e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 3 ) 1 e1 0

Official Journal of the European Paediatric Neurology Society

Review article

SturgeeWeber syndrome: From the past

to the present

Annapurna Sudarsanam, Simone L. Ardern-Holmes*

Children’s Hospital at Westmead, Australia

article info abstract

Article history: SturgeeWeber syndrome is a rare sporadic neurocutaneous syndrome the hallmark of
Received 28 July 2013 which is a facial port-wine stain involving the first division of the trigeminal nerve, ipsi-
Accepted 12 October 2013 lateral leptomeningeal angiomata and angioma involving the ipsilateral eye. Our under-
standing of the disease process has vastly improved since it was first described in 1879,
Keywords: with recent identification of an activating somatic mutation in the GNAQ gene found in
SturgeeWeber syndrome association with both SturgeeWeber syndrome and non-syndromic facial port-wine stain.
Port-wine stain SturgeeWeber syndrome is marked by a variable but usually progressive course in early
Leptomeningeal angioma childhood characterised by seizures, stroke-like episodes, headaches, neurological and
Stroke-like episodes cognitive deterioration, hemiparesis, glaucoma and visual field defects. More recently, the
Epilepsy increased prevalance of otolaryngological, endocrine and emotionalebehavioural issues
Headaches have been established. Neurophysiology and neuroimaging studies provide information
Aspirin regarding the evolution of changes in SturgeeWeber syndrome over time. Early recognition
and aggressive management of symptoms remains cornerstone in the management of this
syndrome. An international collaborative effort is needed to maximise our understanding
of the natural history and response to interventions in SturgeeWeber Syndrome.
ª 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights
reserved.

Contents

1. Historical note . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Neuroimaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. Electroencephalogram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6. Management of facial port-wine stain and SturgeeWeber syndrome (Table 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.1. Facial port-wine stain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.2. SturgeeWeber syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8. Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
* Corresponding author. Department of Neurology, Children’s Hospital at Westmead, Cnr Hawkesbury Rd and Hainsworth St, Westmead,
Sydney, N.S.W. 2145, Australia. Tel.: þ61 2 9845 2551; fax: þ61 2 9845 3905.
E-mail address: simone.ardernholmes@health.nsw.gov.au (S.L. Ardern-Holmes).
1090-3798/$ e see front matter ª 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ejpn.2013.10.003

