ADVANCED NEUROIMAGING STUDIES IN STURGE-WEBER SYNDROME: CLINICAL CORRELATES

Bálint Alkonyi M.D.

PhD thesis

Leader of PhD school and program: Prof. Sámuel Komoly M.D., D.Sc.

Mentor: Zoltán Pfund M.D., PhD.

Study mentor: Csaba Juhász M.D., PhD. (Detroit, USA)

PET Center, Children’s Hospital of Michigan, Detroit, USA

University of Pécs, Faculty of Medicine

Hungary

2011

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“True science teaches us to doubt and, in ignorance, to refrain.”

Claude Bernard (1813-78) French physiologist.

I had the fortunate opportunity to work as a postdoctoral fellow in one of the most

outstanding neuroimaging research laboratories of the United States. As the Children’s

Hospital of Michigan is a national center for studying several interesting pediatric neurological

disorders, I had the chance to study neurological and neuro-radiological implications of a

relatively rare, but fascinating disease, the Sturge-Weber syndrome. Unfortunately, there is no

curative treatment available for this disorder to date. Therefore, similar to many other

neurological conditions, intense research is warranted to uncover the exact pathomechanism

and also identify novel therapeutic targets of this disease. This thesis is a summary of my

scientific work on the advanced neuroimaging findings and their clinical correlates of Sturge-

Weber syndrome. I truthfully hope that my studies significantly add to the knowledge about

this disease and direct further research towards the ultimate goal of eventually finding the cure.

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TABLE OF CONTENTS

ABBREVIATIONS 4.

I. INTRODUCTION: Background of the studies 5.

II. AIMS OF THE STUDIES 23.

III. SUBJECTS 25.

IV. SUMMARY OF PAPERS SUPPORTING THE THESIS

Paper 1 26.

Paper 2 27.

Paper 3 29.

Paper 4 30.

Paper 5 32.

V. PAPERS

PAPER 1 34.

PAPER 2 44.

PAPER 3 51.

PAPER 4 60.

PAPER 5 68.

VI. SUMMARY OF THESIS 76.

VII. BIBLIOGRAPHY 78.

VIII. ACKNOWLEDGEMENTS 84.

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ABBREVIATIONS (in the order of first appearance)

SWS: Sturge-Weber syndrome

CT: computed tomography

GM: gray matter

WM: white matter

HIF-α: hypoxia inducible factor- α

VEGF: vascular endothelial growth factor

GABA: gamma-aminobutyric acid

MRI: magnetic resonance imaging

PWI: perfusion weighted imaging

MRS: magnetic resonance spectroscopy

CSI: chemical shift imaging

NAA: N-acetyl-aspartate

Cr/PCr: creatine/phosphocreatine

Glx: glutamate/glutamine/gamma-aminobutyric acid

DTI: diffusion tensor imaging

FA: fractional anisotropy

MD: mean diffusivity

ROI: region of interest

PET: positron emission tomography

SPECT: single photon emission computed tomography

FDG: 2-deoxy-2[18F]fluoro-D-glucose

AI: asymmetry index

TBSS: tract based spatial statistics

SUV: standardized uptake value 

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I. INTRODUCTION: Background of the studies

I.A. The Sturge-Weber syndrome

The Sturge-Weber syndrome (SWS), also known as encephalofacial angiomatosis, is a

sporadic neurocutaneous disorder, one of the diseases that is classified under the phakomatoses 1. It is a rare congenital syndrome with an estimated incidence of 1 per 50,000 live births with

equal gender distribution 1,2. Although the genetic and environmental factors leading to the

disorder are not clarified, a somatic mutation has been suspected due to the sporadic and

localized nature of SWS 3,4. It has been suggested that a vascular developmental disruption

occurs during the first trimester in utero which manifests in functional and morphological

abnormality of vessels of the facial skin, eye and brain 5. The leptomeningeal angioma, the

classic intracranial sign of SWS is thought to be the result of the failure of the primitive

cephalic venous plexus to regress and properly mature in the first trimester of pregnancy. The

close embryological proximity of the facial ectoderm and the portion of the neural tube

eventually forming the parieto-occipital region of the brain provide a feasible explanation for

the association of the classical facial port-wine stain and posterior brain involvement in SWS 6.

SWS was probably first described by Schirmer in 1860 7. William A. Sturge gave the

first clinical description of the classic syndrome in 1879, and he postulated that an intracranial

angiomatous malformation was responsible for the neurologic symptoms; however, he did not

have any direct proof 8. The radiographic findings, including brain atrophy and intracranial

calcifications of this condition, were first described by the English physician F. Parkes Weber

in 1922 9. It is an interesting historic fact that although Weber publicly disclaimed a place for

his name in the designation of this disease, and many other scientists (i.e., Kalischer, Volland,

Dimitri and Krabbe) have made significant contributions to the initial knowledge about this

condition, the official name remained Sturge-Weber syndrome.

The syndrome itself has a spectrum of neurological and neuroimaging manifestations 10,11; however, the classic hallmark of the disease is the facial cutaneous naevus (the so-called

naevus flammeus or port-wine stain) which is usually located in the territory of the trigeminal

nerve (Figure 1).

Figure 1: Extensive bilateral facial port-wine stain of a 2.8 years old girl with SWS. This patient also had bilateral intracranial involvement. Her seizures became controlled only with vagal nerve stimulator and her neurocognitive development is severely delayed.

Importantly, not all newborns with facial port-wine stains develop SWS. The risk

ranges between 10% and 30% 12,13,14. Conversely, some children with SWS lack a facial

cutaneous malformation despite typical intracranial involvement. Orbital, ocular abnormalities

like buphthalmos (congenitally enlarged eyeball), choroidal hemangioma, and glaucoma are

also often present. The leptomeningeal angiomatosis, most often overlying the parietal and

occipital lobes, is considered to be the primary intracranial abnormality resulting in secondary

intracranial pathologies like brain atrophy and cortical calcifications 15. The pathologic changes

usually involve unilateral brain areas; however, bilateral intracranial involvement may be seen

in 7.5-15% of cases 15. Importantly, the chronic damage of the affected brain region leads to

neurological manifestations of variable degree, including early onset seizures, stroke-like

episodes, visual field cut, motor and cognitive deficits and migraine (see section I.B.).

Neurological manifestations of SWS are often progressive, ultimately leading to profound

neurocognitive decline. However, disease progression varies widely 2. Importantly, the factors

influencing the variable outcome are not completely understood and conventional clinical or

imaging modalities are insufficient to predict clinical outcome at the early stage of the disease.

Histopathological studies of brains affected by SWS demonstrate abnormally

developed, tortuous, thin-walled vascular structures in the thickened leptomeninges 16. The

underlying cerebral cortex is often atrophic and shows neuronal loss, gliosis, calcification and

malformations of cortical development 17,18. Subcortical and cortical calcifications, which can

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also be seen on brain computed tomography (CT) images in vivo, are thought to be the result of

anoxic injury of endothelial, perithelial and glial cells. Abnormal permeability of cerebral

vessels and consequently increased passage of proteins and calcium has also been proposed as

putative factors in calcification 19. Cortical vessels adjacent to the angioma are also thin and

narrowed by subendothelial proliferation. Impaired innervations and altered extracellular

matrix protein expression have also been implicated in the pathogenesis of structurally and

functionally abnormal vessels 5. It has been hypothesized that impaired superficial venous

drainage through the abnormal leptomeningeal vessels leads to venous stasis and chronic

hypoxia of the underlying gray matter (GM) and white matter (WM) 2. Often there are

additional, partly compensatory changes, such as the development of prominent transmedullary

collateral veins, hypoxia induced angiogenesis and remote functional reorganization 17,20,21.

These complex mechanisms are poorly understood and need to be further elucidated. Chronic

cortical ischaemia is associated with various pathological features including altered blood-

brain barrier function and local metabolic dysfunction 22,23. Abnormal autoregulation of blood

flow coupled with the temporary increases in oxygen and metabolic demand during seizures

may also contribute to the progressive brain injury 24. Importantly, transmedullary collateral

veins directing venous blood towards the deep cerebral venous system often become prominent

and excessive and may disrupt WM structure and development 21,25. Recent data provided

evidence that, similar to facial port-wine stains, leptomeningeal angiomas of SWS may also

not be static lesions but can undergo a proliferative process after birth 17. Intriguingly, in

addition to enhanced endothelial cell turnover, increased expression of the hypoxia-inducible

factor- α (HIF-α) and vascular endothelial growth factor (VEGF) have been shown in surgical

angioma specimens. Future studies are needed to elucidate whether ongoing angiogenesis

might be a therapeutic target in SWS. Furthermore, it has been recently recognized that

malformations of cortical development (such as polymicrogyria and focal cortical dysplasia)

are commonly seen in surgical specimens of SWS patients with intractable, severe epilepsy 18.

Early ischemic insults can contribute to the development of these highly epileptogenic lesions,

even in brain areas distant from the angioma. Thus, these cortical malformations are associated

with severe, intractable epilepsy coupled with prominent neurocognitive deficit. Neocortex

affected by SWS shows a number of aberrant features including depolarized membrane

potential and spontaneous firing likely contributing to enhanced excitability and the

development of epilepsy 26. Furthermore, as opposed to other developmental epilepsies,

gamma-aminobutyric acid (GABA) exerts an inhibitory action in the SWS brain. The putative

pathomechanism of brain damage and main neurological manifestations in SWS are

summarized schematically in the following diagram (Figure 2).

I.B. Neurological symptoms in SWS

Neurological manifestations of SWS are highly variable; some patients develop

properly, while others have severe seizures and progressive clinical course. Seizures are often

the presenting neurological symptoms in children with SWS and occur in about 80-85% of

patients. The onset of the first episode is usually (in 75% of the cases) within the first year of

life 10,27. It has been also demonstrated that the likelihood of epilepsy is higher and seizure

onset may occur earlier in patients with SWS and bilateral leptomeningeal angiomatosis than

in those with unilateral lesions 28. The predominant seizure types are partial motor and

complex partial, but infantile spasms may also occur. Epilepsy can be benign in SWS;

however, infantile onset is frequently associated with severe, catastrophic epilepsy and

cognitive impairment 27. A clustering, sporadic, but severe seizure pattern appears to be 8 

 

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common in SWS, rendering treatment decisions with respect to potential surgical resection

difficult 29. Importantly, later onset of seizures, as well as early and long-term control of

epilepsy, have been associated with better neurological outcome 30 31.

Abnormal vascular autoregulation during seizures (especially when frequent and

prolonged) has been suspected as a major mechanism contributing to the exacerbation of brain

injury and cognitive decline 24,32. Recent results also suggest that cortical malformations may

be responsible for early onset, severe epilepsy in SWS, at least in some cases 18. Seizures are

controlled with medication in about 40-50% of the patients 27. If pharmacological treatment

fails to control seizures, surgical techniques such as hemispherectomy, focal resection or

corpus callosotomy are the treatment of choice. Not surprisingly, early resective surgery after

careful evaluation, and complete resection of the affected brain region are related to better

cognitive and seizure free outcome 33,34. It is important to note that successful epilepsy

surgeries have been reported also in a few patients with bilateral intracranial involvement 35,36.

Stroke and stroke-like episodes are also characteristic features of SWS and manifest as

acute, temporary episodes of motor, sensory disturbances or visual field defects not directly

related to epileptic activity. Weakness may even persist for a long time or permanently after a

severe stroke-like episode 37. These episodes are attributed to recurrent thrombosis which

contribute to saltatory neurological decline38; however, the exact pathomechanism remains

elusive.

Migraines are also common (prevalence: 30-45%) in children with SWS 39.

Interestingly, headaches can have as significant impact on the quality of life as seizures 40.

Headache frequency was found to be higher in patients with stroke-like episodes. The exact

mechanism of migraines in SWS is not known, however, increased neuropeptide leakage into

the subarachnoid space and consequent trigeminovascular activation have been suspected 41.

About 50-60% of children with SWS will show developmental delay, mental

retardation, or both 42. Progressive cognitive decline is commonly associated with early onset,

intractable seizures 30,43. As the incidence of cognitive dysfunction (i.e., below-average

cognitive function) is considerably higher in SWS patients than in children with epilepsy

unrelated to SWS (~50-80% vs. ~25%), other neurological features unique to SWS most likely

also contribute to mental retardation. For instance, a recent study demonstrated that WM

volume loss ipsilateral to the angioma may play a major role in cognitive impairment in

children with SWS 44. In addition to cognitive issues, children with SWS show a broad range

and variable degree of neuropsychological dysfunction including mood disorders,

noncompliance, attention–deficit hyperactivity disorder, oppositional behaviors and social

problems 43. Other common neurological findings include hemiparesis and hemianopia;

importantly, these can worsen after severe seizures or stroke-like episodes 45.

I.C. Neuroimaging in SWS

Magnetic resonance imaging (MRI). Conventional MRI techniques, including T1-

weighted post-gadolinium MRI, are often used to establish the diagnosis of SWS and to assess

the extent and severity of intracranial structural involvement and progressive brain damage

during the course of the disease. For clinical purposes, conventional MR imaging protocols

include at least native spin-echo T1-weighted and T2-weighted images, as well as post-

gadolinium T1-weighted images. The latter sequence provides a gold standard for delineation

of the characteristic findings of leptomeningeal angioma 46,47,48(Figure 3).

Figure 3: Axial post-gadolinium T1-weighted MR images of a patient with SWS and left hemispheric angioma. Note the contrast enhancing angiomatosus lesion in the temporo-parietal distribution (solid arrows), the enlarged choroid plexus (dashed arrow) and also the enlarged deep transmedullary veins in the left frontal lobe (arrowhead).

Angiomas are most often located over the posterior quadrant of the brain (parietal, occipital

lobes), but can extend to frontal areas as well. Although rarely, they can affect bilateral parts of

the brain or can involve the infratentorial compartment 49. Other vessel abnormalities, like

enlarged choroid plexus, prominent deep transmedullary and subependymal veins are also

readily identifiable on T1-weighted post-gadolinium images 50,51. Dilated deep transmedullary

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veins function as a compensatory collateral pathway for draining venous blood centripetally

from the cortex with abnormal cortical veins into the deep (galenic) venous system 21. Enlarged

choroid plexus ipsilateral to the angioma is also a common finding in SWS 50. They may be a

result of increased pressure in the deep venous system. Further characteristic neuroimaging

features of SWS include brain atrophy (involving both GM and WM) and ipsilateral

hypertrophy of the cranium52; both of these are well visible on both T1-weighted and T2-

weighted images. Interestingly, T2-weighted MR sequences may show signs (hypo-signal) of

`accelerated myelination` in infants with SWS 53. This early phenomenon is thought to be

attributable to venous congestion and chronic hypoxia. Although gradient-recalled echo (GRE)

images with long echo time are not always part of the routine clinical MR imaging protocol,

they provide means (with better spatial resolution than CT) to visualize cortical calcifications

as hypointense signals 46,54. Since conventional brain MR sequences may miss subtle structural

abnormalities (e.g., small angiomas)55 and are not suitable for assessing functional aspects of

brain involvement, advanced MRI methods have been recently implemented mostly for

research purposes. Due to limited space we mention only the most important ones.

Susceptibility Weighted Imaging (SWI) is a novel MR application which utilizes the

susceptibility differences between tissues, and is exquisitely sensitive to the venous

vasculature. SWI can depict fine details of the abnormal deep venous network, choroid plexus,

as well as calcified gyriform abnormalities 25(Figure 4).

Figure 4: Axial, native SWI image of a child with SWS. Prominent transmedullary veins (solid arrow) as well as cortical calcification (dashed arrow) can be appreciated in the right hemisphere.

Perfusion Weighted Imaging (PWI) is useful for evaluating cerebral hemodynamics by tracking

a bolus of exogenous, non-diffusible, high magnetic susceptibility contrast agent using MRI.

PWI has demonstrated decreased perfusion in areas with meningeal enhancement; however,

perfusion abnormalities may extend beyond the area of leptomeningeal angioma 56,57.

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Hypoperfused tissue volume on PWI was associated with more severe hemiparesis in a small

study with 6 children with SWS 57. Although the utility of PWI in SWS is not completely

established, this approach is a promising tool to detect and quantify the severity of early

perfusion abnormalities related to neurological dysfunction. [1H] MR spectroscopy (MRS) and

chemical shift imaging (CSI) can be used to investigate some functional aspects of the brain

tissue through measuring concentrations of several metabolites. The most widely used proton

[1H] MRS is capable of quantitatively measuring a number of biochemicals, including N-

acetyl-aspartate (NAA), choline, creatine/phosphocreatine (Cr/PCr), lactate, and

glutamate/glutamine/gamma-aminobutyric acid (Glx). SWS studies using single voxel MRS

and a related technique, chemical shift imaging showed decreased NAA and increased choline

peaks, suggestive of neuronal loss and myelin breakdown, respectively 58,59,60. These

alterations were present not only in posterior, apparently abnormal regions, but also in

structurally unaffected grey matter tissue in the frontal lobe. Interestingly, frontal NAA

decreases appeared to be more severe in children with early seizure onset, and were also good

predictors of motor functions 57,60. MR-volumetry is an objective post-processing technique,

which can quantify GM, as well as WM volume loss.  Global or regional cerebral volume

reductions are known to be associated with neurocognitive dysfunctions in various

neurological disorders. In a study of 18 patients with unilateral SWS, the gross hemispheric

volume loss showed a good correlation with overall clinical severity scores and also with

hemiparesis subscores 61. A subsequent study, using a more sophisticated, segmentation-based

method, suggested that the WM volume, ipsilateral to the angioma, may be an independent

predictor of cognitive function (IQ) in children with SWS 44.

Diffusion tensor imaging (DTI) and its application in SWS. During the last decade,

DTI emerged as a sensitive MRI application to measure microstructural changes in WM and

GM 62,63. Detailed description of the basics of DTI is beyond the scope of the present thesis. In

short, DTI is sensitive to the diffusion of water molecules which is known to be higher along

fiber pathways. By fitting a model (diffusion tensor model) to the diffusion measurements in

each image voxel, it is feasible to estimate useful parameters such as the fractional anisotropy

(FA), which is a measure of the degree of diffusion directionality (range: 0-1). Another

important DTI parameter is the mean diffusivity (MD) which represents the overall mobility of

water molecules. Importantly, postprocessing of raw DTI data allow for the isolation

(tractography) and microstructural assessment of certain major fiber tracts (e.g., corticospinal

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tract, arcuate fasciculus) 64. Other possible data processing methods include region of interest

(ROI) based and voxel-wise analysis of extracted FA, MD or other parameter maps 65,66. FA

and MD values may be altered (usually FA decrease and/or MD increase) in pathological

processes affecting tissue integrity that can occur as a result of various pathologic processes 67.

