies.
Head computed tomography
Workup of a child with moyamoya disease typically begins
with a head computed tomography (CT) to assess for more
common pathology including tumors and/or hydrocephalus.
Classically, findings on a head CT in pediatric patients with
moyamoya include hypodensities suggestive of prior
infarctions in watershed areas (especially in the distribution
of the middle cerebral artery), basal ganglia, deep white
mater, and periventricular regions [8, 15, 19]. Although rare
in the pediatric population, head CT imaging will also
reveal hemorrhagic pathology, including intracerebral,
intraventricular, subarachnoid, and subdural hemorrhages
[8, 2427]. Depending upon the severity of prior infarc-
tions, cerebral atrophy and encephalomalacia may also be
detected. Recent advances in the field of CT angiography
has led to its use in both the diagnosis of moyamoya
disease and to evaluate neovascularization after surgical
bypass [42].
Magnetic resonance imaging/angiography
Magnetic resonance imaging (MRI) has become a reliable
diagnostic modality in moyamoya disease. Acute cerebral
infarctions are easily recognized on diffusion-weighted
imaging, with chronic infarcts delineated by both T1- and
Childs Nerv Syst (2010) 26:12971308
T2-weighted imaging [43]. Fluid attenuated inversion-
recovery MRI which demonstrates linear high signal
intensity following a sulcal pattern (ivy sign) has been
used to infer cortical ischemia and is felt to represent slow
flow in the poorly perfused cortical circulation in children
with moyamoya [19, 44]. Magnetic resonance angiography
(MRA) has been used to accurately characterize both the
stenosis and basal collateral formation associated with
moyamoya disease [45]. The MR findings most suggestive
of moyamoya disease remains diminished flow voids in the
ICA, ACA, and MCA bilaterally, with concurrent large
flow voids in the basal ganglia and thalamus representing
collateral moyamoya vessel formation [45, 46]. Recently,
MRI/MRA has been suggested as a reliable alternative to
conventional angiography for diagnosis of moyamoya,
based on the ease and fewer procedural associated risks
in the pediatric population (Fig. 1). In studies by Yamada
et al. [45, 46], compared to conventional angiography,
stenosis was accurately diagnosed via MRA in 88%, 83%,
and 88% of ICA, ACA, and MCA vessels, respectively.
An overall sensitivity and specificity for accurate diagno-
sis of vascular stenosis was 100%, 93% and 100%, 77%,
respectively, for MRA and MRI. In addition, 75% of
moyamoya collateral vessels diagnosed on MRA corrob-
orated with angiographic findings, concluding that MRA
is beneficial in diagnosing larger basal ICA, leptomenin-
geal, and transdural collaterals, whereas smaller collateral
remain underestimated. Of note, the average age of the
patient population in these studies was older, likely
leading to better quality imaging without motion artifact.
The authors concluded that when MRA and MRI imaging
are performed in tandem, a more complete diagnosis and
evaluation of moyamoya disease is obtained. Although
MRA and MRI are not the gold standard, they are sensitive
and specific enough for reliable diagnosis without invasive
Fig. 1 T2-weighted axial MR
images in a child with moya-
moya disease showing incom-
plete flow voids in bilateral
suprasellar cisterns indicating
severe stenosis of the supracli-
noid ICAs (left, white arrows).
There are multiple small flow
voids throughout the bilateral
basal ganglia which represent
moyamoya collateral vessels
(right, black arrows) and peri-
ventricular ischemic changes
1301
testing when moyamoya is suspected in a child, reserving
conventional angiography for pre-operative planning.
