Child’s Nerv Syst (2002) 18:186–190
DOI 10.1007/s00381-001-0518-3

S.E.J. Connor
D. Hewes
C. Ball
J.M. Jarosz

Received: 23 February 2001
Revised: 15 June 2001
Published online: 23 November 2001
© Springer-Verlag 2001
S.E.J. Connor (✉) · J.M. Jarosz
Department of Neuroradiology, Ruskin
Wing, King’s Healthcare NHS Trust,
King’s College Hospital, Denmark Hill,
London SE5 9RS, UK
e-mail: s.connor@talk21.com
Tel.: +44-208-7618344
Fax: +44-207-3463120
D. Hewes · C. Ball
Department of Paediatrics, King’s College
Hospital, London, UK

C A S E R E P O RT

Alagille syndrome associated
with angiographic moyamoya

Abstract We describe the case of a
13-year-old boy with Alagille syndrome in whom intracranial imaging
was performed following a seizure.
The MRI and MRA revealed changes of angiographic moyamoya within
both the anterior and posterior circulation. This very rare manifestation
of the systemic vasculopathy in Alagille syndrome has not been previously documented in a patient without a focal neurological deficit. We
discuss the potential role of routine
intracranial imaging in patients with
Alagille syndrome.

Introduction
‘Alagille syndrome’ (arteriohepatic dysplasia or syndromic paucity of interlobular bile ducts) is a term that has
been used to describe children with a paucity of interlobular bile ducts and the five main features of chronic cholestasis, posterior embryotoxon, butterfly-like vertebral
arch defects, peripheral pulmonary artery hypoplasia or
stenoses and peculiar facies [1, 2]. The syndrome is classified as ‘partial’ if only three or four of the major features are present [2]. Since its initial description [2, 17],
the clinical phenotype has been extended to include
growth and developmental delay [2, 13], renal abnormalities [5, 8, 13], pancreatic insufficiency and intracranial
abnormalities [5, 8, 13, 14, 18]. In addition to the pulmonary arterial abnormalities, there is a propensity for vascular lesions in the renal arteries, mesenteric vessels,
aorta, and intracranial and extracranial carotid arteries
[14, 17, 18].
We describe a child with partial Alagille syndrome
who was investigated with magnetic resonance imaging
(MRI) and magnetic resonance angiography (MRA) fol-

Keywords Alagille syndrome ·
Moyamoya · Magnetic resonance
imaging

lowing a seizure and was noted to have bilateral terminal
carotid steno-occlusive changes and abnormal vascular
networks within the basal ganglia and posterior fossa. In
the context of a known systemic disease, these imaging
features, which are similar to those seen in moyamoya
disease, are termed angiographic moyamoya [11].

Case report
A 3-month-old Caucasian boy presented with prolonged neonatal
jaundice and failure to thrive. He was diagnosed with partial Alagille syndrome on the basis of a butterfly vertebra at T10, angiographic evidence of multiple proximal and distal pulmonary artery
stenoses, and a liver biopsy that demonstrated a paucity of bile
ducts. The parents had no features of Alagille syndrome, and there
was no family history of liver disease.
His initial development was normal, and he remained generally
well until age 6. However, his subsequent course was characterised by poor weight gain, fatigue, pruritus, cholestasis and ascites.
Cholesterol (9.1–16.8 mmol/l) and triglyceride (2.6–3.1 mmol/l)
titres were chronically elevated. This prolonged period of ill
health culminated in hospital admission with melaena and ascites
at age 11, and the boy subsequently underwent orthotopic liver
transplantation. The postoperative course was complex with the

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Fig. 1 a Axial T2-weighted
MR images demonstrate T2 hyperintense infarcts within the
white matter of left frontal and
parietal lobes. b Coronal T1weighted image reveals bilateral narrow-calibre flow voids
corresponding to the basal ganglia collateral vascular channels

Fig. 2 3D TOF MR angiogram: a sagittal and b tilted coronal MIPs of the anterior circulation. There is bilateral signal dropout indicating severe
stenoses of the supraclinoid carotids and proximal aspects of
the anterior and middle cerebral arteries which are more
marked on the left. There are
multiple telangiectatic collateral vessels in the region of the
circle of Willis and the basal
ganglion. A dilated right anterior choroidal artery is noted,
which supplies a prominent
perforating vessel (arrow)