Previous DTI studies in SWS have demonstrated WM microstructural damage

extending beyond the area of apparent cortical abnormalities 66,68. Diffusion abnormality in

posterior WM has been associated with worse cognitive function 66. Another DTI study, using

tractography, showed impairment of the corticospinal tract integrity ipsilateral to the angioma

even before clinical motor symptoms 69. DTI may also be useful in detecting accelerated

myelination during the early course of the disease, when other, conventional MRI techniques

may not show abnormalities 53. In summary, DTI is a sensitive tool to detect early

microstructural changes in the brain of patients with SWS, even before macrostructural

abnormalities become apparent. Results of MR-volumetry and DTI studies further underline

the importance of WM integrity during the course of the disease. These data indicate that

successful protection from WM injury during the early phase of the disease would be a

powerful approach to prevent poor clinical outcome in SWS.

Positron emission tomography (PET) in SWS. PET, as well as single photon

emission computed tomography (SPECT), are non-invasive functional imaging tools which

can detect various chemical and metabolic functions in body organs like the brain. The

physical basis of PET is the emission of positrons by unstable nuclei of isotopes as they decay

into more stable structures. The PET technique employs a camera with multiple pairs of

oppositely situated detectors which are used to record the paired high-energy (511 KeV)

photons traveling in opposite directions (~180°) as a result of positron decay 70. In general,

PET images have a spatial resolution in the mm range which is superior to that of SPECT.

Tracer kinetic models that mathematically describe biochemical or physiologic reactions of

compounds labeled with positron-emitting isotopes allow for the characterization of kinetics

and calculating rates of the biological process being studied. Importantly, SPECT as opposed

to PET, is not able to provide absolute quantifications.

The most widely used PET tracer is 2-deoxy-2[18F]fluoro-D-glucose (FDG) to measure

glucose metabolism of the brain. Under steady-state conditions, the measured FDG uptake

reflects the utilization rate of exogenous glucose. In the brain, this rate is highly related to the

synaptic density and functional activity of the brain tissue. It is important to note that absolute

metabolic rates undergo major maturational changes during the first year of life; however, the

regional glucose metabolic pattern of the brain is largely fixed after this early period 71.

Therefore, focal decreases or increases in FDG uptake can be reliably identified in

radioactivity images without calculating absolute metabolic rates. In addition, in disorders such

as SWS, which most often affect only one hemisphere, the contralateral hemisphere can be

used as an internal control for evaluating unilateral focal abnormalities.

FDG PET is increasingly used in pediatric neurology as a tool for pre-surgical

evaluation of patients with medically intractable epilepsy 72. Although FDG PET is currently

not routinely used in the radiological evaluation of patients with SWS, it can provide useful

information regarding functional imaging correlates of neurocognitive impairment. In SWS,

FDG PET demonstrates reduced glucose metabolism of the cortex underlying the angioma, and

even extending beyond the general area of vascular abnormalities 66,73 (Figure 5).

Figure 5: Demonstrative axial slices of the FDG PET scan of an SWS patient with right hemispheric posterior angioma. Note the severe right temporo-occipital (solid arrow) and moderate right parietal (dashed arrow) hypometabolism.

Earlier studies have also shown that the extent of mild-moderate hypometabolism was larger in

children with frequent seizures 22. Furthermore, a recent longitudinal PET study demonstated

that the major progression of hypometabolic cortex in SWS occurs during the first 3 years of

life, and higher seizure frequency may be a factor in metabolic progression 74. Altogether,

metabolic imaging data provide support for the argument for early, aggressive seizure control

in children diagnosed with SWS and associated epilepsy 75. Interestingly, a paradoxical pattern

of focal interictal glucose hypermetabolism has also been observed in some infants with SWS 73,76. Similarly, increased perfusion (on SPECT) has been reported in infants with SWS who

had never had seizures before, and this hyperperfusion appears to shift to the classic

hypoperfusion with age 77. Unfortunately, the exact mechanism and potential prognostic value

of this phenomenon is currently unknown. The extent and severity of cortical hypometabolism

are important imaging markers of cognitive function.

Interestingly, the relationship between cortical hypometabolism and cognitive function

is complex and most likely not linear 78. Factors like the timing of early structural and 14 

 

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functional brain damage may influence the cognitive deterioration. This notion is supported by

a study from Lee et al. 22, who demonstrated a paradoxical preservation of IQ in some children

who underwent an early, widespread hemispheric injury, reflected by severe, extensive

hypometabolism. It has been suggested that early, severe metabolic demise may facilitate

effective reorganizational processes in relatively intact parts of the brain. Effective

reorganization may also be influenced by the nociferous effects of repeated seizures.

Importantly, PET studies can also be useful in depicting functional reorganization, for which

there is a great potential in unilateral SWS, since the contralateral hemisphere is basically

normal. For instance, a recent FDG PET study provided supporting data for the notion of

functional reorganization in SWS 20. In that study, increased glucose metabolism, probably due

to increased synaptic density, was found in the visual cortex contralateral to the angioma. This

was most prominent in patients with severe ipsilateral occipital hypometabolism. In addition,

an activation study using [15O]water PET showed that interhemispheric reorganization is more

pronounced for language than for motor functions in unilateral SWS 79. It is important to note,

however, that reorganization processes are most likely hindered in the relatively rare cases of

bilateral SWS. This may be an important factor accounting for the generally worse clinical

phenotype in this subset of patients 28.

Although FDG is the primary tracer used in clinical, as well as research settings of PET

imaging in SWS, amino acid tracers like [11C]methionine or [11C]leucine may also provide

important insights into the pathophysiology of SWS. As these PET tracers can be used to

measure proliferative activity of brain tumors 80,81, they may also provide an in vivo marker of

angioma proliferation.

I.D. Therapeutic options in SWS

Currently, SWS cannot be prevented or cured. Management of neurological complications is

largely limited to seizure control. Since seizures, along with complicated migraine attacks and

stroke-like episodes may lead to further brain ischemia and metabolic injury, an aggressive

antiepileptic therapeutic approach is warranted 75. In addition, low-dose acetylsalicylic acid

may reduce the number of stroke-like episodes; however, further studies are needed to

substantiate this 82. Indication of neurosurgical treatment (e.g., focal cortical resection,

hemispherectomy) in SWS is medically resistant epilepsy. As early surgical intervention, after

thorough evaluation, is associated not only with good seizure outcome, but also with improved

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cognitive function, it would be essential to identify patients who likely undergo progression

without surgery. Better understanding of the mechanisms underlying the clinical progression

and the wide variability in neurocognitive outcome may identify future therapeutic targets. In

vivo examination of the brain affected by SWS using advanced neuroimaging tools is a crucial

part of this research.

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45. Comi AM. Update on Sturge-Weber syndrome: diagnosis, treatment, quantitative

measures, and controversies. Lymphat Res Biol 2007;5:257-64.

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46. Elster AD and Chen MY. MR imaging of Sturge-Weber syndrome: role of gadopentetate

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inversion recovery imaging for leptomeningeal disease in children. AJNR Am J Neuroradiol

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syndrome. Neurology 2007;68:243.

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59. Sijens PE, Gieteling EW, Meiners LC, et al. Diffusion tensor imaging and magnetic

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analysis of multi-subject diffusion data. Neuroimage 2006;31:1487-505.

66. Juhasz C, Haacke EM, Hu J, et al. Multimodality imaging of cortical and white matter

abnormalities in Sturge-Weber syndrome. AJNR Am J Neuroradiol 2007;28:900-06.

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syndrome: a diffusion tensor tractography study. Brain Dev 2008;30:447-53.

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72. Juhasz C, Chugani DC, Muzik O, et al. Positron-emission tomography in epilepsy. in

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glucose utilization with positron emission tomography. J Pediatr 1989;114:244-53.

74. Juhasz C, Batista CE, Chugani DC, et al. Evolution of cortical metabolic abnormalities and

their clinical correlates in Sturge-Weber syndrome. Eur J Paediatr Neurol 2007;11:277-84.

75. Comi AM. Sturge-Weber syndrome and epilepsy: an argument for aggressive seizure

management in these patients. Expert Rev Neurother 2007;7:951-56.

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1998;13:606-18.

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II. AIMS OF THE STUDIES

Our studies aimed to investigate structural and functional brain injury in SWS using

advanced imaging techniques. Particular emphasis has been given to explore clinical correlates

and prognostic values of certain neuroimaging findings.

A. Previous studies have demonstrated a relationship between brain tissue damage and clinical

phenotype of SWS. Most studies to date focused on cortical abnormalities. Recent results,

however, showed that subcortical changes, for instance the degree of cortical atrophy, as well

as white matter volume loss, correlate with the overall severity of neurologic impairment and

cognitive performance, respectively. Nevertheless, the role of focal white matter abnormalities

and subcortical, particularly thalamic abnormalities, has not been studied previously in SWS.

Therefore, we analyzed microstructural and metabolic alterations of subcortical (thalamic and

white matter) structures. Specifically, the following questions were addressed:

1. Is the thalamus microstructurally and metabolically impaired in SWS? If yes, are these

abnormalities related to cortical injury?

2. Can thalamic asymmetries provide a simple, independent imaging marker for cognitive and

motor functions in unilateral SWS?

3. Which WM regions are commonly affected in SWS?

4. Is there any detectable WM injury contralateral to the angioma in unilateral SWS?

5. Are there any specific areas whose demise is associated with motor or cognitive

dysfunction?

B. FDG PET usually depicts cortical hypometabolism of variable extent in SWS. However, a

seemingly paradoxical phenomenon of increased glucose metabolism, not related to ongoing

epileptic activity, has been reported in a few children. The potential clinical significance of this

pattern has not been elucidated. Therefore, we utilized a large PET database on SWS to

address the following questions:

24 

 

6. At which stage of the disease course may interictal cortical hypermetabolism occur? Is this

phenomenon related to the appearance of first seizures?

7. What is the longitudinal course of the cortical metabolic pattern of increased glucose

metabolism?

C. Recent data support the notion that leptomeningeal angiomas, the intracranial hallmarks of

SWS, are not static lesions but undergo proliferative changes. Using an amino acid PET tracer

(C11-leucine) suitable for in vivo estimation of protein synthesis, we addressed the following

questions:

8. Is the uptake of 11C-leucine increased in brain regions affected by the angioma?

9. If yes, what is the mechanism of increased uptake: elevated protein synthesis rate and/or

elevated leucine transport?

10. Where are these PET abnormalities located, and what is their relation to glucose

metabolism of the affected cortical regions?

D. Bilateral intracranial involvement is rare (~15%) in SWS, and therefore the imaging and

clinical characteristics of this subset of patients have not yet been well described. We carried

out a retrospective study correlating cortical FDG PET findings with gross clinical

characteristics in a series of young patients with bilateral SWS, and we aimed to answer the

following questions:

11. Do patients with bilateral SWS invariably have severely impaired neurocognitive function?

12. Can cortical pattern or severity of glucose metabolic abnormalities be markers of

unfavorable neurological outcome?

13. Is homotopic bilateral cortical damage particularly unfavorable?

25 

 

14. How often can be seizures controlled with antiepileptic medication or respective surgery in

patients with bilateral SWS?

III. SUBJECTS

The patients involved in our studies were selected from an FDG PET database maintained and

constantly updated at the Children`s Hospital of Michigan (CHM). This database contains data

of 3000 patients, including 110 patients (mostly children) with the clinical diagnosis of SWS.

FDG PET scans were performed either at the University of California at Los Angeles (UCLA;

n=50; 1986-1993) or at the PET Center, CHM (n=60; 1994-2010). Many children were

clinically followed in our institution and/or were involved in a prospective, longitudinal

clinical/imaging research study; thus a subset of patients (n=32) had multiple PET scans. MRI

was routinely performed at the time of PET since 2003, including T1+T2 pre- and T1 post-

gadolinium, SWI, as well as DTI sequences, since 2005. Quantitative analysis of PET scans

and/or MRI data was carried out in a total of 35 patients with unilateral brain involvement; all

PET scans were done at the CHM, while MRI was acquired at the MR Research Facility of the

Harper University Hospital, Detroit Medical Center. Additionally, 14 patients had bilateral

intracranial involvement (UCLA+CHM), whose PET images were analyzed qualitatively.

Patients for specific studies were selected based on the inclusion and exclusion criteria

described in the Methods sections of each article.

26 

 

IV. SUMMARY OF PAPERS SUPPORTING THE THESIS

Paper 1

The role of the thalamus in neuro-cognitive dysfunction in early unilateral hemispheric

injury: A multimodality imaging study of children with Sturge-Weber syndrome

[Alkonyi et al., European Journal of Paediatric Neurology 2010 Sep;14(5):425-433.]

The thalamus is a major relay center of the brain and could be affected directly (by

venous congestion in the deep veins draining the thalamus), as well as indirectly (by way of the

cortico-thalamic connections), in SWS. Furthermore, the thalamus is part of a complex

network responsible for cognitive functions. The functional and structural impairment of the

thalamus in SWS and its potential role in cognitive outcome have not been described.

In this study we applied a combination of diffusion tensor imaging and FDG PET in 20

prospectively collected children (11 girls; age range: 3 years to 12.4 years) with SWS and

unilateral hemispheric involvement to assess the abnormality of the thalamus on the affected

side. Using an ROI method, average FA, MD values, corresponding asymmetry indices (AIs),

as well as FDG metabolic AIs, were measured and compared to normative data of control

subjects. Furthermore, these measures were correlated with the extent of cortical

hypometabolism (in the affected hemisphere) and neuropsychological variables (IQ and

dexterity scores).

Glucose metabolic asymmetry of the thalamus was significantly higher in patients than

in controls (p=0.001) indicating hypometabolism of the thalamus. Although FA and MD of

either side of the thalamus did not differ from that of controls after adjusting for age, the

asymmetry of FA in patients with left hemispheric involvement was significantly higher than

in normal controls (lower FA on the ipsilateral side; p=0.019). In addition, there was a trend of

higher MD asymmetry in patients with left hemispheric involvement compared to normals.

Thalamic metabolic asymmetry correlated significantly with the asymmetry of MD (r=-0.69;

p=0.001), extent of cortical hypometabolism (r=-0.75; p<0.001) and IQ (r=0.59; p=0.006). In

the subgroup of patients with left hemispheric involvement (N=13), thalamic glucose

metabolic asymmetry remained an independent predictor of IQ after controlling for age and the

extent of cortical hypometabolism (r=0.81; p=0.002).

Figure 6:

Partial regression plot of glucose metabolic asymmetry of the thalamus vs. full-scale IQ, after controlling for age and the extent of hypometabolic cortex in the subgroup of children with left hemispheric involvement (N=13).

Furthermore, worse fine motor function in the hand contralateral to the affected hemisphere

was associated with more severe glucose metabolic asymmetry of the thalamus (r=-0.66;

p=0.002), but not with asymmetries of any DTI parameters.

These results demonstrate that the injury of the affected hemisphere in SWS also

significantly affects the structure and function of the ipsilateral thalamus. Microstructural and

metabolic abnormalities of the thalamus are closely related to cognitive functions in unilateral

SWS. Thalamic metabolic asymmetry (assessed by FDG PET) is a simple, but robust

independent imaging marker of neurocognitive outcome in children with early unilateral

hemispheric injury related to SWS.

Paper 2

Focal white matter abnormalities related to neurocognitive dysfunction:

An objective diffusion tensor imaging study of children with Sturge-Weber syndrome

[Alkonyi et al., Pediatr Research, 2011 Jan;69(1):74-79.]

Earlier studies of patients with SWS suggested that the severity of subcortical WM

volume loss, ipsilateral to the angioma, may be a stronger predictor of neurocognitive

functions than the degree of cortical atrophy. Investigation of the WM is of high clinical

relevance, since specific WM regions encompassing various cortico-cortical and cortico-

subcortical tracts play a crucial role in motor and neurocognitive functioning. In this study we

27 

 

aimed to identify specific WM regions with significantly altered microstructural integrity and

regions whose diffusion properties correlate with cognitive or fine motor functions.

Fifteen children with SWS and unilateral hemispheric involvement (age range: 3-12.4

years) were studied and compared to 11 healthy controls (age range: 6-12.8 years). Tract Based

Spatial Statistics (TBSS) was used for objective, voxel-wise comparisons of FA and MD

between the two groups using age as a covariate. Moreover, within the SWS group WM FA

and MD values were correlated with IQ and fine motor scores using age as a covariate.

Correlations with p<0.01 in a minimal cluster size of 3voxels were considered significant.

Extensive (ipsi and contralateral), multilobar areas showed decreased FA compared to

control subjects (mean FA of these regions in SWS patients: 0.56 vs. 0.74 in controls), while

MD changes (increases) were confined to smaller ipsilateral posterior regions (mean MD:

0.882×10-3 mm2/s vs. 0.765×10-3 mm2/s in controls).

Figure 7: White matter areas with significantly reduced FA (red/yellow) and increased MD (blue/lightblue) in patients with SWS as compared to controls after statistically factoring out age effects. Results are projected on a pediatric template FA image in standard (MNI 152) space.

Clusters of voxels with FA values significantly correlating with full-scale IQ (range: 47-128;

mean: 76) were identified in the ipsilateral prefrontal WM, while MD was inversely associated

with IQ in ipsilateral posterior parietal WM. The strongest negative correlation between MD

and fine motor function (i.e., higher MD associated with worse dexterity) was found in the

ipsilateral frontal WM encompassing motor pathways.

28 

 

29 

 

Our analysis revealed microstructural abnormalities of WM regions ipsi- and also

contralateral to the angioma in SWS. Interestingly, although conventional MRI and PET

studies showed no or less injury of the frontal lobes, some frontal areas showed decreased FA

on the group level, suggesting common involvement of the frontal lobe WM. Cognitive and

fine motor dysfunctions are related to the injury of specific ipsilateral WM regions.

Paper 3

Transient focal cortical increase of interictal glucose metabolism in Sturge-Weber

syndrome: Implications for epileptogenesis

[Alkonyi et al., Epilepsia., 2011 Apr 11.; doi: 10.1111/j.1528-1167.2011.03066.x. Epub ahead

of print]

Interictal focal cortical glucose hypermetabolism has been reported in a few infants

with SWS and recent seizure onset. To better understand the phenomenon of this unique

metabolic phenomenon, we studied clinical correlates and longitudinal course of cerebral

glucose hypermetabolism in children with SWS.

FDG PET scans of 60 children (age range: 3 months-15.2 years) with SWS, selected

from the PET database of the CHM, were reviewed for focal hypo- or hypermetabolism.