Conventional angiography
Conventional angiography remains the gold standard for
both the diagnosis and surgical planning for patients with
suspected moyamoya disease. A five- or six-vessel study
should be performed, including imaging of the bilateral
ECA, ICA, and one or two vertebral injections. Angio-
graphic imaging of the bilateral external carotid arteries is
of utmost importance for pre-operative planning to prevent
disruption of these collaterals during the surgical revascu-
larization. Classical findings on angiogram include stenosis
of the supraclinoid ICA, proximal ACA and MCA,
associated with basal ICA, leptomeningeal, and transdural
collaterals giving rise to the classic puff of smoke
appearance [3] (Fig. 2). Furthermore, angiography is
functional in both the detection and anatomical descriptions
of aneurysms and AVM associated with moyamoya disease
[2427]. Angiographic appearance of moyamoya disease
progresses through one of six stages as originally defined
by Suzuki and Takaku [4] in 1969: (1) carotid stenosis
without the presence of moyamoya collaterals; (2) initial
appearance of basal collateral vessels; (3) progressive
stenosis of the distal ICA, with increasing prominence of
the basal collaterals; (4) severe stenosis or occlusion of the
anterior circulation with the formation of ECA collaterals;
(5) prominence of the ECA collaterals, reduction, and
stenosis of the basal moyamoya collaterals; and (6)
complete occlusion of the ICA, disappearance of the basal
moyamoya collaterals, with cortical blood supply solely
provided though ECA collaterals. Angiography can play an
important role in post-operative imaging after surgical
bypass as it is frequently used in addition to MRI/A as a
1302
Fig. 2 ICA injection in a conventional cerebral angiogram in a child
with moyamoya disease revealing stenosis of the supraclinoid ICA
(white arrow) with formation of an extensive network of collateral
vessels
means of assessing neovascularization and cortical perfu-
sion. A grading scheme has been developed to assess
synangiosis-induced collateral formations by Matsushima et
al. [47], with grade A representing synangiosis-induced
filling of greater than two thirds of the MCA circulation,
grade B between one third and two thirds, and grade C
signifying less than one third filling.
Electroencephalography and cerebral blood flow studies
Electroencephalography (EEG) is a diagnostic tool used
in the evaluation of moyamoya, as specific alterations are
found in children affected with this condition. Charac-
teristic findings include posterior and/or centrotemporal
slowing, and a re-buildup phenomenon after the end of
hyperventilation [48]. In all children, hyperventilation
induces a diffuse pattern of high voltage, monophasic
slow waves, referred to as build up, that terminate after
hyperventilation has ceased. In pediatric patients with
moyamoya, there is a return of the high voltage, mono-
phasic slow waves following the end of hyperventilation,
termed re-buildup, which is thought to represent a
diminished cerebral perfusion reserve [8, 15, 19, 48].
Essentially, hyperventilation induces cerebral vasocon-
striction, and upon its cessation, cerebrovascular dilation
(buildup). In children with moyamoya, re-buildup occurs
as a steal phenomenon as blood is diverted from the
dilated cortical vessels to the moyamoya-associated
collaterals, creating a cortical ischemic state, represented
as the reappearance of the high voltage, monophasic slow
waves on the EEG [21, 48]. Over time, re-buildup resolves
and the EEG returns to baseline. Re-buildup has been
Childs Nerv Syst (2010) 26:12971308
found to be present in greater than 50% of children with
diagnosed moyamoya.
Additional imaging studies have been used to monitor
cerebral blood flow in children diagnosed with moya-
moya, both as a pre-operative measure and following
surgical bypass to assess neovascularization induced
cortical perfusion. These studies include transcranial
Doppler ultrasonography, CT and MR perfusion imaging,
xenon enhanced CT, positron-emission tomography, and
single-photon-emission CT [4952].
Treatment options
After a significant stroke or intracerebral hemorrhage, the
pediatric patient with moyamoya is often left with
devastating permanent neurological and cognitive impair-
ments [1, 15, 5355]. Neurological status at the time of
surgical interventions remains the most significant prog-
nostic indicator for long term outcome [19]. Therefore,
early diagnosis and prompt surgical treatment provide the
best chances to improve neurological outcome.
Medical treatment
Currently, there is no definitive medical treatment to reverse
or stabilize the course of moyamoya disease. There are
two classes of medications that play an adjuvant role in
the treatment of moyamoya; antiplatelet agents and
calcium channel blockers [5355]. A proportion of the
ischemic symptoms associated with moyamoya disease
have been attributed to microthrombus formation due to
emboli arising from sites of arterial stenosis [8, 15, 19].
Daily, lifelong aspirin use is prescribed to prevent the
ischemia associated with this embolic phenomenon.