development of proteinuria, renal impairment, renal tubular acidosis and hypertension secondary to the exacerbation of chronic tubulointerstitial damage. Investigation for further deterioration in
liver function and jaundice revealed mild graft rejection and stricturing of the Roux loop biliary anastomosis. The administration of
mycophenolate to prevent graft rejection led to bone marrow suppression. Multiple percutaneous transhepatic biliary dilatations
were required, and surgical revision of the hepaticojejunostomy
became necessary when the patient was 13.
Two weeks after the hepaticojejunostomy, and following discharge from hospital, the child was witnessed to become unresponsive with his eyes deviating to the left. He became floppy and
unrousable for a period of 5 min. Neurological examination following the episode revealed no focal abnormality. A subsequent
electroencephalogram was normal. Computed tomography (CT) of
the brain revealed an area of low density in the left frontal deep
white matter.
Three months after the episode, he was reviewed by a paediatric neurologist. On examination, the boy was found to be small
for his age and to have clinical features of rickets in all four limbs.

He walked with a normal gait, and there was normal tone and
power in all four limbs, but he was generally hyperreflexic. Cranial nerve examination was normal. Full blood count, biochemical
profile including cholesterol and triglyceride levels were within
normal limits.
MRI and MRA were performed for further evaluation of the
CT abnormality. MRI revealed a large left frontal white matter T2
hyperintensity with smaller left parietal white matter and right cerebellar hemisphere T2 hyperintensities (Fig. 1a). A number of narrow-calibre flow voids were demonstrated in both basal ganglia
(Fig. 1b). The intracranial MRA study revealed severe stenoses of
both supraclinoid carotid arteries and their proximal divisions,
which was more marked on the left. Flow within an abnormal proliferation of fine vessels was noted in the region of the circle of
Willis and in the distribution of the lenticulostriate branches
(Fig. 2a, b). A further network of irregular, narrow-calibre vessels
was seen related to the proximal posterior inferior cerebellar arteries (Fig. 3a, b). The MRA of the cervical vessels revealed no evidence of stenosis.

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Fig. 3 a 3D TOF MR angiogram sagittal and b tilted coronal MIPs of the posterior circulation. There are extensive collateral channels near the origins
of the posterior inferior cerebellar arteries (arrowheads) in
addition to dural and leptomeningeal collaterals with courses
in the posterior direction
(arrow)

Discussion
The appearance of angiographic moyamoya has been recorded in three previous patients with Alagille syndrome. Rachmel et al. described a 22-month-old girl
with partial Alagille syndrome who developed a sudden
onset of right hemiparesis. Later investigation revealed
right frontal encephalomalacia and calcification on CT
with bilateral terminal carotid occlusions, partial absence
of the middle cerebral arteries and angiographic moyamoya evident at cerebral angiography [14]. Woolfenden
et al. presented two further children with partial Alagille
syndrome and transient focal neurological deficits. They
demonstrated CT evidence of cerebral infarction, and angiography revealed terminal carotid stenoses and angiographic moyamoya, which was unilateral in one patient
and bilateral in the other [18].
Our case differs in that the patient had experienced no
focal neurological abnormality prior to the diagnosis of
angiographic moyamoya. The patient presented with an
episode that was interpreted as a seizure and which probably resulted from cerebral ischaemia. The site of the supratentorial cerebral infarct in the anterior watershed territory is the commonest site in early-stage anterior-circulation moyamoya disease [7]. Cerebral ischaemia is the
most frequent consequence of moyamoya disease in children [4]. Intraventricular, subarachnoid and intracerebral
haemorrhages can result from the breakdown of collateral vessels or associated cerebral aneurysms in any moyamoya patient [19], but are less common in children [7].
In contrast to previous cases of Alagille syndrome-associated moyamoya, which were documented prior to the
widespread availability of MRI, in this case it was possible to make a conclusive diagnosis noninvasively. MRI
clearly demonstrated the diagnostic features of more
than two flow voids within each basal ganglion, and