Thirty-two patients had two or more consecutive PET scans (most of them particpitaed in a

prospective, longitudinal neuroimaging study on SWS). Age, seizure variables and the

occurrence of epilepsy surgery were compared between patients with and without

hypermetabolism. The severity of increased glucose metabolism was assessed using

standardized uptake value (SUV) ratios (ipsilateral/contralateral) and correlated with seizure

variables.

Interictal cortical hypermetabolism, ipsilateral to the angioma, was seen in 9 patients,

with the most common location in the frontal lobe. Mean age, as well as time between the scan

and onset of the first seizure, was lower in patients with hypermetabolism than in those without

(mean: 1.9 vs. 4.5 years; p=0.022 and 1.0 vs. 3.6 years; p=0.019, respectively). Increased

metabolism was transient and switched to hypometabolism in all 5 children where follow-up

scans were available (Figure 6).

Figure 8: Representative axial slices of the FDG PET scans of a patient with SWS and right hemispheric angioma. Initial scan (A) at the age of 1.9 years (1 year after the first seizures) showed right frontal hypermetabolism in addition to hypometabolism of the other lobes. Follow-up scan 7 months later (B) demonstrated an interval switch of the hypermetabolism to hypometabolism.

Increased metabolism occurred in 28 % of children scanned under the age of 2 years. Children

showing hypermetabolism had higher rate of subsequent epilepsy surgery as compared to those

without hypermetabolism (5/8 vs. 10/43; p=0.039).

Interictal focal glucose hypermetabolism is common in young patients with SWS and is

most often seen within a short time before or after the onset of first clinical seizures. Increased

glucose metabolism detected by PET may reflect ongoing cortical excitotoxic damage due to

hypoxia. Early presence of hypermetabolism predicts later metabolic deterioration and may be

associated with worse seizure outcome.

Paper 4

Increased L-[1-11C]leucine uptake in the leptomeningeal angioma of Sturge-Weber

syndrome: a PET study

[Alkonyi et al., J Neuroimaging. 2011 Jan 11. doi: 10.1111/j.1552-6569.2010.00565.x. Epub

ahead of print]

Leptomeningeal angioma, the characteristic intracranial lesion in SWS, is traditionally

considered to be a static developmental malformation. However, recent histopathology studies

demonstrated endothelial proliferation in the angioma and underlying cortex. L-[1-11C]leucine

PET is useful for the indirect in vivo detection of increased cell proliferation by estimating

brain tissue protein synthesis rate.

In the present study, we used dynamic PET scanning with L-[1-11C]leucine in 7

children (age range: 3 month-13 years) with unilateral SWS to explore if increased amino acid 30 

 

transport and/or protein synthesis rates can be detected in the posterior angioma region and in

less affected frontal regions. Leucine uptake (expressed as asymmetries, compared to

contralateral homotopic brain regions showing no abnormalities on MRI or FDG PET) was

also correlated with glucose metabolic abnormalities measured by glucose PET. Resected brain

and angioma tissues were immunostained for Ki-67 (a proliferative marker) and VEGF-A in an

infant who underwent hemispherectomy due to intractable epilepsy.

Increased leucine uptake was found in the angioma region in all 7 patients (median

increase: 12%) (Figure 7) and less pronounced increases of leucine uptake were also found in

frontal cortex (median increase: 6.9%).

Figure 9: Axial slices of the C11-leucine PET scan of a 10-year old patient with SWS and right posterior angioma. Arrows indicate temporo-parietal regions (angioma regions) with increased leucine uptake.

Kinetic analysis showed that increased leucine uptake was mainly driven by increased tracer

transport, with milder increases of protein synthesis rates. Higher leucine uptake asymmetries

were associated with more severe hypometabolism (r=-0.82, p=0.047). Signs of endothelial

cell proliferation and angiogenesis (a proliferative index of 5-10% and strong VEGF-A

expression in endothelial cells) were seen in resected specimens from an infant who underwent

epilepsy surgery.

Increased leucine transport and protein synthesis rates in the angioma regions suggest

proliferative activity, likely related to active vascular remodeling. This notion is further

supported by our preliminary immunohistochemistry findings. Degree of increased leucine

uptake may be a marker of disease activity contributing to brain tissue damage in children with

SWS.

31 

 

Paper 5

Clinical outcome in bilateral Sturge-Weber syndrome

[Alkonyi et al., Pediatric Neurology, 2011 Jun;44(6):443-449.]

Up to 15% of patients with SWS have bilateral intracranial involvement, and the

prognosis of these patients is believed to be particularly unfavorable. The imaging and clinical

characteristics of this subset of patients have not been well studied. Therefore, the aim of this

retrospective study was to describe clinical and neuroimaging features and identify potential

markers of unfavorable outcome in this rare patient group.

FDG PET scans of 110 patients with the diagnosis of SWS were reviewed, and cases

with bilateral involvement (also confirmed by CT or MRI) were identified. Seizure variables,

presence of hemiparesis, and degree of developmental impairment at last follow-up were noted

and qualitatively correlated with the extent and location of glucose metabolic abnormalities.

Fourteen patients (12.7%; age at PET scan: 8 months-21 years) had bilateral brain

involvement. In these patients glucose metabolic abnormalities had typically an asymmetric

pattern on PET.

32 

 

Figure 10: Representative axial slices of the T1-weighed postgadolinium MRI and FDG PET scans of an 8.3-year old girl with SWS and severe developmental delay. The MRI demonstrated marked atrophy of the left hemisphere and the right frontal lobe along with extensive leptomeningeal angiomatosis in this distribution. The glucose metabolism of the entire left hemisphere was decreased, with relative sparing of the central areas (arrowheads). On the right side, the most severe hypometabolism was seen in the atrophic frontal lobe (solid arrows). In addition to the right temporal and occipital cortex, the right sensorimotor cortex was also largely intact metabolically; she had no hemiparesis.

Although early onset of epilepsy was not necessarily coupled with intractability, total

hemispheric hypometabolism was invariably associated with poor seizure control. Bilateral

frontal hypometabolism was closely coupled with severe developmental impairment. Two

children with bitemporal hypometabolism showed autistic features. Furthermore, hemiparesis

was associated with superior frontal (motor cortex) hypometabolism. Three patients had

resective surgery, resulting in improved seizure control and/or developmental outcome.

Degree of neurological complications and clinical course are variable and highly

depend on the extent and localization of cortical dysfunction in bilateral SWS; bifrontal

hypometabolism is associated with poor developmental outcome and bitemporal

hypometabolism is often coupled with autistic phenotype. Fortunately, good seizure control

and only mild/moderate developmental impairment can be achieved in about half of the

bilateral SWS patients, with or without resective surgery.

33 

 

34 

 

V. PAPERS

Paper 1

The role of the thalamus in neuro-cognitive dysfunction in early unilateral hemispheric

injury: A multimodality imaging study of children with Sturge-Weber syndrome

[Alkonyi et al., Eur J Paediatr Neurol. 2010 Sep;14(5):425-433.]  

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 1 4 ( 2 0 1 0 ) 4 2 5e4 3 3

Official Journal of the European Paediatric Neurology Society

Original article

The role of the thalamus in neuro-cognitive dysfunction inearly unilateral hemispheric injury: A multimodality imagingstudy of children with SturgeeWeber syndrome

Balint Alkonyi a,c, Harry T. Chugani a,b,c, Michael Behen a,b,c, Stacey Halverson a,Emily Helder a, Malek I. Makki a,c, Csaba Juhasz a,b,c,*aCarman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, 3901 Beaubien Blvd, Detroit, MI 48201, USAbDepartment of Neurology, Wayne State University School of Medicine, Detroit, MI, USAcPET Center, Children’s Hospital of Michigan, Detroit, MI, USA

a r t i c l e i n f o

Article history:

Received 6 October 2009

Received in revised form

25 March 2010

Accepted 26 March 2010

Keywords:

SturgeeWeber syndrome

Thalamus

Diffusion tensor imaging

Positron Emission Tomography

Glucose metabolism

Cognitive function

* Corresponding author. Carman and Ann AdBlvd, Detroit, MI 48201, USA. Tel.: þ1 313 96

E-mail address: juhasz@pet.wayne.edu (C1090-3798/$ e see front matter ª 2010 Europdoi:10.1016/j.ejpn.2010.03.012

a b s t r a c t

Background: SturgeeWeber syndrome (SWS) with unilateral hemispheric involvement is

a clinical model of early onset, chronic, often progressive hemispheric injury, resulting in

variable neuro-cognitive impairment.

Aims: To evaluate if abnormal diffusion and metabolism of the thalamus, a central relay

station with extensive cortical connections, may serve as a simple imaging marker of

neuro-cognitive dysfunction in SWS.

Methods: We obtained both diffusion tensor imaging and FDG PET in 20 children (11 girls;

age range: 3e12.4 years) with unilateral SWS. Diffusion parameters as well as FDG uptake

were measured in thalami, compared to normal control values, and correlated with the

extent of cortical hypometabolism, deep venous abnormalities and cognitive (IQ) as well as

fine motor functions.

Results: Children with SWS had significantly higher thalamic glucose metabolic asymmetry

than controls ( p¼ 0.001). Thalamic metabolic asymmetries correlated positively with the

asymmetry of thalamic diffusivity ( p¼ 0.001) and also with the extent of cortical hypo-

metabolism ( p< 0.001). Severe thalamic asymmetries of glucose metabolism and diffusion

were strong predictors of low IQ (metabolism: p¼ 0.002; diffusivity: p¼ 0.01), even after

controlling for age and extent of cortical glucose hypometabolism in children with left

hemispheric involvement. Ipsilateral thalamic glucose hypometabolism was also associ-

ated with impairment of fine motor functions ( p¼ 0.002).

Conclusions: Both diffusion and glucose metabolic abnormalities of the thalamus are closely

related to cognitive functions, independent of age and cortical metabolic abnormalities, in

children with unilateral SWS. Thalamic metabolic asymmetry is a robust but simple

imaging marker of neuro-cognitive outcome in children with early unilateral hemispheric

injury caused by SturgeeWeber syndrome.

ª 2010 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights

reserved.

ams Department of Pediatrics, Wayne State University School of Medicine, 3901 Beaubien6 5136; fax: þ1 313 966 9228.. Juhasz).ean Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

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 1 4 ( 2 0 1 0 ) 4 2 5e4 3 3426

1. Introduction

The SturgeeWeber syndrome (SWS) is a sporadic neuro-

cutaneous disorder characterized by facial port wine stains,

glaucoma and leptomeningeal angiomatosis involving one

cerebral hemisphere in most of the cases (approximately

85%).1 The most common neurologic manifestations of SWS

are early onset seizures, hemiparesis, visual field cut and

cognitive deficit.1 Progressive cognitive decline is apparent in

about half of the patients and is often associated with

intractable seizures. Nevertheless, seizures during the course

of the disease fail to provide sufficient prognostic information

for cognitive outcome.2,3

SWS is a unique clinical model to study themechanisms of

neuro-cognitive impairment due to early, chronic unilateral

hemispheric lesions. It is generally thought that the anoma-

lous vascular formation on the brain surface leads to venous

stasis, secondary impairment of cerebral blood flow, hypoxia

and chronic ischemia in the underlying brain tissue. Increased

venous pressure in the deep venous systemmay affect venous

outflow of deep gray matter structures such as thalamus, but

the role of deep brain structure damage in neuro-cognitive

progression of SWS has not been clarified.

Only a few studies have investigated the relationship

between brain vascular and parenchymal abnormalities and

severity of clinical symptoms during the course of SWS. In

a semi-quantitative analysis, the severity of cortical atrophy

strongly correlated with the general clinical status but only

weakly with cognitive function scores.4 A volumetric study of

children with SWS has shown that hemispheric white matter

volume in the affected hemisphere may be a better predictor

of cognitive impairment than cortical gray matter volumes.5

Subcortical white matter microstructural damage (extending

beyond abnormal cortex), demonstrated by diffusion tensor

imaging (DTI), may also contribute to neuro-cognitive

impairment in SWS.6 Using 2-deoxy-2[18F]fluoro-D-glucose

(FDG) positron emission tomography (PET), we have previously

demonstrated that the cognitive impairment in children with

a relatively limited area of cortical hypometabolism may,

paradoxically, be more severe than in those with early,

extensive hemispheric progression, suggesting that early

demise of the affected brain regions in SWS may lead to more

efficient reorganization.7

Thalamus is a major relay station of the brain and could be

affected both directly (by venous congestion in the deep veins)

and indirectly (via cortico-thalamic connections) in SWS.

Thalamic magnetic resonance imaging (MRI) and PET abnor-

malities have been commonly observed in intellectually

disabled patients due to different pathophysiologic ori-

gins.8e11 Therefore, it can be hypothesized that thalamic

abnormalities may be a marker of abnormal neuro-cognitive

functions in children with SWS. In this study, we have

analyzed thalamic abnormalities using MRI (including DTI)

and FDG PET scanning in a prospectively collected group of

children with unilateral SWS. Specific goals of the study

included: 1. To assess the presence of thalamic microstruc-

tural (using diffusion parameters from DTI) and glucose

metabolic (using FDG PET) abnormalities and evaluate how

these are related to severity of cortical metabolic changes. 2.

To determine whether there is a relation between metabolic/

microstructural abnormalities of the thalamus and the

severity of neuropsychological variables (cognitive and motor

dysfunction) and to determine if thalamic asymmetries can

provide a simple, independent imaging marker for cognitive

and motor functions in SWS.

2. Subjects and methods

2.1. Subjects

Twenty children (11 girls, age: 3 yearse12.4 years; mean age:

6.5 years) with the diagnosis of SWS and unilateral hemi-

spheric involvement were selected from a series of 42

patients, who participated in a prospective clinical and

neuroimaging study of children with SWS. All selected

patients met the following inclusion criteria: (1) age at least 3

years at the time of the imaging studies; this age limit was

selected to include only children where verbal and performance IQ

scores could be obtained using Wechsler intelligence scales; (2)

presence of a facial port wine stain; (3) radiologic (MRI and

FDG PET) evidence of unilateral brain involvement; (4)

imaging studies including FDG PET and MRI with DTI, per-

formed on consecutive days. Gadolinium enhanced MRI

revealed unilateral leptomeningeal angiomatosis in all but

one (patient 12, Table 1) case. In this latter patient, the

presence of unilateral facial port wine stain, ipsilateral

hypometabolism on FDG PET images and the history of

seizures supported the diagnosis of SWS with unihemi-

spheric involvement. Nineteen patients had a history of

seizures and 18 of these patients were on antiepileptic drug

(s), including oxcarbazepine (N¼ 9), levetiracetam (N¼ 6),

carbamazepine (N¼ 3), topiramate (N¼ 2), phenobarbital

(N¼ 2), valproate (N¼ 2) and lamotrigine (N¼ 1). Age at

seizure onset varied from the day of birth to 8 years of age

(mean age: 1.4 years; SD: 1.9). The mean duration of epilepsy

was 5.0 years (SD: 3.1). Annual seizure frequency at the time

of the PET scanning varied from 0 to 200 (median: 3). Clinical

data of the patients were obtained from medical records and

parent interviews (Table 1).

To compare the images of the patient group to normal

controls, we used two control groups: for MRI/DTI images, we

used a healthy control group consisting of 12 children (“DTI

control group”) (5 girls; mean age: 11.8 years; range: 6e15.9

years); for FDG PET, we used images of 9 healthy children

(“PET control group”, mean age: 11.2 years, range: 9.8e12.3

years). Both control groups were significantly older than the

patient group (independent samples t-tests, p< 0.001), therefore,

age was used as a covariate in group statistical analyses

where indicated. Healthy children for the DTI as well as PET

control groups were recruited based on the following inclusion

criteria: (1) age above 5 for DTI and above 8 for PET studies; (2)

global intellectual functioning above 85 (above population

mean� 1SD); (3) absence of current or historical medical, devel-

opmental, or psychiatric problems. All imaging and clinical

studies were performed in compliance with regulations of

Wayne State University’s Human Investigation Committee,

and written informed consent of the parent or legal guardian

was obtained.

Table 1 e Clinical data as well as DTI and FDG PET asymmetries of the thalamus.

PatientNo./affectedside

Gender/age(years)

Age atseizure onset

(years)

Angiomalocation onT1-Gad MRI

PET location ofhypometabolism

FSIQ Affected handfine motor

function scores

FA AI(%)

MD AI(%)

FDG AI(%)

1/L F/3.1 2 LOpostT LTP(O) 112 2 �0.8 1.4 1.2

2/L F/3.4 No epilepsy LPO LT(P) 104 1 �3.6 �0.7 5.0

3/L F/8.9 0.3 LO(T) LTPO 82 3 �10.6 5.7 �12.5

4/L M/3.9 3.5 LO(P) LO(T,P) 110 2 �10.5 0.7 �5.2

5/L F/8.1 0.2 LTPO(F) LTPO 55 3 �1.8 8.6 �23.7

6/L M/9.7 8 LP LTO 87 3 �1.0 0.6 �0.2

7/L M/9.3 0.3 LTPO(F) LTPO(F) 73 3 �14.9 3.5 �15.8

8/L F/3.8 0 LF FTP 91 3 �2.3 1.4 �7.7

9/L F/6.0 0.3 LTPO LTPO(F) 69 3 �2.9 4.7 �18.9

10/L F/3.5 2 LP LP(T) 91 2 �2.5 0.6 �8.9

11/L M/3.3 0.4 LFTPO LFTPO 85 3 3.8 4.2 �16.4

12/L F/4.1 0.5 None LTPO 87 2 �1.7 0.4 �0.2

13/L M/8.2 0.6 LPO LP(T,O) 100 3 �2.6 �1.0 �2.4

14/R M/8.9 1.8 RTPO RTPO 76 3 8.3 �1.2 �3.8

15/R F/11.3 1.7 RP RP 57 3 2.2 �0.4 �9.0

16/R M/12.4 n.a. RFTpostPmedO RFPO 47 3 1.9 1.4 �26.7

17/R F/3.6 0.8 RsupP RP 128 2 5.9 0.0 �7.2

18/R M/6.3 0.8 RFTPO RO(T) 55 1 �4.5 2.7 0.6

19/R M/3.0 0.5 RTPO RPO 92 n.a. �5.1 0.5 �7.9

20/R F/9.5 0.7 RFTPO RFTPO 60 3 11.8 5.6 �30.4

Mean (SD) 6.5 (3.1) 1.4 (1.9) 83 (22) L1.54 (6.3) 1.94 (2.6) L9.5 (9.8)

Note: L, left; R, right; n.a., not available; F, frontal; T, temporal; P, parietal; O, occipital; post, posterior; med, medial; sup, superior; T1-Gad, post-

gadolinium T1-weighted images; MRI, magnetic resonance imaging; PET, positron emission tomography; Letters in parenthesesmean that only

small areas of the indicated lobes were affected. FSIQ, full-scale IQ; FA, fractional anisotropy; MD, mean diffusivity; FDG, 2-deoxy-2[18F]fluoro-D-

glucose; AI, asymmetry index (negative AIs represent lower values ipsilateral to the angioma); SD, standard deviation. Fine motor functions

scores: 1: normal, 2: borderline, 3: impaired.