Patients less than 6 years of age receive 81 mg/day, with
the dose gradually increased into adolescence and adjusted
appropriately if there are any signs of the known side
effects, including easy bruising and bleeding [15]. Anti-
coagulants, such as warfarin (Coumadin), are rarely used
in the pediatric population due to the difficultly in
maintaining steady therapeutic levels, though there have
been some successes in the use of low-molecular weight
heparin (Lovenox) for select children [8, 19]. The second
class of medications used in moyamoya disease is calcium
channel blockers, and evidence exists to support their use
in the treatment of persistent postoperative TIAs and
intractable headaches [8, 15, 19]. The mechanism of
action remains unknown, but calcium channel blockers
are shown to reduce the frequency and severity of
refractory TIAs, with a low side-effect profile in children
[8, 15, 19].
Childs Nerv Syst (2010) 26:12971308
Surgical treatment
Results from several published studies have shown a
favorable response to surgical intervention in moyamoya
disease, especially in the reduction of ischemic events [56,
57]. Although there is no published prospective randomized
controlled clinical trial to define a superior surgical
procedure in children with moyamoya, there have been
several reported successes using a variety of the surgical
revascularization procedures. Revascularization can be
divided into two groups, direct and indirect types. Direct
bypass provides rapid, instant increases in cerebral perfu-
sion, whereas indirect procedures rely on delayed neo-
vascularization through a variety of processes. The most
common direct and indirect revascularization procedures
will be discussed, as well as the surgical outcomes from the
two largest published pediatric series, in addition to the data
from our institution.
Superficial temporal artery-to-middle cerebral artery bypass
(STA-MCA)
Yasargil and Donaghy were the first to perform direct
extracranial-to-intracranial bypass in 1967 for the treatment
of cerebral ischemia, and Yasargil then performed the first
reported case of direct superficial temporal artery-to-middle
cerebral artery bypass (STA-MCA) bypass in a child with
moyamoya [57, 58]. Surgical technique begins with the
identification and dissection of the frontal and/or parietal
branches of the STA [59, 60]. A frontotemporal craniotomy
is carried out over the Sylvian fissure, dura is opened, and a
suitable M3 or M4 recipient vessel is identified. The
recipient vessel is clamped proximally and distally to the
site of anastomosis, as well as distal clamping of the donor
STA. An end-to-side anastomosis is performed. The
temporary clips are removed, and the patency and hemo-
stasis of the bypass is assessed. Dura, bone flap, and skin
closure are then carried out with care taken to avoid
compression of the donor STA. In a study by Schick et al.
[61], long-term patency of STA-MCA bypass, irregardless
of clinical indication, was 91% at a 5.6 year follow up
period. STA-MCA bypass remains the most common direct
revascularization procedure for childhood moyamoya,
though occipital artery-to-middle cerebral artery bypass
has been used in cases where the STA does not provide a
suitable donor [62]. The use of STA-MCA bypass in
combination with indirect procedures, including EMA and
EDAMS, has also encountered success as reported in the
literature.
The major advantage of the direct bypass procedure is an
immediate increase in blood flow to the ischemic brain.
Disadvantages include technical difficulty due in part to the
small diameter of the donor and recipient vessels in the
1303
pediatric population. In addition, direct bypass procedures
may result in transient hypervascular edema of the
revascularized hemisphere, which typically resolves with
no sequelae. While the treatment addresses the MCA
distribution, there is no direct effect upon ACA or PCA
territories. Temporary clipping of the MCA, which may
interfere with already present leptomeningeal and transdural
collaterals, can lead to peri-operative stroke. Furthermore,
the STA-MCA bypass provides only a limited amount of
meaningful blood flow to the entire MCA distribution, thus
placing the child at risk for refractory ischemic events [8,
15].
Encephalomyosynangiosis
Indirect procedures were developed as an alternative to
bypass due to the difficulties encountered in the pediatric
population with direct STA-MCA anastomosis. Indirect
procedures tend to be less invasive, are technically easier
and result in a shorter operative time, do not restrict
treatment to solely the MCA distribution, and most
importantly, do not involve clamping of recipient vessels
[8, 15, 19, 59]. Encephalomyosynangiosis (EMS) was first
used in the treatment of moyamoya disease in the late
1970s, and involves a frontotemporal craniotomy, dural
opening, followed by the removal of the arachnoid over the
region to be treated [63]. The temporalis muscle is placed
over the exposed pia and the dura approximated over the
muscle. Care must be taken to avoid disruption of the
temporalis blood supply both during opening and closing.