Please cite this article in press as: Sudarsanam A, Ardern-Holmes SL, SturgeeWeber syndrome: From the past to the present,
European Journal of Paediatric Neurology (2013), http://dx.doi.org/10.1016/j.ejpn.2013.10.003
2 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 3 ) 1 e1 0
1. Historical note
It has been well over a century since Schirmer first described
the association between facial angioma and buphthalmos in
1860.1 William Allen Sturge later recognised these features
together with neurologic involvement in what is now known
as the SturgeeWeber Syndrome (SWS). In 1879 he reported a
6½ year old girl with focal twitching of the left side of her body
at 6 months of age which later spread to the other side with
loss of consciousness.2 Of interest she had a ‘mother’s mark’
lesion on the right side of her face well demarcated in the
midline. She had a larger right eye (buphthalmos, congenital
glaucoma) with the sclera, retina and choroid all affected by a
vascular malformation on the right side. In addition she had a
patch of the skin lesion affecting her left eye, frontal and
temporal regions. He called these characteristic skin lesions
‘Port-wine stains’ and suggested that the neurological deficit
was caused by a lesion on the ipsilateral surface of the brain
rather than the brain parenchyma itself. This speculation was
held with scepticism until pathological proof was provided by
Siegfried Kalischer in 1901.3 Parkes Weber, in 1922, described
radiologic features including intracranial calcification in a
case with left sided telangiectatic naevus, left buphthalmos
and right hemiparesis pointing to a lesion on the left side of
the brain.4 The X-ray findings in this case proved the existence
of a more or less calcified and apparently ‘festooned’ lesion on
the surface of the left cerebral hemisphere. The term ‘Stur-
geeWeber Syndrome’ was coined in 1935 by Professor Hilding
Bergstrand giving acknowledgement to the previous two
clinicians.5
2. Clinical features
SturgeeWeber Syndrome (SWS) is classically associated with
facial port-wine stain (PWS) in the ophthalmic division of the
trigeminal nerve, glaucoma and vascular eye abnormalities,
and ipsilateral occipital leptomeningeal angiomata.6 It occurs
at an estimated frequency of between1:20,000 to 1:50,000.7,8
Whilst PWS are the most common vascular malformation,
occurring in 0.3% of live births with a sex ratio of 1:1,9 the
overall risk of SWS associated with any kind of facial cuta-
neous vascular malformation is approximately 8%. Port-wine
stains affecting the entire V1 distribution (ophthalmic division
of the trigeminal nerve) are strongly predictive of underlying
neurological and/or ocular disorders (78%), while the overall
risk for ocular and/or neurological disorders with partial V1
involvement has been estimated at 26%.10 Extracephalic port-
wine stains have been reported in as many as 52% of cases in
addition to cephalofacial port-wine stains.11 Association of
SWS with facial port-wine stain significantly increases with
bilateral topography, involvement of the upper eyelid and
extension from V1 to another territory.12 Rarely SWS with
leptomeningeal angiomata presents without any facial
involvement.13e15
Encephalofacial angiomatosis has been divided into three
types recognising variable distribution of the angioma to
include isolated facial involvement only versus associated
Please cite this article in press as: Sudarsanam A, Ardern-Holmes SL, SturgeeWeber syndrome: From the past to the present,
European Journal of Paediatric Neurology (2013), http://dx.doi.org/10.1016/j.ejpn.2013.10.003
leptomeningeal involvement, (Table 1). The Roach Scale has
been used for classification of encephalofacial angiomatosis,
as follows16:
 Type I e Both facial and leptomeningeal angiomas; may
have glaucoma (classic SturgeeWeber syndrome)
 Type II e Facial angioma alone (no CNS involvement); may
have glaucoma
 Type III e Isolated leptomeningeal-brain angioma; usually
no glaucoma
Intracranial angiomatosis is unilateral in the majority of
cases of SturgeeWeber syndrome, mostly posterior, and
usually but not always correlates with the unilateral or bilat-
eral distribution of the facial birthmark. No relationship has
been noted between the extent of the facial lesion and the
severity of the brain lesion.14 Bilateral intracranial involve-
ment, reported in about 15% of patients, is associated with a
higher incidence of seizures with earlier onset and overall
poorer outcome.6,17 In all bilateral cases there is predominant
involvement of one hemisphere.18 Bilateral frontal lobe
involvement appears to be a critical imaging marker of both
developmental and motor outcomes, whereas bitemporal
involvement may comprise a risk factor for autistic features.18
The clinical course of SWS is variable but typically marked
by progressive neurological problems such as seizures, hem-
iparesis, headache, stroke-like episodes, behavioural prob-
lems, mental retardation and visual field defects. Symptoms
and signs stabilise after a period of time.
Aside from the facial port-wine stain, epilepsy is often the
first presenting feature. Seizure onset is usually within the first
two years of life14 although cases of first presentation of SWS
with seizure in adulthood have been reported.11,13 Seventy five
to 100% of SWS patients develop epilepsy.6,13,14 Onset of seizures
occurs before 1 year of age in 75% of children, 86% by 2 years of
age and 95% by the age of 5 years .11 About 30% of cases may have
onset of seizures during febrile episodes and there is an
increased susceptibility for fever induced seizures at any age in
most SWS patients.14 Seizures are usually focal motor which
may secondarily generalise. Epilepsy may also manifest with
generalised tonic clonic seizures at onset, although about half
of affected individuals develop partial seizures as well.14
Myoclonic-astatic epilepsy made worse by oxcarbazepine and
carbamazepine has been reported.19 Infantile spasms have been
associated with SWS and are usually asymmetric.14,20,21 Gelastic
seizures can also occur.22 A pattern of clustering of seizures with
periods of intense seizure activity followed by prolonged periods
Table 1 e Classification of Encephalofacial angiomatosis
(Roach Scale).16
Type Facial angioma Leptomeningeal Glaucoma
angioma
Ia þ þ þ/
II þ  þ/
III  þ /þb
a
Classic SturgeeWeber syndrome.
b
Usually not present.
 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 3 ) 1 e1 0
of quiescence has been described,21,23 and is not necessarily
associated with a poorer prognosis.23 This seizure pattern leads
to difficult treatment decisions, especially in regard to the timing
of potential surgical resection. About 30% of cases may have