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 1 4 ( 2 0 1 0 ) 4 2 5e4 3 3 427

2.2. Neuropsychological evaluation

All children with SWS underwent a comprehensive neuro-

psychologic assessment within 1 day of the PET study. Neu-

ropsychologic testing was performed in the morning, before

sedation for imaging. Intellectual function was assessed using

either the Wechsler Preschool and Primary Scales of Intelli-

gence Scales for Children, Third Edition (WPPSI-III; age 36e87

months),12 or the Wechsler Intelligence Scales for Children,

Third Edition (WISC-III; age> 87 months).13 Global, verbal and

nonverbal intellectual functioning were characterized by full-

scale (FSIQ), verbal (VIQ) and performance IQs (PIQ), respec-

tively. Children with SWS were also administered either the

Purdue Pegboard task,14 if less than 5 years of age, or the

Grooved Pegboard task,15 if older than 5 years of age. These

tasks provide a measure of manual dexterity for both hands.

The non-dominant hand of one of the patients (patient 19)

could not be tested owing to lack of compliance. Raw manual

dexterity scores were then ranked into 3 groups according to

the severity of impairment (normal [T-score> 36]¼ score 1;

borderline [T-score between 30 and 36]¼ score 2; impaired

[raw score< 30]¼ score 3).

2.3. MRI data acquisition

AllMRstudieswerecarriedoutonaSonata1.5TMR instrument

(Siemens, Erlangen, Germany) using a standard head coil.

During thescanningphaseofbothMRimagingandPETstudies,

SWS children younger than 7 years of age were sedated.

Healthy children were never sedated during MRI and PET

scanning. The MRI protocol for the patient group included an

axial 3D gradient-echo T1-weighted, axial T2-weighted turbo

spin-echo, DTI, susceptibility weighted imaging (SWI), followed by

a post-gadolinium (Gad; 0.1 mmol/kg) T1-weighted acquisition.

AdditionalMRsequences includeddynamicperfusionweighted

imaging (PWI), magnetic resonance angiography, and post-

gadolinium SWI, in some cases. DTI acquisitionwas performed

using single-shot, diffusionweighted, echoplanar imaging. The

acquisition parameters included: TR¼ 6600; TE¼ 97ms;

NEX¼ 8; acquisition matrix¼ 128� 128; bandwidth¼ 95 KHz;

FOV¼ 230� 230� 3 mm3, voxel size¼ 1.8� 1.8� 3 mm with

two b values (0, 1000 s/mm2) applied sequentially in 6 non-

collinear directions. In the DTI control group, only diffusion

tensor (using the parameters detailed above) and volumetric

T1-weighted images (not used in the present study) were

obtained.

2.4. PET scanning protocol

The details of FDG PET acquisition and data analysis have

been described previously.7 In brief, PET scans were acquired

using an EXACT/HR PET scanner (CTI/Siemens, Knoxville, TN)

which provides simultaneous acquisition of 47 contiguous

transaxial images with a slice thickness of 3.125 mm. The

reconstructed image resolution obtained was 5.5� 0.35 mm

at full width at half-maximum in-plane and 6.0� 0.49 mm

at full width at half-maximum in the axial direction

(reconstruction: filtered backprojection using Shepp-Logan filter

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 1 4 ( 2 0 1 0 ) 4 2 5e4 3 3428

with 0.3 cycles/pixel cutoff frequency). Scalp EEG was

monitored in all SWS children during the tracer uptake period.

Initially, 5.29 MBq/kg (mean: 127.5 MBq; SD: 71) of FDG

was injected intravenously as a slow bolus followed by

a 30 min uptake period. Forty minutes after injection, a static

20-min emission scan was acquired parallel to the cantho-

meatal plane. Calculated attenuation correction was applied

to the brain images using automated threshold fits to the

sonogram data.16 FDG PET scans were acquired for all of the

patients and PET control subjects using the same scanner;

however, normal controls were administered a calculated

dose (mean: 119.6 MBq; SD: 8.9) of FDG to keep the whole body

radiation dose below the FDA limit defined for volunteers

participating in research studies (injected dose was up to

148 MBq in children below 15 years of age). This slight differ-

ence in the radiation dose between the patients and controls

likely did not influence brain asymmetry measures, which

were used to evaluate thalamic abnormalities in glucose

metabolism.

2.5. Image analysis

2.5.1. DTI image processing and PET/DTI co-registrationFractional anisotropy (FA) and mean diffusivity (MD) maps

were created using the DTI Studio software.17 Initially, the T2-

weighted (b~0 s/mm2) image of the DTI sequence (b0 images),

as well as the FA and MD maps were displayed in three

orthogonal orientations and realigned with the use of an

interactive registration software (VINCI 2.50; Max Planck

Institut, Cologne, Germany)18 in order to achieve a symmetric

appearance of the basal ganglia and thalami. Subsequently,

FDG PET images were co-registered to the b0 series of the DTI

sequences.

2.5.2. Measurements of thalamic abnormalities using regionsof interest (ROIs)Thalamic diffusion and metabolic values were obtained by

using rectangular shaped ROIs drawn on 4 consecutive planes

of the thalamus. This sampling method, rather than an

attempt to delineate the borders of the entire thalamus was

selected because the PET control subjects had no MR images

available, and accurate, reproducible delineation of thalamic

borders on PET images would have been difficult. For thalamic

measurements in the SWS group and also in the DTI control

Fig. 1 e Representative images showing the ROI definition in one

non-diffusion weighted images (i.e., b0 series) of the DTI sequen

on the co-registered FDG PET images. The rectangular shaped R

thalamus was clearly identifiable). ROIs of the same size were

group, ROIs were drawn on b0 images using the software

MIPAV, Version 4.3.0,19 by one of the investigators (B.A.), who

was unaware of the identity of the patients at that time. ROIs

of exactly the same size were defined in left and right,

symmetric portions of the thalami in 4 consecutive planes,

starting with the top axial plane where the thalamus was first

clearly visible. ROIs were then superimposed on FA and MD

maps to calculate FA andMD values for each thalamus (Fig. 1).

Mean FA and MD values were calculated as the average of all

voxels of all ROIs on each side. The total size of the 4 ROIs

encompassing the thalamus on each side ranged between 54

and 100 voxels (525e972 mm3). In order to omit voxels which

likely belong to adjacent white matter structures or the lateral

ventricles, voxels with FA> 0.5 and/or MD> 1.3� 10�3 mm2/s

were removed from the calculation.20 In the patient group, the

same DTI-based thalamic ROIs were also overlaid onto the

co-registered FDG PET images and average radioactivity

concentrations for each thalamus were measured. Since the

PET control subjects did not have MRI scans, ROIs for the

thalamus in this group were drawn directly on the axial PET

images, by implementing the standardized rules of ROI defi-

nition. Subsequently, % asymmetry indices (AIs) for both

DTI measures and PET radioactivity concentration values

of the thalamus were calculated in the patients as follows:

AI (%)¼ 200� [(I� C )/(Iþ C )], where I represents ipsilateral, C

represents contralateral values as compared to the side of the

lesion. In the control group, absolute as well as left minus right

AI (%) values were calculated for between-group comparisons. To

calculate intrarater reliability of the measurements, ROI

placementwas repeated after 3weeks for all 20 patients by the

same investigator. Interrater reliability was evaluated by

comparing ROI drawings of two observers (B.A. and C.J.) in 10

randomly selected patients.

2.5.3. Measurement of the extent of cortical hypometabolismin the affected hemisphereTo evaluate a potential correlation between thalamic and

cortical metabolic abnormalities, the hemispheric extent of

cortical glucose hypometabolism on the side of the angioma

was obtained by using a semiautomated software package as

described earlier.7,21 A 10% asymmetry threshold for the defi-

nition of cortical hypometabolism was used based on consider-

ations described previously.22,23 The size of marked cortical

hypometabolism was expressed as the percent of total

plane of the thalamus (patient 9). ROIs were defined on the

ces and then superimposed on the FA, MD maps as well as

OIs were drawn on 4 consecutive planes (where the

used on both thalami. L[ left, R[ right.

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 1 4 ( 2 0 1 0 ) 4 2 5e4 3 3 429

ipsilateral hemispheric surface, a value independent of the

actual size of the hemisphere.

2.6. Study design and statistical analysis

Initially, intrarater and interrater reliabilities were evaluated.

ROI values of repeated measures were compared by calcu-

lating % differences (mean and SD). Pearson correlations were

also applied to the corresponding values of two ROI drawings.

To evaluate potential presence of thalamic asymmetries in

the control group, paired t-tests were performed to compare

corresponding left and right values of MD, FA and FDG

radioactivity concentrations.

Presence of imaging abnormalities of the thalamus in the

patient group was assessed with group comparisons. Group

comparisons were performed in three ways: (1) Analysis of co-

variance (ANCOVA), with age as a covariate, was applied to

compare thalamic FA and MD values of patients with similar

values of the control subjects; for thalamic FDG PET abnormali-

ties, this analysis was not done, since absolute tracer uptake values

were not evaluated in between-group comparisons. (2) AIs of

thalamic MD, FA and FDG radioactivity concentration values were

compared between the whole SWS group and the corresponding

control groups by performing independent samples t-tests using

absolute values of AIs. This analysis was also repeated with the

subgroup of patients with left hemispheric involvement by using left

minus right asymmetries; the right hemispheric subgroup was not

analyzed separately due to its small sample size. (3) FA, MD as well

as average FDG radioactivity concentration values were also

compared between thalami ipsi- and contralateral to the

affected hemisphere using paired t-tests.

In the next step, potential associations of thalamic meta-

bolic abnormalities were analyzed by correlating thalamic

FDG PET asymmetries (AI values) with potential imaging and

clinical predictors including: (1) AIs of DTImeasures, (2) extent

of cortical hypometabolism, and (3) age as well as age at seizure

onset using Pearson’s correlations. Subsequently, to determine if

extent of cortical hypometabolism was an age-independent predictor

of thalamic FDG asymmetries, a multiple linear regression analysis

was performed with extent of cortical hypometabolism and age as

predictors and thalamic FDG AI values as the outcome.

In the final step, the potential role of thalamic abnormali-

ties in cognitive and finemotor functions was evaluated. First,

univariate correlations (Pearson’s product moment) were per-

formed between FSIQ scores and potential predictors such as

patient age, age at seizure onset, thalamic DTI and PET

asymmetries as well as extent of cortical hypometabolism. In

addition, IQ scores of patients with controlled seizures (no seizures

during the last year before PET scan; N¼ 7) and uncontrolled

seizures (N¼ 12) were also compared using an independent samples

t-test. All variables with alpha values ( p< 0.1) were entered

into a subsequent multiple linear regression analysis to

determine the independent contribution of each variable to

IQ. This procedure was repeated for cognitive subdomains

(VIQ and PIQ) and tested for the whole group as well as in the

larger subgroup with left hemispheric involvement (n¼ 13) to

assess side-specific effects of thalamic injury; again, the right

hemispheric subgroup was not analyzed separately due to its limited

sample size. Finally, to test the potential association between

the FDG AIs of the thalamus and the ranking scores for

dexterity in the affected hand (contralateral to the angioma),

Spearman’s correlation was applied. Statistical analysis was

performed using SPSS 17.0 (Chicago, IL) software package and

p< 0.05 was considered significant.

3. Results

Both intra- and interrater reliabilities were very high for both

DTI and FDG PET values, with correlation coefficients above

0.98 ( p< 0.001) for intra- and above 0.91 ( p< 0.001) for inter-

rater measurements. Mean� SD of differences between two

ROI drawings ranged from 0.3� 0.4% to 1.1� 1.0% for intra-

and from 0.5� 0.6% to 3.3� 2.4% for interratermeasurements.

There was no significant difference between left and right

thalamic FA (0.305 vs. 0.302, respectively, p¼ 0.49) and MD

values (7.91� 10�4 mm2/s vs. 7.86� 10�4 mm2/s, respectively,

p¼ 0.19) in the control subjects. Therefore, average values of

the two sides were used in the group comparisons. Average

FDG radioactivity concentration of the left and right thalami

also did not differ in the PET control group ( p¼ 0.48).

3.1. Diffusion and metabolic abnormalitiesof the thalamus

In the between-group comparisons, neither FA nor MD values

of the ipsi- (mean� SD: 0.277� 0.025 and 8.0� 10�4 mm2/

s� 4.4� 10�5 mm2/s) or contralateral thalami (mean� SD:

0.281� 0.02 and 7.8� 10�4 mm2/s� 3.4�10�5 mm2/s) differed

from the values of the DTI control group (left-right mean� SD:

0.304� 0.02 and 7.9� 10�4 mm2/s� 1.9�10�5 mm2/s) after

controlling for age ( p> 0.35). Also, neither FA AI nor MD AI

values of the SWS group differed significantly from those of the

control group (p¼ 0.30 and p¼ 0.33, respectively); however, the FA

AI values of the subgroup of SWS patients with left hemispheric

involvement were significantly higher (p¼ 0.019) and the MD AI

values were slightly higher (p¼ 0.085) than those of the control

group. Also, FDG AIs of the whole SWS group as well as the

subgroup with left hemispheric involvement were higher than those

of the control group (p¼ 0.001 and p¼ 0.004, respectively).

In paired comparisons (comparing ipsi- vs. contralateral

thalamus in the whole patient group), MD values of the ipsi-

lateral thalami were higher than those of the contralateral

thalami ( p¼ 0.004). In addition, higher MD ( p¼ 0.013) and

lower FA values ( p¼ 0.014) were found on the affected (left)

side in the subgroup of patients with left hemispheric

involvement (n¼ 13). The average FDG radioactivity concen-

tration of the thalamus on the affected side was significantly

lower than that on the contralateral side ( p¼ 0.001).

3.2. Imaging and clinical correlates of metabolicabnormalities of the thalamus

There was a significant correlation between the glucose

metabolic AIs and MD AIs (r¼�0.69; p¼ 0.001, indicating that

lower ipsilateral thalamic glucose metabolism was associated

with higher MD values). This correlation was even stronger in

the subgroup of patients with left hemispheric involvement

(N¼ 13; r¼�0.88; p< 0.001). However, there was no correla-

tion between the FA AI and glucose metabolic AI of the

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 1 4 ( 2 0 1 0 ) 4 2 5e4 3 3430

thalamus ( p> 0.3). The extent of cortical hypometabolism

varied widely among the patients (between 1 and 84% of the

hemispheric surface), and showed a strong correlation with

the glucose metabolic AI of the thalamus (r¼�0.75; p< 0.001,

indicating that lower ipsilateral thalamic glucose metabolism

is associated with larger extent of cortical hypometabolism).

In addition, thalamic glucosemetabolic AIs were higher (more

negative) in older patients (r¼�0.45; p¼ 0.04), but there was

no correlation with the age at seizure onset ( p¼ 0.11). Finally,

the multiple regression analysis (with age and extent of

cortical hypometabolism) showed that the extent of cortical

hypometabolismwas an independent predictor of the glucose

metabolic AI of the thalamus (r¼�0.70; p¼ 0.001).

3.3. Relationship between cognitive functions,motor functions and glucose metabolic asymmetriesof the thalamus

Table 1 summarizes the neuropsychological data of the 20 patients.

FSIQ, VIQ and PIQ scores ranged between 47 and 128 (mean: 83), 46

and 139 (mean: 90) and 47 and 111 (mean: 79), with values falling

below the population mean� 2 SD (i.e., below 70) in 6, 5 and 7

patients, respectively. In univariate analyses, we found a signif-

icant correlation between FSIQ and thalamic metabolic

(r¼ 0.59, p¼ 0.006) as well as MD AIs (r¼�0.48, p¼ 0.03) in the

whole group. These relationships were even stronger in the

left subgroup of patients (for FDG AI: p< 0.001; for MD AI:

p¼ 0.001). IQ was also inversely associated with the patients’

age (r¼�0.70, p¼ 0.001), and there was also a trend for

correlation with the extent of cortical hypometabolism

(r¼�0.44, p¼ 0.051). The age at onset of seizures as well as seizure

control did not show association with IQ (p¼ 0.45 and p¼ 0.63,

Fig. 2 e FDG PET images of two patients with SturgeeWeber syn

occipital, temporal) cortical involvement (solid arrows). (A) The

thalamic hypometabolism (dashed arrows; measured AI: L5.2%

110). (B) The image of an 8 years old girl (patient 5) shows severe

patient’s cognitive functions were severely impaired (full-scale

respectively). The two potential predictors of IQ (age and extent

of cortical hypometabolism) were entered in the subsequent

multiple regression analysis, together with thalamus MD and

glucose metabolic AIs as predictors (two separate regression

analyses were performed for these thalamic variables).

Although neither glucose metabolic nor MD AIs of the thal-

amus showed a significant correlation (r¼ 0.38, p¼ 0.12;

r¼�0.45, p¼ 0.058, respectively) with FSIQ in the multiple

regression analysis of the whole SWS group, in the subgroup

of children with left hemispheric involvement, both of these

imaging variables were significant independent predictors of

FSIQ (FDG AI: r¼ 0.81, p¼ 0.002; MD AI: r¼�0.73, p¼ 0.01) (see

Figs. 2 and 3). Similar correlations of the thalamic glucose

metabolic andMD asymmetrieswere foundwith both VIQ and

PIQs (detailed data not shown). Motor function of the hand

contralateral to the affected hemisphere also correlated with

the glucose metabolic AI of the thalamus (r¼�0.66; p¼ 0.002),

but not with FA ( p¼ 0.33) and MD AIs ( p¼ 0.26).

4. Discussion

The present study demonstrates significant metabolic, but

less robust microstructural, impairment of the thalamus in

the affected hemisphere in children with unilateral SWS. The

clinical relevance of the thalamic abnormalities is that meta-

bolic and diffusion asymmetries of the thalamus are strongly

associated with cognitive functions; thalamic metabolic

asymmetry is also a good predictor of fine motor functions.

Importantly, in the subgroup of patients with left hemispheric

involvement, thalamic metabolic and diffusion asymmetries

predict IQ independently of the patients’ age and extent of

drome, with mild (A) and severe (B) left posterior (parietal,

image of a 4 years old boy (patient 4) shows minimal

) on the left side. This patient had normal IQ (full-scale IQ:

thalamic hypometabolism (dashed arrow; AI:L23.7%). This

IQ: 55). L[ left, R[ right.