Angiogenesis occurs over several weeks to months due to
the rich blood supply of the temporalis muscle by the deep
temporal artery [63, 64]. Even though EMS is a less
invasive procedure, there are distinct disadvantages, includ-
ing the necessity of a larger craniotomy and dural opening,
cosmetic deformation, and more importantly, post-operative
complications such as seizure, brain edema, and symptom-
atic mass effect associated with the large space-occupying
muscle [59, 63].
Encephaloduroarteriosynangiosis
Encephaloduroarteriosynangiosis (EDAS) was introduced
as a surgical alternative for the treatment of moyamoya
disease in 1980 [65]. In this technique, the intact donor
STA (parietal branch) is dissected free, a craniotomy flap is
turned, and the STA is sutured by its adventitia/galeal cuff
to a linear opening in the dura [8, 15, 59]. The donor STA
is left intact, as opposed to its sacrifice in the STA-MCA
bypass. In modified variants, the dura near the middle
meningeal artery is either inverted onto the cortical surface,
or it is split into both an outer and inner layer with the
heavily vascular outer layer placed in direct contact with
1304
the cortex [8, 59]. This modification derives from the
finding that the vascular dura near the middle meningeal
artery has been shown to be more inclined to form vascular
collaterals in patients with moyamoya disease [66]. A
further modification, encephalomyoarteriosynangiosis
(EMAS) consists of a combination of both EMS and
EDAS. In this procedure, the temporalis muscle along with
a superficial branch of the STA is placed in contact with the
cerebral cortex. Besides the typical disadvantages of the
indirect procedure, failure of EDAS and EMAS (in addition
to EDAMS and pial synangiosis) typically render the STA
ineffective for use in future direct bypass procedures.
Pial synangiosis
Scott [1, 8], first introduced pial synangiosis as a
modification to the EDAS procedure. This technical
modification was derived from the thought that the
arachnoid layer served as a preventative barrier to vascular
in-growth in the standard EDAS procedure [59]. The
technique involves the following steps [8]: (1) a suitable
donor vessel, typically the parietal branch of the STA, is
dissected from distal to proximal along with a galeal cuff
and surrounding soft tissue; (2) a large craniotomy is turned
in the region adjacent to the donor vessel; (3) the dura is
opened in a stellate fashion into a minimum of six flaps
to increase the surface area of dural to pial contact, and
avoiding disruption of potential meningeal collateral
vessels; (4) the arachnoid is opened widely and removed
in the area exposed by the dural opening; (5) the intact
donor artery is sutured through its adventitia, using four to
six interrupted 10-0 nylon sutures, to the pial surface; and
(6) the bone flap is replaced over a Gelfoam cover of dura,
the temporalis muscle and skin are closed paying close
attention to avoid compression of the donor vessel. Despite
opening the arachnoid widely and no dural closure, risk of
CSF leak remains extremely low [1].
Encephaloduroarteriomyosynangiosis
Encephaloduroarteriomyosynangiosis (EDAMS) was intro-
duced in 1984 as a combination of multiple indirect
procedures to provide the greatest chance for neovascula-
rization. The technique involves the following procedures
[67]: (1) dissection and isolation of a branch of the STA
with a galeal cuff, (2) a large craniotomy and dural opening
into multiple leaflets avoiding disruption of the middle
meningeal artery, (3) opening of the arachnoid overlying
the entire craniotomy, (4) the outer surface of the dural
leaflets are folded inward to contact the pial surface and
sutured in place, (5) the STA and galeal cuff are laid onto
the pial surface and affixed to the dural margin, and (6) the
temporalis muscle is stretched to cover the brain and
Childs Nerv Syst (2010) 26:12971308
sutured to the dural edges. This procedure provides
multiple sources for the development of collateralization,
including the highly vascular outer dural layer, the STA and
its galeal cuff, and the temporalis muscle via the deep
temporal artery. In one study, EDAS was compared to
EDAMS, and EDAMS with STA-MCA bypass both clinically
and radiographically. EDAMS, regardless of the combined
STA-MCA anastomosis, was more effective in achieving
angiographic revascularization and reduction of pre-operative
ischemic symptoms compared to EDAS alone [68].