onset of seizures during febrile episodes and there is an
increased susceptibility for fever induced seizures at any age in
most SWS patients.14 Status epilepticus is not uncommon and is
frequently associated with prolonged weakness on one side of
the body or new onset visual field deficit (lasting several days,
weeks, or months), referred to as a stroke-like episode.24 Such
episodes may also be caused by ischaemic events, and the
electroencephalogram is important in directing most appro-
priate treatment in individual cases.25 Early onset of seizures,
medical intractability, bilateral intracranial involvement and
severe unilateral lesions are indicative of a poor prognosis.11,13,14
Cognitive impairments are common in patients with SWS.
In one case series borderline IQ to severe retardation was re-
ported in 53% of cases. None in this series of 55 patients ach-
ieved superior or middle schooling even in those with
complete or almost complete seizure control.14 Early onset and
refractory epilepsy was associated with lower mental level and
more severe motor impairment. Attention, emotional and
behavioural problems are also common in SWS, including a
higher prevalence of depressed mood, ADHD, oppositional-
defiant disorder and conduct disorder compared with unaf-
fected siblings.14 Increased incidence of depression affects
older children and adults especially those who are intellectu-
ally normal11,26 and has been associated with the presence and
size of the port-wine stain.26 Problems with social skills are
more common in those with seizures and cognitive deficits.26
While epilepsy and mental retardation are the most com-
mon symptoms, migraine-like headache has been recognized
as an important feature of SWS.27 Rarely migraine-like head-
ache with prolonged aura may be the sole symptom in SWS.28
Twenty-eight percent of patients with SWS may experience
headache having clinical characteristics of migraine.27 The
prevalence of migraine in children less than 10 years of age is
significantly higher than the general population at 31% versus
5% respectively.27 Hemiplegic migraine in the setting of SWS
has also been described.29,30 The episodes of headache may
last for several days. Multimodality imaging during the
symptomatic period is suggestive of delayed hyperperfusion,
hypermetabolism, increased leptomeningeal enhancement
with venous stasis and leakage in the affected area.28,30 These
imaging changes may resolve completely following recovery
from the headache episode. EEG may show significant slowing
over the affected side without epileptiform changes.30
Neurological deficits can be acquired slowly over time, or
as the result of stroke-like episodes associated with seizures
and/or migraines.6 Toddlers and young children are particu-
larly prone to stroke-like episodes triggered by falls with
minor head injury.31 On account of this, patients with SWS
should be advised to avoid recreational activities that are ex-
pected to frequently involve blows to the head. Seizure onset
at <6 months of age has been related to increased severity of
hemiparesis in a cohort of 77 patients seen at one centre.23
Most adults with SWS brain involvement have some degree
of focal neurological deficit, usually hemiparesis.11 Neurolog-
ical deterioration is more common in infants and young
Please cite this article in press as: Sudarsanam A, Ardern-Holmes SL, SturgeeWeber syndrome: From the past to the present,
European Journal of Paediatric Neurology (2013), http://dx.doi.org/10.1016/j.ejpn.2013.10.003
3
children, but strokes and acquisition of new neurological
deficits can occur in adults.
Hydrocephalus has rarely been reported, and is presumed
secondary to impaired venous drainage and cerebrospinal
fluid resorption. Intracranial haemorrhage is also rare, but has
been attributed to SWS in some cases.22
A study exploring ear, nose and throat problems in chil-
dren with SWS reported that these were common.32 The most
common complaints involved the sinuses and frequent ear
infections. Patients with facial tissue hypertrophy were also
felt to be at risk for obstructive sleep apnoea. Addressing these
issues may not only significantly improve quality of life but
potentially improve seizure control and stroke-like episodes,
and hence overall neurological status.
More recently endocrine problems namely central hypo-
thyroidism and growth hormone deficiency have been asso-
ciated with SWS. There is an 18 fold increase in the incidence
of growth hormone deficiency over and above the general
population.33 The cause of this remains uncertain as the hy-
pothalamic pituitary axis appears normal on neuroimaging.
Growth hormone deficiency should be actively sought and
treated in patients with short stature. Central hypothyroidism
was identified in 2 of 83 patients with SWS at one centre,
estimated at 500 to 10,000 times the prevalence in the general
population. Although the authors acknowledge an association
with anticonvulsant use, given the increased predilection for
central growth hormone deficiency in SWS, the possibility
remains that hypothyroidism may be driven by dysfunction of
the hypothalamic pituitary axis associated with the disease
process.34
The prevalence of glaucoma amongst SWS patients varies
from 30% to 60%.11,13 The age of onset shows three peaks:
during the first year (40%), between 5 and 9 years (23%) and
after the age of 20 years (20%).11 The late onset of glaucoma
necessitates continued ophthalmologic evaluation indefi-
nitely in SWS patients. Annual examinations with intraocular
pressure monitoring are recommended. Glaucoma is not al-
ways ipsilateral to PWS and hence it is important that both the
eyes are reviewed.11
3. Neuroimaging
SWS with intracranial involvement should be suspected in
any individual with facial PWS. Historically, plain skull X-rays
and angiography were used in the diagnosis of SWS, with the
classic “tram-line” or “tram-track” calcifications recognised in
older children on X-rays, and angiography demonstrating a
lack of superficial cortical veins, non-filling of the dural si-
nuses, and tortuous course of veins toward the vein of Galen.
Magnetic resonance imaging (MRI), specifically T1
weighted imaging with gadolinium contrast, together with
susceptibility-weighted imaging (SWI) is now the recom-
mended imaging modality for demonstrating characteristic
findings of SWS in the early pre-symptomatic phase,
including leptomeningeal changes with enlargement of
transmedullary and periventricular veins (Fig. 1(a),(b)).35e37
Associated dilation and enhancement of the choroid plexus
on the involved side is often present in older children and
adults along with dilated deep draining venous vessels
4 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 3 ) 1 e1 0