Fig. 3 e Partial regression plot of glucose metabolic

asymmetry of the thalamus vs. full-scale IQ, after

controlling for age and the extent of hypometabolic cortex,

in the subgroup of 13 children with left hemispheric

involvement. The values represent residuals from

regressing asymmetry and full-scale IQ on age and extent

of hypometabolic cortex. Full-scale IQ showed a strong

negative correlation with glucose metabolic AI of the

thalamus even after controlling for other predictors.

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 1 4 ( 2 0 1 0 ) 4 2 5e4 3 3 431

cortical involvement. The lack of such a strong predictive value of

these asymmetries in the whole group suggests that the impact of

thalamic impairment on cognitive functioning in the two hemi-

spheres of the brain may differ; larger studies including more

patients with right-sided involvement are required to understand

such differences. Although this is a cross sectional study with

limited number of subjects, our multimodal imaging data

strongly suggest that structural and functional impairment of

the thalamus, conveniently assessed by DTI and FDG PET

imaging, is a strong, objective marker of cognitive and motor

functioning in children with SWS.

4.1. Potential predictors of neuro-cognitive outcomein SWS

SturgeeWeber syndrome is often a progressive disease with

widely varying degree of clinical and structural impairment

among patients. Although cognitive impairment is often

associated with intractable seizures, several studies failed to

reveal sufficient prognostic value of seizure variables.2,24,25

Consistent with these previous results, age at seizure onset

did not correlate with neuropsychological variables and neu-

roimaging abnormalities in our study. Notably, seizures of

most patients involved in our study were relatively well

controlled. Furthermore, accurate estimation of long-term

seizure severity would have been difficult due to the common

sporadic, clustering seizure pattern described in SWS.25

Young children with severe, intractable seizures, who

commonly undergo early resective surgery, were not included

in this study. Therefore, investigation of the potential role of

seizure frequency was beyond the scope of the present study.

Our previous SWS studies looking at neuroimaging correlates

of cognitive decline evaluated the potential role of cortical

hypometabolism as well as gray and white matter volume

changes.5,7,26 A cross sectional PET study from our group

described that early, severe cortical hypometabolism in the

affected hemisphere, surprisingly, was associated with better

intellectual function.7 It has been hypothesized that early

onset, rapid progression of unilateral cortical dysfunctionmay

trigger effective reorganization leading to relatively preserved

cognitive functions in some children.7,26 In a semi-quantita-

tive analysis, Kelley et al. (2005)4 found a weak correlation

between the degree of cortical atrophy and cognitive function.

The results of an MRI/PET multimodality analysis in 13 chil-

dren with SWS suggested that white matter damage under-

lying the cortical hypometabolism as well as in adjacent areas

may also contribute to cognitive deficit.6 In concordance with

this finding, a recent study found that ipsilateral white matter

volume appeared to be a predictor of full-scale IQ.5 However,

white matter volumes cannot be used as a simple, clinically

feasible imaging marker of neuro-cognitive functions.

4.2. Thalamic dysfunction in SWS

Although simultaneous DTI and glucose PET analysis of the

thalamus/thalamocortical pathways has already been per-

formed in a few studies in different patient populations,27,28

functional and microstructural impairment of the thalamus

in children with early hemispheric damage, such as caused by

SWS, has not been evaluated. Our data demonstrate that the

metabolism of the ipsilateral thalamus is significantly

impaired in patients with unilateral SWS. Since diffusion

asymmetries of the thalamuswere less robust, DTI images are

more difficult to interpret for assessment of thalamic damage.

Despite this, glucose metabolic asymmetries showed a tight

correlation with mean diffusivity but not with FA asymme-

tries. A plausible reason for the lack of association between FA

AI and glucose metabolic AI of the thalamus can be that

functional impairment of the thalamus may be more related

to neuronal loss and the expansion of the extracellular space

rather than tissue disorganization. A similar explanation was

suggested in previous studies where diffusivity was found to

be a more sensitive diffusion index than FA in identifying

epileptogenic cortex.29,30 Therefore, despite the small asym-

metries, MD appears to be a more useful diffusion measure in

evaluating microstructural abnormality of the thalamus in

SWS.

The mechanism of functional deterioration of the thal-

amus in SturgeeWeber syndrome is not completely clear.

Thalamic dysfunction (in the form of “diaschisis” or ipsilateral

atrophy) is commonly seen following cortical injury.20,27,31e34

The association between the cortical extent of hypo-

metabolism with the degree of thalamic hypometabolism in

our study supports this mechanism. In addition, increased

venous pressure on the brain surface may force deep draining

veins to channel blood to the deep venous system that also

drains venous blood from the thalami. These pressure

changes may directly affect thalamic venous outflow, leading

to hypoxic injury, or could indirectly affect the thalamus via

hypoxic injury of white matter tracts connected to various

thalamic nuclei.

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 1 4 ( 2 0 1 0 ) 4 2 5e4 3 3432

4.3. Relation between cognitive functionand the thalamus

Previous research has failed to identify one central executive

region responsible for “intelligence” in healthy subjects, but

revealed the potential role of multiple, anatomically and

functionally connected areas, including distinct cortical

regions, cerebellumandthalamus.35,36Thethalamus isamajor

relay center of the brain with both afferent sensory as well as

extensive reciprocal cortical connections. Recent studies have

also suggested that thalamus is an integrator of multisensory

and sensorimotor functions.37 Therefore, it is not surprising

that even isolated damage of the thalamus may result in

cognitive dysfunction.38 Studies investigating the potential

neuroanatomical substrates of cognitive impairment from

various causes demonstrated abnormalities of the

thalamus.8e11 Recent neuroimaging and EEG data also sup-

ported the participation of the thalamus in the network

responsible for cognitive performance.39,40 In line with these

previous findings, herewedemonstrate that the damageof the

thalamus, a central structure integrating and therefore repre-

senting abnormalities of widespread, connected white matter

and gray matter regions, may be a simple, robust predictor of

IQ. In addition, thalamic hypometabolism strongly correlates

with dexterity of the affected hand in patients with SWS. The

thalamus is indeed part of a complex network responsible for

fine motor function,41,42 therefore, the observed correlation

with dexterity scores actually represents association with

anatomically and functionally connected structures.

4.4. Methodological considerations

There are some limitations that need to be noted when

interpreting our results. Firstly, the patients were selected

using a lower age limit of 3 years. Although the neurologic

manifestations of SWS often present at earlier ages, including

only children above 3 years allowed us to analyze a patient

sample with a wide range of cognitive and motor dysfunction

and obtain accurate, uniform cognitive and motor scores.

A standard shaped ROI was used in a simple, well repro-

ducible way, but at the same time to minimize partial volume

effects from adjacent structures. The diffusivity and anisot-

ropy values in our work are comparable to previous studies

delineating the entire thalamus20,43; thus, we believe that our

DTI metric values are good estimates of the entire thalamus.

Furthermore, the extremely high concordance between

repeated measurements demonstrates the reliability of this

approach. The application of an asymmetry-based method

with respect to glucose metabolism is advantageous because

it is not confounded by interindividual differences in absolute

glucose metabolic rates arising from brain development, as

well as global effects of antiepileptic drugs.44e46 In addition,

this approach eliminates the use of normalized values of

glucose uptake, which can show age-related changes in the thal-

amus during human brain development47 and would require an age-

matched control group to perform accurate comparisons.

It should be also noted that we have used, for the first time,

a pediatric control group for FDG PET studies. This was done

after careful consideration and review of all available data

regarding potential health risks from low-dose radiation. The

studies overwhelmingly indicate that radiation doses from

a single PET scan are not above the “noise” of adverse events

of everyday life, and none of the previous studies has been

able to show unequivocal carcinogenic effect of low-level

radiation doses.48e50

4.5. Conclusion

In summary, our findings suggest that metabolic asymmetry

of the thalamus demonstrated by FDG PET is a simple, robust,

clinically useful imaging marker of neuro-cognitive functions

in SWS. Future longitudinal studies are needed to assess

whether thalamic dysfunction in children with SWS is

progressive and if early damage of the thalamus could predict

cognitive outcome in the later course of the disease.

Acknowledgements

This work was supported by the grant from the National

Institute of Neurological Disorders and Stroke (R01 NS041922

to C. Juhasz). The authors thank Thomas Mangner, Ph.D. and

Pulak Chakraborty, Ph.D. for the reliable radiosynthesis of

2-18F-fluoro-2-deoxy-D-glucose, as well as Galina Rabkin,

CNMT, Angie Wigeluk, CNMT, Carole Klapko, CNMT and Mei-

Li Lee, MS, for their expert technical assistance in performing

the PET studies. We also thank the SturgeeWeber Foundation

for referring patients to us. We are grateful to the families and

children who participated in the study.

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44 

 

Paper 2

Focal white matter abnormalities related to neurocognitive dysfunction:

An objective diffusion tensor imaging study of children with Sturge-Weber syndrome

[Alkonyi et al., Pediatr Res., 2011 Jan;69(1):74-79.]

51 

 

Paper 3

Transient focal cortical increase of interictal glucose metabolism in Sturge-Weber

syndrome: Implications for epileptogenesis

[Alkonyi et al., Epilepsia. 2011 Apr 11.;

doi: 10.1111/j.1528-1167.2011.03066.x. Epub ahead of print]

Transient focal cortical increase of interictal glucose

metabolism in Sturge-Weber syndrome: Implications for

epileptogenesis*yBalint Alkonyi, *yzHarry T. Chugani, and *yzCsaba Juhasz

*Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, Michigan, U.S.A.;

yPositron Emission Tomography Center, Children’s Hospital of Michigan, Detroit, Michigan, U.S.A.; and

zDepartment of Neurology, Wayne State University School of Medicine, Detroit, Michigan, U.S.A.

SUMMARY

Purpose: To investigate clinical correlates and longitudi-

nal course of interictal focal cortical glucose hypermetab-

olism in children with Sturge-Weber syndrome (SWS).

Methods: Fluorodeoxyglucose positron emission tomog-

raphy (FDG-PET) scans of 60 children (age range

3 months to 15.2 years) with Sturge-Weber syndrome

and epilepsy were assessed prospectively and serially for

focal hypo- or hypermetabolism. Thirty-two patients had

two or more consecutive PET scans. Age, seizure vari-

ables, and the occurrence of epilepsy surgery were com-

pared between patients with and without focal

hypermetabolism. The severity of focal hypermetabolism

was also assessed and correlated with seizure variables.

Key Findings: Interictal cortical glucose hypermetabo-

lism, ipsilateral to the angioma, was seen in nine patients,

with the most common location in the frontal lobe. Age

was lower in patients with hypermetabolism than in those

without (p = 0.022). In addition, time difference between

the onset of first seizure and the first PET scan was much

shorter in children with increased glucose metabolism

than in those without (mean: 1.0 vs. 3.6 years; p = 0.019).

Increased metabolism was transient and switched to

hypometabolism in all five children where follow-up scans

were available. Focal glucose hypermetabolism occurred

in 28% of children younger than the age of 2 years. Chil-

dren with transient hypermetabolism had a higher rate of

subsequent epilepsy surgery as compared to those with-

out hypermetabolism (p = 0.039).

Significance: Interictal glucose hypermetabolism in young

children with SWS is most often seen within a short time

before or after the onset of first clinical seizures, that is,

the presumed period of epileptogenesis. Increased glu-

cose metabolism detected by PET predicts future demise

of the affected cortex based on a progressive loss of

metabolism and may be an imaging marker of the most

malignant cases of intractable epilepsy requiring surgery

in SWS.

KEY WORDS: Sturge-Weber syndrome, Positron emis-

sion tomography, Glucose metabolism, Epileptogenesis.

The Sturge-Weber syndrome (SWS) is a sporadic neuro-cutaneous disorder characterized by facial port wine stains,glaucoma, and leptomeningeal angiomatosis involving onecerebral hemisphere in most of the cases (Roach & Boden-steiner, 2010). The intracranial venous abnormalities are theresult of a failed regression of the primitive embryonal vas-cular plexus in utero. They may undergo a proliferative pro-cess even after birth, resulting in chronic hypoxia and oftenprogressive structural and functional deterioration of theunderlying and also adjacent brain tissue (Comi, 2003;

Comati et al., 2007). The most common neurologic mani-festations of SWS include early onset seizures, hemiparesis,peripheral visual field cut, and cognitive deficit (Roach &Bodensteiner, 2010).

Functional neuroimaging in SWS using 2-deoxy-2[18F]fluorodeoxyglucose (FDG) positron emission tomog-raphy (PET) can depict metabolic dysfunction in theaffected cortical regions and also in functionally connectedsubcortical structures (Chugani et al., 1989; Alkonyi et al.,2010). FDG-PET typically demonstrates cortical hypome-tabolism extending beyond the structural abnormalitiesidentified by other imaging modalities in SWS (Chuganiet al., 1989; Lee et al., 2001). Previous studies have sug-gested that the extent of cortical hypometabolism as well asseverity of thalamic hypometabolism is closely associatedwith cognitive function in children with SWS (Lee et al.,2001; Alkonyi et al., 2010). In addition, longitudinal

Accepted February 15, 2011; Early View publication Xxxxx XX, 20XX.Address correspondence to Csaba Juh�sz, M.D., Ph.D., Departments of

Pediatrics and Neurology, Wayne State University, PET Center, Children’sHospital of Michigan, 3901 Beaubien Blvd, Detroit, MI 48201, U.S.A.E-mail: juhasz@pet.wayne.edu

Wiley Periodicals, Inc.ª 2011 International League Against Epilepsy

Epilepsia, **(*):1–8, 2011doi: 10.1111/j.1528-1167.2011.03066.x

FULL-LENGTH ORIGINAL RESEARCH

1

metabolic changes during the early course of the disease arerelated, at least partly, to frequent seizures (Juhasz et al.,2007). Interestingly, a seemingly paradoxical pattern ofinterictal glucose hypermetabolism has been reported inthree young patients; a follow-up scan of one of themshowed the typical pattern of hypometabolism seen in mostpatients with SWS (Chugani et al., 1989). Concordantly, ahigh proportion (75%) of infants showed hyperperfusion onsingle photon emission computed tomography (SPECT) inthe affected hemisphere before seizure onset, and thisphenomenon appeared to be transient regardless of the sub-sequent presence of epilepsy (Pinton et al., 1997).

Previous studies have not addressed the potential clini-cal relevance of these intriguing transient metabolic andperfusion patterns. Therefore, to understand better thesignificance of interictal hypermetabolism, we studiedthe prevalence and clinical correlates of focal increasesof cerebral glucose metabolism in a prospectively col-lected cohort of children with SWS and associated epi-lepsy. In particular, the localization and longitudinalchanges of these hypermetabolic regions, as well as theirtemporal relationship to seizure onset as well as intracta-ble epilepsy were analyzed.

Methods

SubjectsFDG-PET scans of 60 children (age range 3 months to

15.2 years; median 2.7 years) with the diagnosis of Sturge-Weber syndrome, acquired in our institution between 1995and 2010, were reviewed. The inclusion criteria for the pres-ent study included age younger than 18 years, presence ofepilepsy some time during the clinical course (onset of firstseizure either before or after initial PET scanning), and thepresence of at least two of the following three features:(1) facial port-wine stain, (2) leptomeningeal angioma oncontrast-enhanced magnetic resonance imaging (MRI),(3) focal or hemispheric cortical glucose metabolic abnor-mality (hypo- or hypermetabolism) on interictal FDG-PET.Patients with previous epilepsy surgery were excluded fromthe study. Children with PET scans acquired in the ictal statewere also excluded. Included patients were either clinicallyfollowed in our institution (due to epilepsy and/or other neu-rologic complications of SWS) or were prospectivelyinvolved in a longitudinal clinical/imaging research study(with or without seizures at the time of their first PET scan);therefore, a subset of patients had multiple scans (n = 32;two PET scans in 15 and three PET scans in the remaining17 patients). Mean imaging follow-up time in patients withmultiple PET scans was 2.8 years (5 months to 11.1 years).Onset of first seizure occurred mostly before (N = 57) butoccasionally after (N = 3) the first PET scan, and variedfrom a few days after birth to 9 years of age (median0.7 years). Altogether four patients had bilateral intracranialinvolvement on MRI scans.

PET acquisition protocolThe details of FDG-PET acquisition and data analysis

have been described previously (Lee et al., 2001). In brief,all PET scans were acquired using an EXACT/HR PETscanner (CTI/Siemens, Hoffman Estates, IL, U.S.A.), whichprovides simultaneous acquisition of 47 contiguous transax-ial images with a slice thickness of 3.125 mm. The recon-structed image resolution obtained was 5.5 € 0.35 mm atfull width at half-maximum in-plane and 6.0 € 0.49 mm atfull width at half-maximum in the axial direction (recon-struction: filtered backprojection using Shepp-Logan filterwith 0.3 cycles/pixel cutoff frequency). Scalp electroen-cephalography (EEG) was monitored in all children duringthe tracer uptake period. Initially, 0.143 mCi/kg of FDGwas injected intravenously as a slow bolus followed by a30-min uptake period. Forty minutes after injection, a static20-min emission scan was acquired parallel to the cant-homeatal plane. Calculated attenuation correction wasapplied to the brain images using automated threshold fits tothe sonogram data. Based on the EEG data, none of thescans were acquired in the ictal state (no clinical or subclini-cal seizures were detected during tracer uptake).

The study was approved by the Human InvestigationCommittee at Wayne State University, and written informedconsent of the parent or legal guardian and verbal assent(between ages 7 and 13 years) was obtained in all patientswho participated in the longitudinal clinical/imagingresearch study.

Sedation during PET studiesChildren younger than 2 years of age were sedated with

chloral hydrate (50–100 mg/kg by mouth), and childrenaged 2–8 years were sedated with Nembutal (3 mg/kg), fol-lowed by fentanyl (1 lg/kg), as necessary. Sedative medica-tion was administered after the 30-min–long tracer uptakeperiod. All sedated subjects were continuously monitoredby pediatric nurses, and physiologic parameters (heart rate,pulse oximetry, respiration) were measured during thestudies.

Qualitative and quantitative image analysisFDG-PET scans were reviewed by two investigators (C.J

and H.T.C) with extensive experience in assessment of pedi-atric brain glucose PET. Reviewers were blinded to clinicaland imaging data except for the diagnosis (SWS and, if pres-ent, epilepsy). Based on this visual assessment, all PETscans were initially classified into two groups: (1) presenceof focal hypermetabolism (with or without additionalhypometabolism), and (2) no focal hypermetabolism withthe presence of focal hypometabolism or normal glucosemetabolic pattern.

Furthermore, quantitative analysis of glucose uptake wasperformed in patients with apparent focal hypermetabolismdetected on visual assessment to quantitatively confirm thepresence and assess the degree of hypermetabolism. None

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of these patients had clinical or subclinical seizures duringtracer uptake (as determined by concurrent EEG) and noneof these patients had very recent clinical seizures before thescanning procedure (see Table 1 for clinical and imagingdata of these patients).