MRA revealed steno-occlusive disease of the terminal
internal carotid arteries and their proximal divisions [4].
It is appreciated that MRA may overestimate the degree
of stenoses and would be inaccurate in delineating the
extent of transdural and leptomeningeal collateral vessels. However, conventional angiography under general
anaesthetic, with its associated risk of inducing ischaemia, would only be indicated if surgical treatment became necessary.
Finally, this case demonstrated an abnormal network
of collateral vessels in relation to the posterior inferior
cerebellar arteries and infarction within the right cerebellar hemisphere. There are no previous descriptions of a
posterior circulation vasculopathy in Alagille syndrome.
Occlusive lesions related to the vertebral arteries of patients with moyamoya disease generally result from
proximal progression of posterior cerebral artery and
basilar artery lesions [9].
Recent reports have indicated a 12–14% incidence of
intra- and extra-axial intracranial haemorrhage and infarction in patients with Alagille syndrome [5, 8, 13]. Intracranial haemorrhage was the cause of death in 4 of 16
[8] and 2 of 3 [5] deceased patients in two outcome studies. There may be a predisposition to traumatic intracranial haemorrhage because of the thin cranial bones,
which result from the metabolic bone disease of liver
and renal dysfunction [5]. The presence of hypertension
and anticoagulation abnormalities could also precipitate
haemorrhage. We postulate that unrecognised angiographic moyamoya may also be implicated in both intracerebral haemorrhage and infarction in these patients. In
fact, Hoffenburg et al. noted multiple thin-walled vessels
at autopsy in one Alagille syndrome patient with intracranial haemorrhage [5]. It is also possible that angiographic moyamoya underlies some of the associated
mental retardation that is present in 16% of Alagille syn-

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drome patients and in 41% of adult moyamoya patients
[3].
The histopathology of the intracranial vascular lesions
in Alagille syndrome remains unproven. The vascular
and other manifestations of Alagille syndrome are
caused by mutations in the JAG1 gene, which encodes a
ligand for the Notch receptor [12]. Abnormalities of the
Notch intercellular signalling process are also responsible for CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukencephalopathy), which is a familial syndrome that includes subcortical ischaemic strokes and vascular dementia [16]. It is
probable that the cerebrovascular steno-occlusive disease
is a result of the same process, which leads to arterial
stenoses elsewhere and indicates that JAG1 is also expressed in the intracranial vasculature. The atherosclerotic potential of cholestasis-induced hypercholesterolaemia
[6], thromboembolism from extracranial carotid lesions
and paradoxical cerebral emboli, in the presence of an
associated congenital cardiac defect, should also be considered in the context of Alagille-associated cerebrovascular occlusions; however, such features were not present in our case. Hypertension has been associated with
angiographic moyamoya [11], and it is not possible to
discount its contribution to the steno-occlusive changes.
Autopsy studies of other conditions producing angiographic moyamoya have revealed different histological
findings from those seen in idiopathic moyamoya disease, so that the similarity of angiographic appearances
does not necessarily imply a similar pathogenesis [6].
The natural history of Alagille-associated vascular
stenoses, as observed on serial angiography, appears to
be that of gradual progression [18]; however, the angiographic stage tends to stabilise after adolescence [7]. The
angiographic moyamoya in our case was recognised at
age 13, which is much later than in the earlier cases, in
which the patients presented at 2, 22 and 24 months of
age, and this may influence the predicted rate of subsequent progression.
Any advantage gained by early detection of the angiographic moyamoya changes prior to the onset of neurological deficit is dependent on whether it alters manage-

ment of the patient. It is noteworthy that both the seizure
prompting cerebral imaging in this patient and the ischaemic event in the similar patient presented by Woolfenden et al. developed shortly after, and may have been
precipitated by, a general anaesthetic. Patients with Alagille syndrome often require a number of interventions
under general anaesthetic, and it would be important to
recognise steno-occlusive cerebrovascular changes so
that cerebral blood volume, blood pressure and arterial
carbon dioxide parameters could be optimised and ischaemic damage prevented [4]. The fact that the child was
relatively asymptomatic at the time of investigation suggests that there may be a need for routine imaging evaluation of patients with Alagille syndrome, particularly
prior to the administration of a general anaesthetic. Since
MRI itself may require general anaesthesia in some children, transcranial Doppler ultrasound with power Doppler may be an appropriate screening investigation [10],
with MRA being performed only when the ultrasound is
positive [15]. Treatment of moyamoya changes may be
medical, using vasodilators, anticoagulation and fibrinolytics, or surgical. However it is not clear at present
which treatment is of benefit, because no randomised
study has been performed in moyamoya disease or angiographic moyamoya.
In conclusion, we report a patient with Alagille syndrome and appearances suggestive of angiographic
moyamoya on MRI and MRA. This probably represents
a manifestation of the systemic vasculopathy present in
such patients. The recent recognition of an increased incidence of intracranial haemorrhage and infarction and
the known association with mental retardation lead us to
speculate that cerebrovascular steno-occlusive disease is
more common than previously recognised. Such lesions
should be identified, since they produce an increased risk
of cerebral ischaemia in patients experiencing fluctuations in blood pressure arising from general anaesthesia,
surgery or cardiac manipulation. It has been demonstrated that angiographic moyamoya may be present even in
the absence of neurological symptoms, which raises the
question of whether noninvasive intracranial arterial imaging should be performed prior to such interventions.

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