underlying the affected cortical region. At initial presentation
in infancy there may be little evidence of atrophy, however
during infancy atrophy and calcification evolve, and are well
seen on computed tomography (CT) scans. Involvement of
infratentorial structures has also been reported but may be
relatively subtle and needs to be actively sought.38 Post
contrast fluid-attenuated inversion recovery (FLAIR) imaging
and high-resolution blood oxygen level dependent (BOLD)
magnetic resonance venography may also increase sensitivity
for detecting the leptomeningeal angioma compared with
contrast-enhanced T1 weighted imaging alone.39,40
The optimum age for screening neurologically normal in-
fants with facial PWS with MRI brain is not clear but it has
been suggested that if the child is developing normally, has a
normal neurological examination, no history of seizures, and
a normal MRI with contrast after the age of 1 year, that child
probably does not have SWS brain involvement.12,41 It should
be noted that MRI with contrast is insensitive in newborns
possibly because the venous stasis and impaired blood flow
dynamics have not yet developed. A recent study assessed the
extent of leptomeningeal angiomatosis demonstrated on MRI
compared with clinical features in SWS, finding hemispheric
angiomatosis and atrophy in 50% of the cohort of 86 patients
(aged 2 months to 56 years), with focal involvement in the
remaining individuals. Of those with one hemisphere pri-
marily involved, 9 of 43 patients also had extension of the
angioma to the contralateral side. Seizure onset occurred
earlier in those individuals with more extensive (hemispheric)
brain involvement. Focal angiomatosis did not appear to
become more extensive over time.42
Diffusion and perfusion imaging provide information
regarding blood flow and have been correlated with clinical
features such as seizures, hemiparesis and cognitive out-
comes.43,44 Visual functional MRI recently showed that SWS is
associated with abnormal patterns of occipital activation and
the authors speculated that functional MRI may be helpful in
decisions of surgical management.45
Disturbances in glucose metabolism demonstrated by FDG
PET (Fig. 1(c)), and cerebral perfusion abnormalities assessed
by SPECT, may precede clinical symptoms as well as the
detection of atrophy and calcification on CT or MRI in
SWS.35,46,47 As such, these investigations may provide prog-
nostic information to assist with early identification of chil-
dren at risk of complications of SWS. SPECT studies in young
infants with SWS have demonstrated that cerebral perfusion
declines from being generous in the very young infant to being
deficient in the involved cortical regions by the end of the first
year of life even in the absence of seizures. In addition, SPECT
studies have shown reduced increases in the blood flow to the
seizing hemisphere suggestive of an abnormal vascular
response to seizures in SWS which is likely to further pre-
dispose these patients to ischaemic brain injury.36 Children
with advanced SWS showed markedly depressed glucose
metabolism in the anatomically affected cerebral hemisphere
in a distribution that extends beyond the area of radiological
abnormality.46 When uncontrolled, seizures in young children
were associated with further deterioration in glucose meta-
bolism over time in the affected brain regions. In contrast, if
seizures are well controlled for a prolonged period of time,
glucose metabolism on PET imaging may improve.48 A study
of cortical metabolism with FDG PET in children with unilat-
eral SWS found an association between severely asymmetric
cortical metabolism with relatively preserved cognitive func-
tion suggesting that functional reorganization occurred more
readily when cortex is severely rather than mildly damaged,49
an observation that potentially supports the argument for
early surgical intervention. A recent study using FDG PET in 60
children with SWS observed transient hypermetabolism in
the affected cortex in 9 cases, followed by hypometabolism in
all five children where follow-up scans were available. Chil-
dren with transient hypermetabolism had a higher rate of
subsequent epilepsy surgery as compared to those without
hypermetabolism suggesting that this may be an imaging
marker of the most malignant cases of intractable epilepsy
requiring surgery in SWS.50
It is of historical interest to note the appearance of occipital
calcification in patients with epilepsy coincident with coeliac
disease has been compared and contrasted with SWS. Anti-