To measure the magnitude of increased glucose metabo-lism, a region-of-interest (ROI) approach was implemented.Cortical regions showing apparently increased glucosemetabolism were outlined using the software MIPAV 4.3.0(McAuliffe et al., 2001) by one of the investigators (B.A.).In addition, ROIs of similar size were also placed on contra-lateral, homotopic cortical areas. Subsequently, standard-ized uptake values (SUVs) were calculated as the ratiobetween the average radioactivity concentration obtainedfrom each region and the injected dose per weight (mCi/kg).Finally, SUV ratios were calculated by dividing the SUV ofthe ipsilateral ROI by that of the contralateral homotopicROI. An SUV ratio of ‡1.10 (i.e., ‡10%) was consideredglucose hypermetabolism.

Four of the patients with initial glucose hypermetabolismhad follow-up scans available in digital format [the storagemedium containing an additional patient`s (no. 9) digital

follow-up image was damaged and these images could notbe retrieved for quantitative analysis]. These PET imageswere co-registered to the corresponding initial scans usingVINCI 2.50 (Cizek et al., 2004) and the original ROIs(slightly modified to account for brain growth between thetwo scans) were transferred to these coregistered images toevaluate interval changes of SUVs and SUV ratios.

Statistical analysisAge and seizure variables (age at seizure onset, duration

of epilepsy, as well as absolute time difference between firstPET scan and age at seizure onset) of patients with and with-out increased glucose metabolism apparent on the first PETscan were compared using the nonparametric Mann-Whitney U-test, since these variables did not show normaldistribution (the Kolmogorov-Smirnov test was significant).Because hypermetabolism appeared to be more common inyoung patients, Fisher`s exact tests (two-sided) were per-formed to assess the occurrence of glucose hypermetabo-lism in younger versus older SWS patients using two cut-offages (1 and 2 years of age). The same test was used to com-pare the incidence of subsequent epilepsy surgery between

Table 1. Clinical, EEG, and imaging data of the patients

Patient

no.

Age

(mo)

Seizure

onset

(mo)

Brain

abnormality

on MRI

Last seizure

before PET EEG/PET

Loc. of

hypermet.

Loc. of

hypomet.

(1st scan)

SUV ratio

(1st scan)

SUV

ratio

(follow-up)

1. 3 5 rF, T, P No seizures

before PET

Diminished amplitude

over the right

hemisphere

rF, C, ant Cing,

(rsupT)

(rP > lp) 1.18 0.86

2. 5 4 lF, P, O 3–4 w Decreased amplitude

over the left hemisphere

lF, (lT) lP, O 1.16 0.91

3. 7 1.5 lP 4 d Slowing over the post.

quadrant of the left

hemisphere

lP, O, (lT) lF, rP 1.21 n.a.

4. 10 3 rF, T, P, O 7 d Background attenuation

over the right

hemisphere

rF rT, P, O 1.18 n.a.

5. 11 2.5 rF, T, P, O 9 d Background activity slow

for age, intermittent

slowing over the left

hemisphere

rF, T, P rT,O, (lP) 1.75 0.66

6. 19 7 rF, T, P, O 6 mo Background attenuation

over the right

hemisphere

rF rT, P, O 1.11 n.a.

7. 23 6 rF, T, P, O,

(lmedO)

1 y Background attenuation

over the right

hemisphere

rF rT, O, (rP) 1.13 0.79

8. 61 11 rF, T, P, O 1 y Background attenuation

over the right

hemisphere

rF rT, P, O,

(lpreF, lmedF)

1.10 n.a.

9. 65 60 rT, P, O 9 d Normal rF rT, P, O 1.11 <1.0a

mo, months; d, days; y, years; w, weeks; r, right; l, left; EEG/PET, EEG monitored during FDG uptake; F, frontal; preF, prefrontal; med, medial; C, central; T, tem-poral; sup, superior; ant, anterior; P, parietal; O, occipital; Cing, cingulate; SUV, standardized uptake value; SUV ratio, average SUV of the hypermetabolic region/average SUV of homotopic contralateral region; Follow-up SUV ratio was calculated in the same region on follow-up PET scans of the patients. n.a., not available;Letters in parentheses indicate possible or mild involvement of the indicated lobe.

aThe digital format of the follow-up scan of patient no. 9 has been damaged; however, the printed copy shows hypometabolism in the area of initial hypermetabo-lism in addition to the posterior regions.

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patients with and without initial glucose hypermetabolism.It is important to note that only patients with subsequentclinical follow-ups [mean follow-up of patients with no sur-gery: 5.4 years (range 1.0–14.1)] were included in the lattercomparison. The age of children whose hypermetabolismwas localized only to the frontal lobe (a common site ofhypermetabolism) and that of children with additional/otherlocalization of the hypermetabolism was compared alsousing the Mann-Whitney U-test. Correlations betweenclinical variables and SUV ratios for patients with increasedglucose metabolism were tested using nonparametricSpearman’s product moment correlations, again, due to theviolation of the assumption of normal distribution. An alphalevel of p = 0.05 was considered as the limit of significance.

Results

Focal interictal cortical hypermetabolism was visuallyobserved in nine patients (15% of all patients), includingone infant whose first clinical seizure occurred 2 monthsafter the first PET scan. The other eight children already had

epilepsy at the time of their first PET scan. FDG SUV ratiosof apparent hypermetabolic areas in these nine patients ran-ged between 1.10 and 1.75 (mean 1.21; Table 1). All 51patients with no hypermetabolism showed at least one areaof decreased cortical metabolism on visual evaluation.

Patients with foci of increased cortical glucose metabo-lism were significantly younger than those withoutincreases (mean 1.9 vs. 4.5 years; p = 0.022). Five of the 15patients 1 year of age or younger showed glucosehypermetabolism as opposed to 4 of the 45 who were olderthan 1 year (33.3% vs. 8.9%; p = 0.036). The prevalence ofincreased glucose metabolism was 28% in patients 2 yearsof age or younger in contrast to 5.7% older than 2 years(p = 0.027). Hypermetabolism never occurred on follow-upscans in patients whose first scan was normal or showedhypometabolism; instead, increased metabolism was tran-sient and switched to hypometabolism (range of SUV ratiofor the four analyzed follow-up scans: 0.66–0.91; mean0.80) in all five patients (including the one with no digitalimages available) who had follow-up scans (follow-up time0.6–2.5 years) (see Figs. 1 and 2). Interestingly, time differ-ence between the onset of first seizure and the first PET scanwas much shorter in children with increased glucose

Figure 1.

Representative axial and coronal images of initial and follow-up

FDG-PET scans of a child (Patient 5) with Sturge-Weber syn-

drome and epilepsy. The first scan was performed at the age of

11 months and showed increased glucose metabolism in the

right frontal, temporal, and parietal lobes of the right hemi-

sphere (solid arrows), in addition to hypometabolism in the

posterior parietotemporal and occipital cortex. The second

FDG-PET scan, performed 2 years later, demonstrated a

switch to hypometabolism in the corresponding areas (dashed

arrows). L, left; R, right.

Epilepsia ILAE

Figure 2.

Representative axial and coronal sections of initial and follow-

up FDG-PET scans of an infant (Patient 1) with Sturge-Weber

syndrome. The initial scan was done at the age of 3 months,

2 months before the onset of first seizures, and depicted

increased glucose uptake in the right hemisphere, predomi-

nantly in the frontal cortex (solid arrow). The follow-up PET

scan was performed 2.5 years after the initial scan, and showed

an interval switch of glucose hypermetabolism to

hypometabolism (dashed arrows).

Epilepsia ILAE

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metabolism than in those without (mean 1.0 vs. 3.6 years;p = 0.019).

In all of the cases, hypermetabolic cortical regions wereaccompanied by hypometabolic areas, sometimes in thesame lobes (see Table 1). Focal increases of glucose metab-olism were localized purely to the frontal lobe in five chil-dren, whereas other lobes were (also) involved in fourchildren (see Table 1). The age of patients with pure frontallobe hypermetabolism (N = 5) was significantly higher thanthat of children with increased metabolism involving (addi-tionally or exclusively) other, nonfrontal regions (mean 2.9vs. 0.5 years; p = 0.019).

Within the group of patients with apparent increases ofglucose metabolism the rank order of FDG SUV ratio wasstrongly associated with the rank order of age at seizureonset, indicating more severe hypermetabolism in patientswith earlier onset of epilepsy (r = )0.94; p = 0.0002).

Five of the eight children who had long-term follow upwith increased metabolism on their initial PET scan eventu-ally developed uncontrolled seizures and underwent epi-lepsy surgery, whereas the seizures of the other threebecame relatively controlled by medication (surgery rate5/8, 62.5%). In contrast, only 10 (23.3%) of the 43 patientswithout glucose hypermetabolism on their first scanunderwent resective surgery due to intractable seizures(p = 0.039).

Discussion

The present study demonstrates that focal corticalincrease of interictal glucose metabolism is a relativelycommon phenomenon in young children with SWS. In ourcohort, 28% of patients younger than 2 years of age showedthis seemingly paradoxical pattern of metabolism. The closerelationship between the onset of first seizure and the occur-rence of cortical hypermetabolism suggests that this meta-bolic phenomenon may be associated with processes relatedto epileptogenesis. Interestingly, hypermetabolism wasalways transient and its localization appears to be age-dependent: posterior cortex, the most common site of theprimary pathology, was involved early (in youngerpatients), whereas pure frontal hypermetabolism, associatedwith posterior hypometabolism, was seen at older ages.From a clinical point of view, high rate of intractable epi-lepsy requiring epilepsy surgery in children with increasedmetabolism is perhaps the most interesting finding; this sug-gests that FDG-PET hypermetabolism may be an imagingmarker of drug-resistant seizures in SWS.

Glucose hypermetabolism in SWSThe phenomenon of increased cortical glucose metabo-

lism in SWS along with the typical hypometabolic patternin advanced stages of SWS was initially demonstrated byChugani et al. (1989). In that study, interictal glucosehypermetabolism was seen in three patients of the whole

series of 12 cases. A subsequent multimodality imagingstudy also reported two infants with glucose hypermetabo-lism (Pfund et al., 2003). Similarly, interictal hyperperfu-sion of the affected brain region was seen on SPECT studiesin infants before epilepsy onset but not in older children(Pinton et al., 1997). Interictal hypermetabolism andhyperperfusion appear to be transient phenomena, sinceavailable follow-up SPECT and PET scans (including thosein the present study) invariably demonstrated an intervalswitch to decreased perfusion and metabolism, respectively.By studying a relatively large series of patients with this raredisorder, we have now provided further details about theprevalence, localization, and longitudinal course of corticalhypermetabolism.

Interestingly, the most common location of glucosehypermetabolism in our patients was the frontal lobe.Indeed, increased glucose metabolism was solely localizedto the frontal lobe in older patients, with concomitantposterior hypometabolism, whereas in younger children(infants) increased glucose uptake was seen in posterior cor-tical areas as well. The exact evolution and regression pro-cess of cortical hypermetabolism is unknown. Because themajority of PET scans showed no signs of increased metab-olism even in young children with SWS, it is likely thataffected patients represent a distinct subgroup, although thetrue prevalence of this metabolic phenomenon is probablyhigher, as some patients may have undergone a transienthypermetabolic state before their first PET scan. It is alsoconceivable that a substantial portion of the affected cortexshows a transient increase in metabolic demand some timeduring the very early course of the disease, and then thisswitches to hypometabolism, as the cortical injury expandsfrom posterior angioma–affected regions to structurallyless-affected frontal areas.

Glucose hypermetabolism and epilepsyIncreased metabolic activity in the region of the seizure

focus, as a consequence of excessive neuronal firing andincreased energy consumption, is commonly seen duringseizures or even in the presence of persistent focal interictalepileptiform activity in patients with epilepsy (Engel et al.,1982; Bittar et al., 1999). In the present study, however, thePET scans of all nine patients showing cortical hypermetab-olism were acquired in the interictal state at least days aftera clinical seizure and without the concomitant presence ofepileptiform discharges on scalp EEG performed during thePET scan (see Table 1). Therefore, it can be argued that thepathomechanism of the detected focal hypermetabolism inSWS may not be associated directly with epilepsy, or withongoing epileptiform activity. However, our data show thatthis transient phenomenon occurs mostly in young (mainlyyounger than 2 years of age) patients during a limited periodbefore and shortly after the first clinical seizures. Transientinterictal glucose hypermetabolism seems to be a uniquefeature of SWS associated with epilepsy, given the fact that

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partial epilepsy is commonly associated with focal glucosehypometabolism (in the interictal state). Furthermore, hy-pometabolism is relatively rare (and hypermetabolism hasnot been reported) in new-onset (nonlesional) partial epi-lepsy (Kuhl et al., 1980; Gaillard et al., 2002). Similarly,transient hypometabolism, but not hypermetabolism, hasbeen reported in children with recent-onset West syndrome(Maeda et al., 1994; Natsume et al., 1996).

Mechanism of increased glucose metabolism:implications for epileptogenesis

Interictal glucose hypermetabolism has been reportedrarely in neurologic conditions other than SWS. In thenickel-induced epilepsy model of rats, the intracortical pat-tern of glucose hypermetabolism and the presence ofhypermetabolism in the absence of seizures indicated thatnot only the seizure activity itself, but also excitotoxic tissuedamage may play a key role in increased glucose metabo-lism (Cooper et al., 2001). A recent report of two siblingswith West syndrome demonstrated the atypical finding offocal glucose hypermetabolism in the interictal state (Ku-mada et al., 2006). Paradoxical increase in focal corticalglucose metabolism has also been reported in a few epilepticpatients with malformations of cortical development (Pod-uri et al., 2007). Interestingly, cortical malformations havebeen identified recently in patients with SWS, and intracta-ble epilepsy and may be the primary cause of epilepsy, atleast in some cases, although no direct evidence has beenprovided for this notion (Maton et al., 2010). In addition,transient glucose hypermetabolism in bilateral basal gangliahas been reported in a newborn with hypoxic–ischemicencephalopathy and developed epilepsy as well as dystoniccerebral palsy (Batista et al., 2007). Based on earlier mag-netic resonance spectroscopy findings showing increasedglutamate concentration in the basal ganglia following peri-natal hypoxia, it has been also suggested that the transientincrease in glucose metabolism may be associated withhypoxia-induced excessive glutamatergic activity, a majorsource of excitotoxicity.

It has been shown that a significant proportion of energymetabolism of the brain is utilized for glutamatergic synap-tic activity (Sibson et al., 1998). Imbalance in ionic homeo-stasis as well as excitotoxicity plays a crucial role also inposttraumatic cerebral glucose hypermetabolism (Bergsne-ider et al., 1997). Furthermore, perinatal hypoxia can leadto excessive stimulation of glutamate receptors along withthe downregulation of c-aminobutyric acid (GABA) recep-tor and glutamate decarboxylase genes; decreased levels ofcomponents of the GABA pathway play an important role incell injury and may lead to high susceptibility to seizures(Johnston, 2005; Anju et al., 2010). An earlier study alsoshowed increased regional glucose metabolism in five of sixinfants with hypoxic–ischemic encephalopathy, and sug-gested that detection of early cerebral hypermetabolismmay have clinical predictive value (Blennow et al., 1995).

Indirect evidence supports the notion that hypoxia-inducedexcitotoxicity can be the underlying mechanism of initialhypermetabolism and hyperperfusion in infants with hyp-oxic-ischemic encephalopathy (Hagberg et al., 1993).Because a tight coupling between glucose metabolism andglutamate cycling has been demonstrated in patients withpartial epilepsy (Pfund et al., 2000), ischemic injury of thecortex in SWS may lead to glutamate excitotoxicity in con-junction with glucose hypermetabolism. In addition, theappearance of glucose hypermetabolism in young ages,within close temporal proximity to the first clinical seizures,suggests that the underlying excitotoxic damage ultimatelymay reach a critical level to trigger seizures. Althoughsomewhat speculative, transient focal hypermetabolismmay be also related to enhancement of GABAergic synaptictransmission that could transitorily compensate for theongoing glutamate-mediated injury (Liang et al., 2009),imposing further metabolic demand to the affected brainregion. Failed compensation may eventually result in exces-sive excitotoxic damage and seizure generation.

A recent study on cortical tissue samples obtained frominfants with SWS and epilepsy (Tyzio et al., 2009) pro-vides support that the above-detailed mechanisms mayindeed play a role in SWS-related epileptogenesis. In thatstudy, cortical neurons were found to be depolarized anddisplayed synchronous activity driven by glutamatergicconnections. This pattern was more consistent with ische-mic damage than injury resulting from the epileptogenicprocess itself. Interestingly, the authors also found that,despite the young age of the patients, GABA exerted aninhibitory and anticonvulsive role via a shunting mecha-nism in SWS cortex; this was clearly different from theexcitatory GABA action described in human epileptic cor-tex of other etiology (such as cortical dysplasia) (Cepedaet al., 2007). Altogether, these results suggested the pres-ence of an SWS-specific epileptogenic process (perhapsdue its unique, chronic ischemia-induced cortical damage),which may explain why early metabolic patterns are differ-ent in some children with SWS as compared to other pedi-atric epilepsy syndromes.

The presence of glucose hypermetabolism even shortlyafter the first clinical seizure(s) in children with SWS is notsurprising, since epileptogenesis is a dynamic processextending well beyond the onset of the first seizure (Wil-liams et al., 2009), and progressive, age-dependent meta-bolic changes (hyper- as well as hypometabolism) occur inthe brain of rats during epileptogenesis (Dube et al., 2000,2001; Guo et al., 2009). Interestingly, chronic inflamma-tion, angiogenesis, and blood–brain barrier leakage (the lat-ter two are also present in SWS), as potential mechanisms ofepileptogenesis, appeared to be age-dependent in a rodentmodel (Marcon et al., 2009). Increased glucose metabolism(measured by autoradiography) was found also in nondam-aged brain regions of rats after induced status epilepticus,possibly indicating processes working against or controlling

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seizure activity (Dube et al., 2000). Combined in vivomeasurements of substrates of the glutamate and GABApathways and glucose utilization (MR-spectroscopy/FDG-PET) in infants with SWS could shed more light on theunderlying mechanisms of cortical hypermetabolism.

Finally, our data suggest that epilepsy surgery due touncontrolled seizures tend to be more frequent in patientswhose FDG-PET scan showed interictal hypermetabolismthan in those whose early scan did not detect hypermetabo-lism. If further, prospective studies confirm this observa-tion, early PET scanning in SWS using the tracer FDGcould have a crucial clinical value in identifying childrenwith higher risk for intractable seizures.