Omental transplantation
Omental transplantation is a rarely used technique used to
treat pediatric moyamoya disease, and is classically
reserved for cases in which both direct and indirect
revascularization procedures have failed. Omental trans-
plantation was first introduced in 1973 as a treatment for
cerebral ischemia as studies in a canine model showed
neovascularization between the omentum and underlying
neural tissue; several years later it became a viable option
for the treatment of moyamoya disease [69]. In this
procedure, either an intact omental flap is tunneled from
the abdomen, thru the chest and neck, and placed on the
cortical surface, or a free flap is anastomosed via the
gastroepiploic artery and vein to the superficial temporal
artery and vein, respectively [15]. The patency rate for
omental grafts have been reported to be as high as 70% and
neovascularization is attributed to lipid factors in the
omentum that may have intrinsic angiogenic properties [59].
Cranial bur holes
Multiple cranial bur holes have been used as adjuncts to
other revascularization procedures, including STA-MCA
bypass, EMS, EDAMS, and pial synangiosis [1]. Typically,
the bur holes are placed, the underlying dura, arachnoid,
and pia are opened, and a pericranial flap is placed in
contact with the cortex. In a study by Sainte-Rose et al.
[71], 14 children underwent placement of 1024 bur holes
per hemisphere. Follow-up MR perfusion and correlation
with conventional angiography, in the five most recent
cases showed excellent revascularization of the ischemic
cortex by ECA collaterals, with no postoperative ischemic
events in these children.
Peri-and postoperative considerations
Regardless of surgical procedure, there are specific peri-
operative risks for children undergoing revascularization for
moyamoya. The risk of stroke is highest in the first 30 days
following surgery. Then, the risk decreases noticeably after
the first month with a 96% probability of remaining stroke-
Childs Nerv Syst (2010) 26:12971308 1305

Table 1 Children treated with moyamoya at the Johns Hopkins free over the subsequent 5-year period [8]. Focus has
Childrens Center
concentrated on preventing ischemic events in the initial
Variables Johns Hopkins Hospital 30 days following surgery. Methods to reduce pain, crying,
and hyperventilation induced cerebral vasoconstriction
No. of pediatric patients (age 14 (0.113.92 years) include effective pain control with peri-operative sedation
range at time of surgery)
No. of surgical procedures 23
and the use of painless wound dressings and absorbable
sutures [8, 19]. Intra-operatively, hypotension, hypovole-
1. Pial synangiosis 13
mia, hyperthermia, hypercapnia, and hypocapnia should be
2. EDAMS 7
avoided. The use of intra-operative scalp EEG to detect
3. Combined STA-MCA and 3
EDAMS ischemic events during the induction and maintenance of
Moyamoya type general anesthesia has also been employed [8]. Addition-
1. Disease 8 ally, the use of aspirin in both the peri-operative period and
2. Syndrome 6 (sickle cell disease 3, Downs long-term has become routine care.
syndrome 2, NF1 1)
Presenting symptoms Surgical outcome data
1. Ischemic (TIA & CVA) 12 (85.8%)
2. Seizure 1 (7.1%) To date, there have been two large published series in the
3. Headache 0 (0%) English language dealing with the surgical treatment of
4. Hemorrhage 0 (0%) moyamoya in the pediatric population. Each has docu-
5. Incidental 1 (7.1%) mented success with surgical revascularization, one via the
Postoperative complications 3 indirect method, and one via the direct. The largest series is
1. TIA 2 reported by Scott et al. from The Childrens Hospital,
2. Pseudomeningocele 1 (non-operative) Boston in which 143 patients underwent 271 revasculari-
zation procedures (96 in whom both hemispheres were
treated in the same sitting), all with pial synangiosis [1].