Fig. 1 e MRI and FDG PET images for a 3 year old boy with bilateral facial PWS, left sided hemiparesis and seizures; (a). (b).
axial and coronal T1 weighted MRI with gadolinium contrast respectively showing assymetric leptomeningeal
enhancement, prominent choroidal vessels and right sided atrophy; (c). FDG PET showing right sided hypometabolism most
prominent in the right frontal region.

Please cite this article in press as: Sudarsanam A, Ardern-Holmes SL, SturgeeWeber syndrome: From the past to the present,
European Journal of Paediatric Neurology (2013), http://dx.doi.org/10.1016/j.ejpn.2013.10.003
 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 3 ) 1 e1 0
gliadin antibodies associated with coeliac disease should be
assayed in cases lacking abnormal enhancement and lobar or
hemispheric atrophy on neuroimaging studies which would
be expected with SWS.51
4. Electroencephalogram
The typical electroencephalogram (EEG) is asymmetric (Fig. 2),
with the affected hemisphere showing a reduction in voltage
and slowing of the background.52 This asymmetry may be
detected from the first months of life, but becomes more
evident as atrophy of the hemisphere progresses. The focal
discharges occur principally in the affected cerebral hemi-
sphere, but may appear in the contralateral hemisphere in
many cases.20 EEG is also extremely useful in distinguishing
migraines and stroke-like events from seizures as causes of
acute paroxysmal events. Studies using quantitative EEG
(qEEG) showed that asymmetry in qEEG correlates with degree
of clinical impairment in children and adults with known
SWS.53 A more recent study demonstrated the ability for qEEG
to discriminate between those infants with SWS brain
involvement and those with neurologically asymptomatic
port-wine stain.54 The authors suggest qEEG may have a role
in predicting which infants with port-wine stain will develop
SWS brain involvement.
5. Pathophysiology
Histologic studies of SWS brain angiomas have revealed
tortuous and abnormal vascular structures in the thickened
leptomeninges. These vessels all have similar appearance,
calibre, and morphological characteristics. The areas of
angiomatosis are described as capillary-venous type vascular
malformations. Underlying brain tissue can be atrophic and
display neuronal loss, astrogliosis, dysgenic cortex, and
Fig. 2 e Electroencephalogram for the patient shown in Fig. 1, showing decreased right sided amplitudes correlated with
imaging changes.
Please cite this article in press as: Sudarsanam A, Ardern-Holmes SL, SturgeeWeber syndrome: From the past to the present,
European Journal of Paediatric Neurology (2013), http://dx.doi.org/10.1016/j.ejpn.2013.10.003
5
calcification in the cortical layers.55e57 The cortical vessels
underlying the meningeal angioma are thin-walled, narrowed
by hyalinization and subendothelial proliferation, and are
increased in number.55,58 Cerebral angiography demonstrates
an aberrant pattern of both the arterial and venous cerebral
circulation. Along with areas of arterial thrombosis, there is
an abnormal venous drainage, with manifest paucity of the
superficial draining veins, venous occlusions, and alternative
venous discharge through deep subependymal channels.59,60
This abnormal vasculature is hypothesized to result in
chronic ischaemia from insufficient venous outflow made
worse by recurrent seizures, associated with failure of the
normal increase in blood supply to the epileptic area aggra-
vating the state of chronic ischaemia.21
The aberrant cortical vessels in SWS are also abnormally
innervated,61 most closely resembling cortical veins, although
with a richer innervation pattern. These abnormal cortical
vessels are supplied with perivascular nerve fibres, forming a
loose network with a predominant circular orientation around
the long axis of the vessel. The nerve endings at the tunica
media-adventitia border lack pre/post synaptic specialization
and end in a synaptic cleft several nanometres wide. The
authors reporting these observations, proposed these changes
would correlate with slow development of neurogenic tone. In
contrast to normal cortical veins, SWS vessels did not receive
any cholinergic or sensory nerve supply but showed only
neuropeptide Y and noradrenaline in the nerve endings.
Although the significance of this is unclear, the authors hy-
pothesized that sustained adrenergic constrictor tone would
drive the autoregulatory curve to the right and, therefore, in-
crease the lower autoregulatory limit. This would endanger
the circulation in the affected areas in case of hypotension or
of highly elevated transient metabolic needs, such as during
epileptic activity.
The role of extracellular matrix proteins (ECM) in the
pathogenesis of SWS has also been considered. Fibronectin is
the prototypic ECM molecule and has key roles in regulating
6 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 3 ) 1 e1 0
angiogenesis and vasculogenesis, as well as brain tissue re-
sponses to ischaemia and seizures. The gene expression of
fibronectin was significantly increased and a trend for
increased fibronectin protein expression was found in SWS
surgical brain samples compared with postmortem controls,
and SWS port-wineederived fibroblasts compared with fi-
broblasts from SWS normal skin.62 Endothelin is a vasocon-
strictive peptide for which expression is generally stimulated
by high pressure and shear stress resulting from high blood
flow. The peptide expression of endothelin by intracranial
vascular malformations of four patients with SWS has been
found to be uniformly increased over that in normal vessels.63
The extent to which these changes are the cause or effect of
the disease process has been unclear, though advances in
understanding the genetic basis of disease is expected to
provide further insights.