Acknowledgments

This study was supported by a grant from the National Institutes ofHealth (R01 NS041922 to C.J.). The content is solely the responsibility ofthe authors and does not necessarily represent the official views of the NIH.The authors thank Thomas Mangner, Ph.D. and Pulak Chakraborty, Ph.D.for the reliable radiosynthesis of the PET tracers. We are also grateful toGalina Rabkin, CNMT, Angie Wigeluk, CNMT, Andrew Mosqueda,CNMT, and Carole Klapko, CNMT for their expert technical assistance inperforming the PET studies; and to Majid Khalaf MD, Anna Deboard RN,and Jane Cornett RN for performing sedation. We also thank the Sturge-Weber Foundation for referring patients to us. We are grateful to the fami-lies and children who participated in the study.

Disclosure

None of the authors has any conflict of interest to disclose. We confirmthat we have read the Journal`s position on issues involved in ethical publi-cation and affirm that this report is consistent with those guidelines.

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Paper 4

Increased L-[1-11C]leucine uptake in the leptomeningeal angioma of Sturge-Weber

syndrome: a PET study

[Alkonyi et al., Journal of Neuroimaging 2011 Jan 11.;

doi: 10.1111/j.1552-6569.2010.00565.x. Epub ahead of print]

Clinical Investigative Study

Increased L-[1–11C] Leucine Uptake in the LeptomeningealAngioma of Sturge-Weber Syndrome: A PET Study

Balint Alkonyi, MD, Harry T. Chugani, MD, Otto Muzik, PhD, Diane C. Chugani, PhD, Senthil K. Sundaram, MD,William J. Kupsky, MD,Carlos E. Batista, MD, Csaba Juhasz, MD, PhDFrom the Carman and Ann Adams Department of Pediatrics (BA, HTC, OM, DCC, SKS, CEB, CJ); Department of Neurology (HTC, SKS, CJ); Department of Pathology (WJK);and PET Center (BA, HTC, OM, DCC, SKS, CEB, CJ), Children’s Hospital of Michigan, Wayne State University School of Medicine, Detroit, MI.

Keywords: Sturge-Weber syndrome,positron emission tomography, leucine,proliferation, glucose metabolism.

Acceptance: Received March 12, 2010,and in revised form July 27, 2010.Accepted for publication September 19,2010.

This study was supported by a grant fromthe National Institutes of Health (R01NS041922 to CJ).

The authors report no conflict of interest.

Correspondence: Address correspon-dence to Csaba Juhasz, MD, PhD,Departments of Pediatrics and Neu-rology, Wayne State University, PETCenter, Children’s Hospital of Michigan,3901 Beaubien Blvd, Detroit, MI 48201.E-mail: juhasz@pet.wayne.edu.

J Neuroimaging 2011;XX:1-7DOI: 10.1111/j.1552-6569.2010.00565.x

A B S T R A C T

BACKGROUND AND PURPOSEWe used L-[1–11C]leucine (LEU) positron emission tomography (PET) to measure aminoacid uptake in children with Sturge-Weber syndrome (SWS), and to relate amino aciduptake measures with glucose metabolism.METHODSLEU and 2-deoxy-2[18F]fluoro-D-glucose (FDG) PET were performed in 7 children (age:5 months-13 years) with unilateral SWS. Asymmetries of LEU uptake in the posteriorbrain region, underlying the angioma and in frontal cortex, were measured and correlatedwith glucose hypometabolism. Kinetic analysis of LEU uptake was performed in 4 patients.RESULTSIncreased LEU standard uptake value (SUV, mean: 15.1%) was found in the angioma regionin 6 patients, and smaller increases in LEU SUV (11.5%) were seen in frontal cortex in4 of the 6 patients, despite normal glucose metabolism in frontal regions. High LEU SUVwas due to both increased tracer transport (3/4 patients) and high protein synthesisrates (2/4). FDG SUV asymmetries in the angioma region were inversely related to LEUSUV asymmetries (r = –.83, P = .042).CONCLUSIONSIncreased amino acid uptake in the angioma region and also in less affected frontalregions may provide a marker of pathological mechanisms contributing to chronic braindamage in children with SWS.

IntroductionSturge-Weber syndrome (SWS) is a sporadic neurocutaneousdisorder characterized by a facial port wine stain and lep-tomeningeal angiomatosis. The abnormal, tortuous veins onthe cortical surface lead to impaired cerebral blood flow, hy-poxia, and chronic ischemia of the underlying brain tissue.1,2

The often progressive neurological complications include hemi-paresis, visual field defects, seizures, and mental retardation.3

Leptomeningeal angiomas are generally considered to be devel-opmental malformations, the results of a failed regression of theprimitive embryonal vascular plexus during the first trimesterof gestation.4 Recent studies, however, suggested that these an-giomas may not be static lesions but, may undergo dynamicproliferative changes.5,6 These studies have provided evidencefor increased expression of vascular cell proliferation markersin the resected angioma and brain tissue. Histological studieshave shown neuronal degeneration, gliosis, and calcificationin the brain tissue adjacent to the angioma in SWS.5,7 Thesedegenerative changes are consistent with decreases in glucose

metabolism demonstrated by positron emission tomography(PET).8

Increased cell proliferation has been studied in vivo usingPET to measure glucose metabolic rates, amino acid uptake (tomeasure protein synthesis), and uptake of thymidine analogs(to measure DNA synthesis); these approaches are commonlyused in the clinical setting to estimate proliferative activity ofmalignancies.9,10 In brain tumors, amino acid uptake generallyprovides a more accurate estimate of proliferative activity thanmeasures of glucose metabolism.11,12

Among several available amino acid PET tracers, 11C-labeled leucine is very suitable to estimate tissue protein synthe-sis rates because of its kinetic modeling.13,14 In this study, wemeasured L-[1–11C]leucine (LEU) uptake in angioma regionsand in brain regions not directly affected by the angioma inchildren with SWS who had unilateral, predominantly poste-rior, brain involvement associated with seizures. We hypothe-sized that the posterior brain regions, affected directly by theangioma, would show increased uptake of LEU on PET. To

Copyright ◦C 2011 by the American Society of Neuroimaging 1

evaluate potential pathological correlates of abnormal aminoacid uptake in the angioma region, histopathological features,including vascular proliferative activity and glial markers, wereassessed directly in a resected angioma of an infant who under-went hemispherectomy following LEU PET. In addition, wehypothesized that higher increases of LEU uptake would beassociated with more severe glucose metabolic abnormalities,measured by 2-deoxy-2[18F]fluoro-D-glucose (FDG) PET, dueto more severe tissue damage underlying the angioma.

Materials and MethodsSubjects

Seven children (5 boys, age range: 5 months-13 years, medianage: 6 years at the time of LEU PET; Table 1) with the clinicaland radiological diagnosis of SWS who had unilateral hemi-spheric involvement and history of seizures underwent MRimaging as well as PET scanning using the tracers FDG andLEU in the Children’s Hospital of Michigan, Detroit. Thesechildren were selected from a series of 48 consecutive chil-dren with SWS who were recruited between October 2004 andAugust 2009 for a prospective neuroimaging research study,including yearly clinical and imaging follow-ups, approved bythe Institutional Review Board at Wayne State University. Allselected patients (15% of the recruited patients) met the fol-lowing inclusion criteria: (1) age below 14; (2) radiologic (mag-netic resonance imaging [MRI] and FDG PET) evidence ofunilateral brain involvement; (3) history of seizures; (4) no ev-idence of seizure(s) during PET; (5) parents‘ approval for asecond PET scan (LEU) in addition to FDG PET and MRI.Five patients had right hemispheric, whereas two patients hadleft hemispheric involvement. In one patient (patient no. 5),leptomeningeal angioma could not be visualized on MRI; how-ever, the presence of a right facial port wine stain as well asright central transmedullary veins indicated right hemisphericinvolvement. Some imaging studies were collected 1 year apartfrom each other (see Table 1) as the patients participated ina prospective, longitudinal study with yearly follow-ups (ex-cept the infant who underwent hemispherectomy after initialimaging). The MRI and FDG PET image data, which were theclosest to the LEU PET scan in time, were used for analysis(Table 1). FDG and LEU PET scans were done at the sametime (1 day apart) in 5 patients and 1 year apart in the remain-ing two (patients no. 4 and no. 7). These latter patients were 5and 11.8 years old at the time of the first scan; thus, both of themwere older than 3 years when major metabolic progression hadbeen observed.15 Written informed consent was obtained fromthe parents or legal guardians.

FDG PET Data Acquisition

All PET scans were performed using a CTI/SiemensEXACT/HR scanner (Siemens, Knoxville, TN). This scannerhas a 15 cm field of view and generates 47 image planes with aslice thickness of 3.125 mm. The FDG PET scanning protocolhas been described in detail previously.16 The reconstructed in-plane resolution is 5.5 mm (±.35) full width at half maximumand 6.0 mm (±.49) in the axial direction. Initially, a venous linewas established to inject FDG (.143 mCi/kg). After 40 minutes T

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2 Journal of Neuroimaging Vol XX No XX 2011

of FDG uptake, a static 20-minute emission scan of the brainwas acquired in 3-dimensional (3D) mode. Calculated attenua-tion correction was applied to the brain images using automatedthreshold fits to the sinogram data. All FDG PET scans wereperformed in the interictal state as indicated by EEG monitor-ing performed during the FDG uptake period.

LEU PET Data Acquisition

The tracer L-[11C]-leucine was produced at Children’s Hospi-tal of Michigan using a synthesis module designed and built inhouse.17 Details of the imaging procedure have been describedpreviously.14 Four of the 7 patients had blood input data ob-tained during the PET study for more detailed quantification.The PET sequence began with a transmission scan of the chest.Subsequently, the tracer L-[1–11C]-leucine (.1 mCi/kg) was in-jected, and a 20-minute dynamic PET scan of the heart wasperformed (sequence: 12 × 10 s, 3 × 60 s, 3 × 300 s) in orderto obtain the left ventricular (LV) input function. Continua-tion of the input function was then accomplished by combiningthe time-activity curve derived from a small region-of-interest(ROI) in the center of the LV with venous blood samples ob-tained at later times. Subsequently, beginning at 25 minutesfollowing tracer injection, seven 5-minute scans of the brainwere performed in 3D mode followed by a 15-minute transmis-sion scan of the brain. Measured attenuation, scatter, and decaycorrection were applied to all PET images. Scalp EEG was notmonitored during the LEU uptake period.

MRI Data Acquisition

All MRI studies were carried out on a Sonata 1.5 T MRI scan-ner (Siemens, Erlangen, Germany) using a standard head coil.For the purpose of the present study, only the postgadoliniumT1-weighted images (T1-Gad) were used (as a reference forcoregistration of PET images). The acquisition parameters ofthis sequence were as follows: TR/TE:20/5.6 ms; flip angle:25◦; voxel size: 1 × .5 × 2 mm3.

Sedation during Imaging Studies

Children aged <2 years were sedated with chloral hydrate (50-100 mg/kg by mouth), and children aged 2-8 years were sedatedwith nembutal (3 mg/kg), followed by fentanyl (1 μg/kg), asnecessary. All sedated subjects were continuously monitoredby pediatric nurses, and physiological parameters (heart rate,pulse oximetry, respiration) were measured during the studies.

ROI Definition

FDG PET images as well as summed and individual framesof the LEU PET images were initially rigid-body coregisteredto each patient‘s T1-Gad MR images using a 3D registrationtechnique (VINCI 2.50).18 Subsequently, ROIs encompassingthe angioma region (including the angioma and the underly-ing cortex; these structures were not delimited separately, sincethey cannot be distinguished on PET images due to their closeproximity) as well as mirror regions in the contralateral hemi-sphere were defined on the gadolinium-enhanced MRI imagesusing ROI Editor 1.4.1 (www.mristudio.org). All these regionswere located mainly in the posterior (temporal, parietal, occip-ital) cortex. In patient no. 5, with no leptomeningeal angioma

visualized on MRI, similar posterior cortex was included inthis ROI. In addition, ROIs were drawn on at least three im-age planes in apparently spared (no atrophy and angioma) orless affected (mild hypometabolism in some cases; see Table 1)frontal cortical regions ipsilateral to the angioma as well as incontralateral homotopic regions. All ROIs were then superim-posed on the coregistered FDG and LEU PET images includingthe dynamic LEU image sequences, in cases where blood inputdata were available. In subjects, who had MRI and PET scansacquired 1 year apart, small manual adjustments of the ROIshad to be carried out to adjust for interim changes in brain size.

Semi-Quantitative Analysis of FDG and LEU Uptake

Standardized uptake values (SUVs) for FDG and LEU uptakewere calculated for all regions by dividing the average radioac-tivity concentration obtained from each region by the injectedFDG and LEU dose per total body weight, respectively. Sub-sequently, asymmetry indices (AIs) for SUVs were calculatedas follows: AI (%) = 200 × [(I – C)/(I + C)], where I repre-sents ipsilateral, C represents contralateral values as comparedto the side of the lesion. For FDG, AI values above 10% wereconsidered to be abnormal.15,16 For LEU, normal control asym-metries were calculated using LEU PET images of five healthyadults (all males, mean age: 39 years), where absolute values ofright-left SUV AIs were calculated for both posterior and frontalregions, separately, and AI values above the normal mean ± 3standard deviations (SDs) were considered to be abnormal inthe patients. We used the conservative 3 SDs because of theunknown age-related differences in normal AIs of cortical LEUuptake.

Quantitative Analysis of Protein Synthesis

To study mechanisms of LEU uptake abnormalities, unidirec-tional uptake rate constant (K-complex) and volume of distri-bution (VD) were derived from the Patlak graphical analysis19

in 4 cases where blood input data were available. Details ofthis approach have been described previously.14 Asymmetries(AIs) for K-complex and VD were calculated similar to thosefor SUVs. Again, AI values above the normal mean ± 3 SDs,derived from the normal controls, were considered to be abnor-mal. Absolute SUV, K-complex, and VD values of the patientswere not compared to those of the healthy adults due to po-tential developmental differences in cerebral protein synthesisrates.20

Statistical Analysis

Hemispheric asymmetries in the angioma and frontal regionswere compared using Wilcoxon‘s signed-rank test. Associationbetween glucose metabolic and LEU uptake asymmetries wastested using Spearman’s rank correlation. P < .05 was consid-ered statistically significant.

Histological assessment of resected tissue samples

Resected specimens were available from one patient, an infantwho underwent hemispherectomy at 6 months of age. In ad-dition to standard histological processing of the resected brainand angioma tissues (including hematoxyilin-eosin, cresyl vi-olet, Masson trichrome, glial fibrillary acidic protein [GFAP],

Alkonyi et al: Leucine PET in Sturge-Weber Syndrome 3

Fig 1. Representative co-registered T1 postgadolinium MRI (A), FDG PET (B), and L-[1–11C]leucine (LEU) PET (C) images of a 6-year-oldgirl (patient no. 4) with left hemispheric angioma in the temporo-parieto-occipital region. Solid arrows indicate the angioma region, which washypometabolic (AI = –61%) but showed abnormally increased LEU uptake (AI = 12%). Although the MRI showed deep transmedullary veinsin the frontal lobe, the angioma did not extend to the frontal cortex. However, this region was also mildly hypometabolic (dashed arrow; AI =9%) and showed moderately increased LEU uptake (SUV AI = 9%) compared to the contralateral homotopic area.

and synaptophysin immunostaining, Luxol fast-blue/periodic-acid Schiff), angioma specimens were also immunostained us-ing Ki-67 antibody (clone K-2, Ventana), colabeled with theendothelial marker CD31 (JC70A, Ventana, Tucson, AZ, USA)to demonstrate proliferative activity in the endothelial cells ofthe angioma.6,21 Furthermore, the expression of vascular en-dothelial growth factor-A (VEGF-A) was also assessed (usingmouse antihuman monoclonal antibodies; sc-7269, Santa CruzInc., Santa Cruz, CA, USA) in the resected angioma specimen.Immuno-histochemistry results of resected brain tissues of 7(non-SWS) patients (age range: 4 months-7 years), who under-went epilepsy surgery, are also presented for comparison.

ResultsFDG and LEU Uptake Asymmetries

LEU SUV asymmetries in the angioma and frontal regionsexceeded the calculated normal cutoff values (3.8% for the an-gioma region and 3.3% for frontal cortex) in 6 and 4 cases,respectively (mean AIs for these abnormal cases: angioma—15.1%, frontal—11.5%; see Fig 1). FDG SUV asymmetries wereabnormal (>10%) in 5 patients in the angioma region (meanAI: 55.7%) and in none of the patients in the frontal region.Glucose metabolic asymmetries of the angioma region weresignificantly higher than those of the frontal regions (–39.7%vs. –2.3%; P = .028). However, LEU uptake asymmetries ofthe angioma region were only slightly higher than those of thefrontal regions (12.7 vs. 6.6%; P = .09).

Quantification of LEU Uptake

Four patients had blood input data to estimate regional pro-tein synthesis rates. K-complex asymmetries exceeded the nor-mal AI limit (angioma region: 4.8%; frontal: 4.4%) in the 2youngest children (ages: 2.4 and 2.9 years) where quantifica-tion was available in the angioma region (increases; AI: 8.7%and 6.5%, respectively) and in none of the cases in the frontal

cortex (Table 1). VD asymmetry was above the normal AI limit(angioma region: 28%, frontal: 30%) in the angioma region in3 patients and in the frontal region in 1 child, always with highervalues ipsilateral to the angioma.

Association between Glucose Hypometabolismand LEU Uptake

We found a significant negative correlation between FDG SUVasymmetries and LEU SUV asymmetries for the 6 patients olderthan 2 years of age in the angioma regions (r = –.83, P = .042,see Fig 2) and a trend for the same association in the frontalregions (r = –.77; P = .07), indicating that higher LEU up-take was associated with more severe hypometabolism. For thisanalysis, we excluded patient no. 1, a 5-month-old infant. Inthis age group, patients with SWS often show increased glu-cose metabolism and blood flow, followed by a transition fromincreased to decreased metabolism and blood flow.22 This pa-tient’s data point may be an outlier (see point denoted by X inFig 2) in this comparison for this reason.

Histopathological Assessment

The surgical specimen from the infant who underwent epilepsysurgery showed marked leptomeningeal vascularity, corticalmalformation (polymicrogyria and heterotopias), neuronal loss,gliosis (positive GFAP immunostaining), and prominent calci-fication. Positive Ki-67 labeling was seen in the nuclei of en-dothelial cells (Fig 3A) but not in cortical cells (Fig 3B). The cal-culated proliferative index (proportion of labeled endothelialcells) was between 5% and10%. In comparison, no endothelialKi-67 staining was seen in control tissues (Fig 3E). In addition,we also found strong VEGF-A expression in endothelial cellsof the angioma as well as in cortical neurons (Figs 3C, D). Pe-diatric epilepsy control tissues showed no, or weak, staining forVEGF (Fig 3F).