Preoperative stroke and TIAs occurred in 67.8% and 43.4%

Table 2 Children treated with moyamoya at three different hospitals

Variables The Childrens Hospital, Boston, Stanford University, Johns Hopkins Hospital,
Massachusetts California Maryland

No. of patients (age range at time of 143 (0.521 years) 96 (117.9 years) 14 (0.113.9 years)
surgery)
No. of surgical procedures 271 168 23
1. Direct 0% 76.2% 0%
2. Indirect 100% 23.8% 87%
3. Combined 0% 0% 13%
Moyamoya type
1. Disease 66 80 8
2. Syndrome 77 16 6
Presenting symptoms
1. Ischemic 67.8% stroke, 51% 85.7%
43.4% TIA
2. Hemorrhagic 2.8% 2.1% 0%
3. Headache 6.3% 44% 0%
4. Seizure 6.3% NR 8.3%
5. Choreiform movements 4.2% NR 0%
6. Incidental 4.2% NR 8.3%
Immediate postoperative complications (<30 days)
CVA 11 2 0
1. TIA (severe) 3 0 2
2. Hemorrhage 0 1 0
1306
of children, respectively, with only 11 episodes of stroke
and three severe TIAs in the immediate 30 day post-
operative period. The success of pial synangiosis is evident
by the fact that in 126 patients followed for more than
1 year, there were only seven late-onset complications: four
suffered a late-onset stroke, one experienced a severe, but
completely resolved TIA, and two with persistent TIAs. Of
the 46 patients with the sole presentation of stroke followed
for more than 5 years, only two developed new strokes in
this follow-up period.
The second largest series dealing with the surgical
treatment of pediatric moyamoya has been published by
Steinberg et al. [38] from Stanford University Medical
Center. In this series (which included both adult and
pediatric patients for a total of 450 revascularization
procedures), there were 96 children undergoing 168
procedures, of which, 76.2% were direct bypass with
STA-MCA anastomosis, and 23.8% with various indirect
measures including EDAS. Within the immediate 30 day
post-operative period, there were only three reported events
in the pediatric population: two documented strokes and
one hemorrhage with complete neurological recovery. TIAs
which were documented to occur between post-operative
day 3-7 and last until day 14, were all associated with a
complete recovery. Of note, it was found that in children
presenting with stroke, there was a trend towards a higher
rate of post-operative complications, with those treated with
indirect revascularization being 2.5-fold more likely to
suffer postoperative stroke then those treated with STA-
MCA bypass.
From October 1999 to October 2009, we have treated 14
children (age ranging from 0.1 to 13.92 years) with
moyamoya at the Johns Hopkins Childrens Center. Twenty
three procedures have been performed, including 13 for pial
synangiosis, seven for encephaloduroarteriomyosynangio-
sis, and three for a combination of STA-MCA bypass with
EDAMS. The idiopathic form was present in eight children
and six children had the moyamoya syndrome (three with
sickle cell disease, two with Downs syndrome, and one
with neurofibromatosis-1 with bilateral optic nerve glio-
mas). Presenting symptoms in the majority of cases was
ischemic disease (12 of 14), with one case associated with
seizures, and one as an incidental finding. Within the
immediate 30 days post-operative period, there were only
two events, both TIAs with complete resolution. There was
no evidence of CSF leak, but one case of a pseudomenin-
gocele managed conservatively (Tables 1, 2).
Conclusions
Despite being relatively uncommon, moyamoya disease is
becoming more widely recognized worldwide as a cause of
Childs Nerv Syst (2010) 26:12971308
pediatric cerebrovascular events, and should be considered
in any child who presents with symptoms of cerebral
ischemia. Rapid diagnosis of the pediatric patient with
moyamoya is disease is essential, as neurological status at
the time of treatment is more predictive of long-term
outcome then age. Diagnosis is confirmed by MR and
conventional angiographic imaging. Associated clinical
conditions and syndromes should be assessed for, as they
are a risk for both the development of moyamoya and its
progression. If left untreated, moyamoya disease pro-
gresses, and frequently results in permanent neurological
and cognitive deficits. Although there is no curative
medical treatment for moyamoya, numerous studies have
shown long-term improvement in children undergoing
surgical revascularization procedures. As there has been
success with both the direct and indirect revascularization
procedures in children, each case should be handled on an
individual basis, with the ultimate goal to arrest and/or
reverse the chronic state of ischemia.
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