From a developmental perspective, the angioma found in
classic SWS has been suggested to result from failure of the
primitive cephalic venous plexus to regress and properly
mature in the first trimester of development.64,65 Maiuri
et al. suggested that at this stage, the embryologic proximity
of the ectoderm destined to form the upper portion of facial
skin to the portion of the neural tube that will form the
parietal-occipital area of the brain could explain the noted
association between the facial port-wine stain and the
parietal-occipital leptomeningeal angioma in SWS.65 A so-
matic mutation involving these embryologic tissues has
been proposed as one mechanism for the occurrence of this
disease.66 This hypothesis is supported by the observation
of monozygotic twins where one is affected and the other
unaffected by SWS.67
Efforts to identify the genetic basis of PWS and SWS have
considered known genes governing vascular formation such
as the RASA1 gene. Mutations in this gene have been linked to
familial capillary malformation (PWS) and arteriovenous
malformation.68 Families have been identified with an indi-
vidual affected by SWS and multiple other members with PWS
suggesting that, at least in these families, mendelian genetics
may have a role. However, this is does not account for the
majority of patients with PWS or SWS.
A likely causative somatic activating mutation to explain
the majority of cases of non-syndromic PWS and SWS has
been reported this year based on results of whole-exome
sequencing.69 A single nucleotide variant occurring in
GNAQ on chromosome 9q21 was identified in affected skin of
individuals with non-syndromic PWS, and both affected skin
and leptomeningeal angioma in patients with SWS. This
variant was absent from unaffected tissues, and occurs in a
region usually highly conserved. The variant results in an
amino acid substitution in the guanine nucleotide binding
protein (G protein), known as q polypeptide (Gaq) which is
encoded by GNAQ. The Gaq subunit plays an important role
in signalling between G protein coupled receptors, including
endothelin, and downstream effectors. Timing of the so-
matic mutation in GNAQ during development likely impacts
on the clinical phenotype, ranging between uncomplicated
PWS and SWS.
Whilst ongoing work will provide further insights into the
role of this mutation in pathogenesis of SWS, consideration
should also be given to observations and proposed hypotheses
Please cite this article in press as: Sudarsanam A, Ardern-Holmes SL, SturgeeWeber syndrome: From the past to the present,
European Journal of Paediatric Neurology (2013), http://dx.doi.org/10.1016/j.ejpn.2013.10.003
regarding how changes in brain structure and function relate
to the clinical variability seen in patients with SWS. For
example, cognitive function (i.e. intelligence quotient) has
been strongly associated with white matter volume loss ipsi-
lateral to the angioma, and also with cortical as well as
thalamic glucose hypometabolism on 2-deoxy-2-fluoro-D-
glucose positron emission tomography (FDG PET).70 White
matter injury is presumed to occur due to hypoxia secondary
to venous stasis and thrombosis in the abnormal vasculature.
Myelination underlying the areas of leptomeningeal angioma
is also advanced, which may be evident earlier than cortical
changes are seen on MRI or SPECT studies.71 Accelerated
myelination has been proposed to be secondary to either
transient hyperperfusion or venous congestion.71,72 However
it has also been suggested that the appearance of accelerated
myelination may be due to increased deoxy haemoglobin
within the venous system.73
Cortical malformations, focal dysplasia and polymicrogyria
occur in children with SWS and epilepsy, especially infantile
onset and medically intractable forms.74 One hypothesis is
that these cortical changes occur secondary to ischaemia
during the second trimester of development.57 Alternatively,
the abnormal expression of a specific factor, or dysregulation
of signalling pathways important to both vascular and cortical
development could result in cortical dysgenesis.57
Sreenivasan et al. recently published the findings of their
study on urine vascular biomarkers in SWS based on the
knowledge of their abnormality in vascular anomalies. They
looked at the urine levels of Matrix Metalloproteinases
(MMP) MMP-2, MMP-9, Vascular Endothelial Growth Factor
(VEGF) and basic Fibroblast Growth Factor (bFGF) in the non-
invasive monitoring of SWS progression.75 The results sug-
gest that MMP-2 and MMP-9 levels may be useful in
assessing SWS progression, as well as indicating which
patients might benefit from more aggressive treatment,
while bFGF levels may be useful in judging the efficacy of
neurologic treatment in SWS.
Whilst many questions remain regarding phenomena
resulting in the variable clinical severity of SWS, current un-
derstanding of the pathophysiology has therapeutic and
pharmacological implications, supporting the use of aspirin,
vigorous medical management of stroke-like episodes and
seizures, and early consideration of epilepsy surgery in re-
fractory cases, to prevent neurologic deficits and optimise
cognitive functioning and quality of life in children with SWS.
6. Management of facial port-wine stain and
SturgeeWeber syndrome (Table 2)
6.1. Facial port-wine stain
In the assessment of patients with facial port-wine stain, an
ophthalmology examination is indicated in all cases where
the V1 distribution is involved. Neuroimaging is also recom-
mended for patients with V1 distribution facial PWS in asso-
ciation with at least one of these additional features:
ophthalmic or neurologic involvement, extension of the facial
naevus to the eyelid, V2 or V3 divisions or bilateral facial
involvement.12
 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 3 ) 1 e1 0 7

Early referral to dermatology should be made for the prospective randomised controlled trial to scientifically
management of the cutaneous naevi. Laser therapy of the answer this question have precluded acceptance of this as
lesion should be sought where appropriate to avoid the psy- routine practice. Sound parental education in early seizure
chosocial embarrassment and stigma associated with PWS as recognition including that of subtle seizures and the provision
well as to prevent the development of cumulative changes in of a benzodiazepine as rescue medication even before definite
the skin and soft tissue secondary to the angioma.76 brain involvement in at-risk infants is the logical next best
solution. Development of care plans in association with par-
6.2. SturgeeWeber syndrome ents and local hospitals for loading the child with phenytoin
and commencing regular anticonvulsant therapy in the event
Management of seizures and stroke-like episodes is the key of a first focal seizure has also been advocated.41 Aggressive
for preventing progression of neurological injury in SWS. Early management of acute illness ensuring good hydration,
recognition and aggressive management of seizures is rec- oxygenation and fever control may prevent precipitation of
ommended. The question of use of prophylactic anti-epileptic seizure and stroke-like episodes and hence prevent progres-
medication has been raised with the suggestion that such sion of neurological injury. Screening and treatment of iron-
intervention may reduce the incidence of mental retarda- deficiency anaemia is another simple and practical measure
tion.77 However the high variability in the natural course of in stroke prevention.
the disease along with pragmatic issues in developing a Anticonvulsants remain the cornerstone in managing epi-
lepsy in SWS. A range of agents may have a role. It is noteworthy
that cases of central hypothyroidism have recently been re-
Table 2 e Recommendations for management of ported in SWS children treated with oxcarbazepine.34 There-
SturgeeWeber syndrome. fore, monitoring of thyroid function should be considered
Clinical issue Recommendation during surveillance for side effects of anticonvulsant treatment.
Facial port-wine Dermatology referral As a routine, emphasis on good sleep hygiene and avoidance of
stain (PWS) epilepsy triggers is important, particularly during adolescence.
V1 distribution Ophthalmology evaluation þ follow Seizures may be medically intractable in 30e50% of SWS pa-
up tients.13,14 The modified Atkins’s diet which does not restrict
V1 distribution Ophthalmology evaluation þ follow fluid and calories has been reported to be useful in managing
with eye and CNS up
refractory seizures in SWS.78 This may be an option in cases in
abnormalities þ MRI
which surgery is not feasible either because of bilaterality of the
V1 þ V2/3 distribution Ophthalmology evaluation þ follow
up disease or due to risk of postsurgical neurodeficits.
þ MRI For the majority of the refractory epilepsy cases, surgery
Seizures Parental education at diagnosis of offers the best option, with various approaches including
PWS lesionectomy, callosotomy and hemispherectomy.21 Despite
Early aggressive medical the well documented effectiveness of surgery in SWS, optimal
management
timing and patient selection remains open to debate. The de-
with anti-epileptic medication
Consider surgical options in
cision for surgery is reasonably easy in those with intractable
refractory cases epilepsy, particularly in the context of significant hemiparesis
Stroke-like episodes Aspirin(3e5 mg/kg/d); hydration and mental retardation. However determining the optimal
during illness timing for surgical intervention is more difficult for patients
Headaches Standard abortive and with relatively limited neurodeficits (including visual field de-
preventive agentsa
fects), and those with glaucoma affecting the ipsilateral eye. A
Glaucoma Annual ophthalmology surveillance
recent study surveyed the results of 32 hemispherectomies
Medical treatment/surgical
intervention worldwide and found that 81% of patients were seizure free,
Focal neurologic deficit that motor function did not worsen, and that older children did
Hemiparesis Multidisciplinary team/Rehab input as well as those children whose surgery was performed at an
Visual field defect Regular surveillance; adaptive early age.79 Surgery may also be an option in bilateral SWS with
training epilepsy arising predominantly from one side.
Cognitive Impairment Neuropsychological assessment
Studies on the pathophysiology of SWS have clearly high-
Intervention and individualised
lighted the contribution of venous congestion, stasis and
educational programmes
Psychosocial Surveillance and early referral to thrombosis in the symptomatology of progressive brain injury
support services in this disease. Historically the suggestion has been made that
Endocrine Monitor growth and thyroid stepwise deterioration in SWS occurs on an ischemic rather
function than an epileptic basis, and that paroxysmal episodes may
ENT Surveillance for ENT infections and respond better to measures aimed at reducing platelet ag-
obstructive sleep disorders
gregation than anticonvulsants.80 In such setting the role of
Other Annual influenza vaccination
Aggressive management of acute
aspirin appears very plausible. Indeed in a case series there
illness optimising management of were 65% fewer strokes in the children treated with aspirin
fever and hydration although this group did not report any decrease in seizure
a frequency.24 A recent study using internet-based question-
Data lacking on efficacy of specific agents.
naire reported on the frequency of use, effectiveness, and

Please cite this article in press as: Sudarsanam A, Ardern-Holmes SL, SturgeeWeber syndrome: From the past to the present,
European Journal of Paediatric Neurology (2013), http://dx.doi.org/10.1016/j.ejpn.2013.10.003
8 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 3 ) 1 e1 0
safety of aspirin treatment in SturgeeWeber syndrome.81
Thirty five percent of SWS patients reported having used
aspirin with a significant reduction in the frequency of both
the stroke-like episodes and seizures. Thirty-nine percent of
subjects reported a history of complications (predominantly
increased bruising or gum/nose bleeding) while on aspirin;
however, none reported discontinuing aspirin because of side
effects. There has been a case report of significant bleeding in
a patient on aspirin, but this is rare.82 There is also the po-
tential of Reye’s syndrome in children although low at the
recommended dose (3e5 mg/kg/day). For this reason attention
to immunisation, particularly with regard to varicella and
annual influenza vaccination has been recommended.83 The
risk benefit ratio is yet to be clearly elucidated in prospective
trial settings. The optimal time to start aspirin therapy is also
unclear at present, although commencement in the setting of
stroke-like episodes is warranted. The use of other anticoag-
ulants or antiplatelet agents in SWS hasn’t so far been studied.
Headaches should be managed in a standard manner with
avoidance of triggers, and abortive medications. Preventative
medications which treat symptoms of both epilepsy and
migraine are effective. Use of triptans has been reported by 22%
of 74 individuals with migraine headaches responding on an
internet-based survey. However, the potential vascular effects
warrant careful consideration, and more information is needed
regarding efficacy and safety of individual agents in SWS.83
Glaucoma surveillance should be an annual routine for all
patients with SWS at any age as adult onset has been docu-
mented. Ocular pain or other new visual symptoms should
prompt interval ophthalmology evaluation. Management of
glaucoma associated with SturgeeWeber syndrome is often
difficult and may be resistant to medical therapy.84 Surgical
intervention may be required,13,84 and carries a risk of com-
plications especially in the presence of diffuse choroidal
haemangioma.
Psychosocial support has an important role in manage-
ment of patients and families of individuals with SWS. Whilst
the clinical consequences of the disorder can be mild in some
cases, in others they are severe with associated cognitive/
behavioural, motor, visual deficits, refractory epilepsy despite
optimal medical and surgical intervention, in addition to
susceptibility to other medical conditions. Significant stress
can be associated with the presence of facial haemangioma
alone. Ensuring early referral to supportive agencies for pa-
tients and families is essential to maximise access to neces-
sary resources.
7. Conclusion
The long-term clinical prognosis varies considerably among
patients with SturgeeWeber syndrome, and predicting long-
term outcomes during the early course of the disease is chal-
lenging. Recent studies have vastly improved our under-
standing of the disease process, with identification of an
activating somatic mutation in the GNAQ gene which causes
dysregulation of signal transduction between G protein
coupled receptors and downstream effectors. Nevertheless,
many unanswered questions remain regarding the details of
disease pathogenesis and optimal management. It is
Please cite this article in press as: Sudarsanam A, Ardern-Holmes SL, SturgeeWeber syndrome: From the past to the present,
European Journal of Paediatric Neurology (2013), http://dx.doi.org/10.1016/j.ejpn.2013.10.003
anticipated that early diagnosis and careful neuroimaging
surveillance will identify patients at risk of significant com-
plications of disease and facilitate early aggressive symptom-
atic management with improved outcomes in the future. Well
designed prospective multicentre studies will be essential to
systematically address remaining questions, with a view to
altering the natural history of disease using existing treat-
ments and exploring potential novel treatment approaches.
Disclosures
The authors have no relevant disclosures regarding this
manuscript.
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