4 Journal of Neuroimaging Vol XX No XX 2011

Fig 2. Relationship between glucose metabolic (FDG) versusL-[1–11C]leucine (LEU) uptake asymmetries (AIs) in the angiomaregion. Black circles represent datapoints from the six older (abovethe age of 2 years) patients with chronic disease. A correlation forthese patients’ data indicates that higher LEU uptake ipsilateral to theangioma is associated with more severe glucose hypometabolism(r = –.83, P = .042). In addition, the cross indicates the data ofan infant with recent onset seizures. This case was not included inthe correlation since glucose uptake is not an appropriate measureof cortical damage in the initial stage of the disease when potentialtransition of cortical hypermetabolism to hypometabolism occurs.

DiscussionThe main finding of this study is the increased LEU SUV ofthe angioma region and in the frontal lobe in some cases inchildren with SWS. Based on the available data with quantifi-cation, these increases are driven by elevated VD of labeledleucine indicating elevated LEU transport in 3 of the 4 casesand also by increased protein synthesis rates reflected by theK-complex in 2 of the 4 cases. These results increase our under-standing of pathological changes occurring in brain underlyingthe angioma and beyond in frontal cortical regions showing rel-atively normal glucose metabolism. Elevations in amino acidtransport and protein synthesis may be related to endothelialand glial proliferation, which were observed in the one case inwhich brain tissue was available for pathological studies. Al-tered blood-brain barrier (BBB) is also a probable mechanismfor increased amino acid uptake near the angioma. Furtherstudies are needed to understand these mechanisms more fully.

This is a preliminary study with a limited number of subjects.Additional major limitations include that FDG and LEU PETimages were acquired 1 year apart from each other in somecases. Furthermore, detailed kinetic analysis could be carriedout in only a subset of the study group. Importantly, the an-gioma and the underlying cortex could not be distinguished onthe PET images since partial volume effects preclude the reli-able separate analysis of these structures. Therefore, our resultsmost likely represent a summed effect of abnormal amino acidtransport and protein synthesis in these structures, at least inthe angioma-affected regions. In addition, changes in glucosemetabolism during development in the region of the angioma

complicate our analysis. In SWS, FDG PET often detects pro-found cortical hypometabolism of the affected hemisphere, pre-dominantly under the angioma but frequently extending wellbeyond the apparent structural abnormalities seen on MRI.16,22

We found a significant inverse association between the severityof hypometabolism and the increase in LEU uptake in chil-dren above 2 years of age. In the only infant (a 5-month-oldboy), LEU uptake showed the highest AI value, while FDG AIwas relatively moderate. However, this latter may not reflectthe true degree of tissue damage in this young age, as infantswith SWS are known to show transient hypermetabolism,22

followed by a transition from hyper- to hypometabolism in theaffected brain regions. Therefore, it is possible that in this infant,FDG PET underestimated the severity of cortical involvement.In the 6 older children, higher LEU uptake associated withlower glucose metabolism suggests that the degree of aminoacid transport and protein synthesis (related to BBB damage,glial, or vascular proliferation) is associated with tissue damageas reflected by low glucose metabolism.

Recent studies have demonstrated that intracranial vascularmalformations in SWS are not static lesions but may undergodynamic remodeling.5 Enhanced endothelial cell turnover aswell as increased expression of key angiogenetic factors, suchas VEGF and its receptor, provided evidence for ongoing an-giogenesis and suggested the progressive nature of angiomas.5,6

In addition to the leptomeningeal angioma, the structure andneural regulation of cortical vessels are also affected in this dis-order.23,24 Whether these vascular changes contribute to clini-cal disease progression remains to be clarified.

In our study, the increased LEU uptake in the angiomaregion was mainly driven by the increase in the VD of thetracer, suggesting increased amino acid transport. The markedincrease of LEU VD may be due to the retention of the aminoacid by increased vascular beds, disruption of the BBB, in-creased capillary permeability, and/or increased expression ofthe large amino acid transporter (LAT1).23,25 Contrast enhance-ment of the leptomeningeal angioma on MRI suggests BBB dis-ruption, which itself can lead to increased amino-acid uptake.26

Increased uptake of two other amino-acid tracers (ie, 11C-methionine and α-[11C]methyl-L-tryptophan, where increasedVD, but not high K-complex, was associated with contrast en-hancement) has been demonstrated in brain tumors and otherpathological conditions associated with BBB breakdown.27,28

In contrast, FDG uptake is not sensitive to BBB disruption,29,30

thus, glucose metabolic rates on PET may remain low evenin the case of impaired BBB. Accumulation of 11C-methionine(which, similar to leucine, is a substrate of LAT1) on PET was re-ported in the angioma region of an adult with SWS,25 but quan-tification of methionine uptake has not been performed. Themechanism of the increase in the K-complex macroparameteralso remains to be determined. Based on a study from Comatiet al. and our previous work demonstrating proliferative activ-ity and angiogenesis in the vascular malformations,5,6 increasedprotein synthesis may be expected in the angioma due to ac-tive remodeling. This is supported by immuno-histochemistryfindings in our youngest patient, showing endothelial Ki-67 pro-liferative index of 5-10%, similar to what could be expected inlow-grade tumors.31 Importantly, other factors, such as cortical

Alkonyi et al: Leucine PET in Sturge-Weber Syndrome 5

Fig 3. Immunostaining for the proliferation marker Ki-67 (costained with endothelial marker CD31; A) and VEGF-A (C) in resected angiomatissue as well as cortex (B and D) of an infant (patient no. 1) who underwent hemispherectomy at 6 months of age. These representativeimages show positive Ki-67 labeling (brown stain) in numerous endothelial nuclei of the leptomeningeal angioma (one of the Ki-67 positivenuclei is shown by a red arrow) as well as intense VEGF-A staining (brown) in leptomeningeal vessels. No Ki-67 staining was seen in the cortexbut numerous cells showed VEGF-A expression. The representative images at the bottom show no endothelial Ki-67 expression (E) and noneuronal staining for VEGF (F) in tissue samples of one of the control subjects (a 4-year-old patient with intractable temporal lobe epilepsy).

glial proliferation or increased expression and deposition of ex-tracellular matrix proteins such as fibronectin4 could also con-tribute to high protein synthesis in the angioma region. In addi-tion, cortical malformations (also seen in our infant) have beenreported in patients with SWS32 and these epilepsy-associateddevelopmental abnormalities can show increased amino aciduptake.33 Detection of such malformations by imaging could beof high clinical importance in SWS as these lesions are highlyepileptogenic and should be considered when partial resec-tion is planned in children with SWS and intractable epilepsy.Although mechanisms of increased LEU uptake are currentlyspeculative and warrant further studies, our imaging findingssuggest that increased LEU uptake on PET may be a usefulmarker of underlying pathology not only in angioma-affectedregions but also in frontal cortex even when it shows no ap-parent abnormalities on conventional imaging in children withSWS.

This study was supported by a grant from the National Institutes ofHealth (R01 NS041922 to CJ). The content is solely the responsibilityof the authors and does not necessarily represent the official views

of the NIH. The authors thank Thomas Mangner, PhD and PulakChakraborty, PhD for the reliable radiosynthesis of the PET tracers. Weare also grateful to Galina Rabkin, CNMT, Angie Wigeluk, CNMT, andCarole Klapko, CNMT for their expert technical assistance in perform-ing the PET studies and to Anna Deboard RN for performing sedation.We also thank the Sturge-Weber Foundation for referring patients tous. We are grateful to the families and children who participated in thestudy.

References1. Bentson JR, Wilson GH, Newton TH. Cerebral venous drainage

pattern of the Sturge-Weber syndrome. Radiology 1971;101:111-118.

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32. Maton B, Krsek P, Jayakar P, et al. Medically intractable epilepsy inSturge-Weber syndrome is associated with cortical malformation:implications for surgical therapy. Epilepsia 2010;51:257-267.

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Paper 5

Clinical outcome in bilateral Sturge-Weber syndrome

[Alkonyi et al., Pediatric Neurology, 2011 Jun;44(6):443-449]

Clinical Outcomes in Bilateral

Sturge-Weber SyndromeB�alint Alkonyi, MD*†, Harry T. Chugani, MD*†‡, Samir Karia, MD*‡§,

Michael E. Behen, PhD*‡, and Csaba Juh�asz, MD, PhD*†‡

Approximately 15% of patients with Sturge-Weber syn-drome demonstrate bilateral intracranial involvement,and the prognosis of these patients is consideredparticularly unfavorable. We reviewed the clinical andneuroimaging features of patients with Sturge-Webersyndrome and bilateral intracranial involvement.Seizure variables, the presence of hemiparesis, and thedegree of developmental impairment at most recentfollow-up were compared with imaging abnormalities.Of 110 Sturge-Weber syndrome patients, 14 demon-strated bilateral brain involvement, with an asymmetricpattern on glucose metabolism positron emission tomog-raphy. Although most patients manifested frequent sei-zures initially, associated with frontal hypometabolismon positron emission tomography, six (43%) hadachieved good seizure control during follow-up. Bilateralfrontal hypometabolism was associated with severe de-velopmental impairment. Two children with bitemporalhypometabolism exhibited autistic features.Hemiparesiswas associatedwith superior frontal (motorcortex) hypo-metabolism. Three patients underwent resective surgery,resulting in improved seizure control and developmentaloutcomes. The severity of neurologic complications andclinical course depend on the extent of cortical dysfunc-tion in bilateral Sturge-Weber syndrome. Bilateral fron-tal and temporal hypometabolism is associatedwith poordevelopmental outcomes. Good seizure control and onlymild/moderate developmental impairment can beachieved in about 50% of patients with bilateralSturge-Weber syndrome, with or without resective sur-gery. � 2011 Elsevier Inc. All rights reserved.

Alkonyi B, Chugani HT, Karia S, Behen ME, Juh�asz C.Clinical outcomes in bilateral Sturge-Weber syndrome.Pediatr Neurol 2011;44:443-449.

From the *Carman and Ann Adams Department of Pediatrics, WayneState University School of Medicine, Detroit, Michigan; †PositronEmission Tomography Center, Children’s Hospital of Michigan, Detroit,Michigan; ‡Department of Neurology, Wayne State University School ofMedicine, Detroit, Michigan; and §Division of Pediatric Neurology,Department of Neurosciences, Medical University of South Carolina,Charleston, South Carolina.

� 2011 Elsevier Inc. All rights reserved.doi:10.1016/j.pediatrneurol.2011.01.005 � 0887-8994/$ - see front matter

Introduction

Sturge-Weber syndrome is a rare congenital neurocuta-neous disorder, with an estimated incidence of one per50,000 live births [1]. Sturge-Weber syndrome is character-ized by facial port wine stains, glaucoma, and intracranialleptomeningeal angiomatosis [2]. The intracranial venousabnormality is thought to result from a failure of the prim-itive vascular plexus at the cephalic end of the neural tubeto regress properly during the first trimester in utero [3]. In-tracranial angiomatosis is unilateral in the majority ofcases, and is mostly posterior, and does not correlate withthe unilateral or bilateral appearance of the facial birth-mark [4]. The extent of the angioma and the underlyingcortical involvement are highly variable in Sturge-Webersyndrome. Similar to the variability in extent of angioma-tous involvement, the clinical presentation and diseasecourse in Sturge-Weber syndrome exhibit a wide rangewith respect to the presence, onset, and intractability of ep-ilepsy, motor dysfunction, and neurocognitive impairment[5-7]. Importantly, an early onset of catastrophic seizures isa bad prognostic factor for cognitive and motor deficit [8].Previous studies of patients with unilateral brain involve-ment sought simple imaging correlates and predictors ofdifferent neurologic outcomes. For instance, a semiquanti-tative measure of cortical volume asymmetry correlatedwell with overall clinical status [9]. Cognitive function(i.e., intelligence quotient) was strongly associated withwhite matter volume loss ipsilateral to the angioma, andalso with cortical as well as thalamic glucose hypometab-olism on 2-deoxy-2[18F]fluoro-D-glucose positron emis-sion tomography (referred to henceforth as glucosepositron emission tomography) [10,11].

Bilateral intracranial involvement, reported in about15% of patients, is associated with an earlier onset of

Communications should be addressed to:Dr. Juh�asz; Department of Pediatrics, Wayne State University Schoolof Medicine; 3901 Beaubien Boulevard; Detroit, MI 48201.E-mail: juhasz@pet.wayne.eduReceived September 13, 2010; accepted January 10, 2011.

Alkonyi et al: Bilateral Sturge-Weber Syndrome 443

seizures and worse cognitive development, compared withunilateral cases [2,5]. These patients are generally notconsidered surgical candidates, although epilepsy surgery(focal resection or hemispherectomy) was reported asbeneficial in terms of seizures and subsequentdevelopment in a few cases [12,13]. Because of the rarityof Sturge-Weber syndrome with bilateral intracranial in-volvement, the imaging and clinical characteristics ofthis subset of patients have not been well characterized.Therefore, the present study aimed to examine the relation-ship between neuroimaging findings (with particular em-phasis on glucose positron emission tomography, whichwas available to all patients) and clinical characteristics(seizure severity, motor deficits, and developmental out-comes) in a relatively large series of patients with bilateralSturge-Weber syndrome, collected over more than two de-cades. We specifically investigated the relationship be-tween these clinical features and cortical patterns ofglucose metabolism.

Materials and Methods

Patients were selected from a positron emission tomography database

that included patients with a clinical diagnosis of Sturge-Weber syndrome.

Positron emission tomography studies were performed at one of two insti-

tutions: the Division of Nuclear Medicine and Biophysics, University of

California at Los Angeles (between 1986-1993), or at the Positron Emis-

sion Tomography Center, Children’s Hospital of Michigan, in Detroit (be-

tween 1994-2010). In total, the database contained 110 patients with

Sturge-Weber syndrome. Patients with bilateral brain involvement (n =

14) were selected according to computed tomography or magnetic reso-

nance imaging as well as glucose positron emission tomography findings.

Nine patients had undergone magnetic resonance imaging examinations.

Patients evaluated in the late 1980s and early 1990s did not receive mag-

netic resonance imaging. Moreover, all selected patients manifested a uni-

lateral or bilateral facial port wine stain.

Positron emission tomography scans were performed using either the

NeuroECAT positron tomograph (CTI, Knoxville, TN) at the University

of California at Los Angeles, or the CTI/Siemens EXACT/HR positron to-

mograph at the Children’s Hospital of Michigan. Details of the acquisition

parameters were described previously [14,15]. All patients underwent

a full neurologic evaluation as part of their medical care. The available

medical records of the 14 selected patients were reviewed. For each

patient, clinical details were documented, including age at onset of first

seizure, types of seizure, effectiveness of seizure control, the presence

of motor deficit on neurologic examination, and the degree of

developmental impairment at most recent contact with the patient.

Control of seizures in the past and (if changed) during the most recent

follow-up was categorized into three groups. Seizure control was consid-

ered good if the patient was seizure-free or manifested clinical seizures

less than once per month on average. Moderate seizure control indicated

that the patient exhibited monthly seizures, but not more than one seizure/

week. If weekly or more frequent seizures occurred, the epilepsy was con-

sidered poorly controlled.

The degree of developmental impairment was assessed retrospectively

by a neuropsychologist (M.E.B.), based on available interview data, in-

cluding parental report of the child’s achievement of major developmental

milestones, functional-adaptive behavior status in various domains (com-

munication, daily living, social, and motor skills), and school classifica-

tion or placement as of the most recent follow-up. Based on these data,

patients were categorized into three groups: (1) with development and

adaptive behavior within normal limits, and attending regular school;

(2) with mild-moderate developmental delay-impairment, and some mod-

ifications to academic program, or mildly impaired adaptive behavioral

444 PEDIATRIC NEUROLOGY Vol. 44 No. 6

function in at least one domain; or (3) severely-profoundly impaired,

with significantly delayed milestones across domains, classification or

placement in a special education setting, and severely impaired adaptive

behavior across domains. Age at onset of first seizures was compared be-

tween patients with severe andmild-moderate developmental impairment,

using an independent t test and Predictive Analytics SoftWare Statistics,

version 18 (SPSS, Inc., Chicago, IL). Initial glucose positron emission to-

mography studies were reviewed in each case, and the extent and location

of glucose metabolic abnormalities were qualitatively correlated with neu-

rologic complications. The relationship between intractable seizures and

developmental impairment was also investigated qualitatively.

Results

During the study period, a total of 14 patients withSturge-Weber syndrome (12.7% of the whole series; ninewere male; average age at positron emission tomographyscan, 9 years) with bilateral intracranial involvement hadundergone glucose positron emission tomography scan-ning at least once. The clinical and imaging findings ofthese patients are provided in Tables 1 and 2,respectively. Based on the magnetic resonance imagingreports and images (n = 9), signs of intracranialinvolvement (e.g., atrophy or vascular abnormalities)were more pronounced in one side of the brain (Table 2).Concordantly, hemispheric involvement, as assessed byglucose positron emission tomography, appeared to beasymmetric in all cases, with a predominant (more exten-sive) abnormality in one hemisphere. One entire hemi-sphere was hypometabolic in three patients. Patient 6underwent a right hemispherectomy because of intractableseizures at a different institution before receiving positronemission tomography scanning. In that patient, only thecontralateral hemisphere was evaluated. Long-term fol-low-up data were available for eight of the 14 patients aftertheir positron emission tomography scan, with a follow-upperiod of 1-16 years (median, 9 years; Table 1).

Seizure Characteristics

All patients experienced seizures during the course oftheir disease, with an onset before positron emission to-mography scanning in all cases. The age at onset of firstseizures was available in 12 patients, and ranged from 2weeks to 7.1 years (median, 6 months). Eight of these 12patients demonstrated their onset of seizures before age 6months. The primary seizure type was partial (mostly com-plex partial), with occasional secondary generalization. In-terestingly, six patients (43%) eventually achieved goodseizure control, including four with frequent seizures ini-tially. None of these patients exhibited total hemispherichypometabolism on positron emission tomography (oneof these patients underwent a hemispherectomy beforereceiving positron emission tomography). In addition,patients with poor seizure control (with or without subse-quent improvement) always manifested a frontal glucosemetabolic abnormality (mostly hypometabolism) on posi-tron emission tomography.

Table 1. Clinical data of patients

Patient

Number/Sex

Age at

PET Scan

Age at

Most Recent

Follow-Up

Age at

Onset of First

Seizures

Types of

Seizure

Seizure

Control Hemiparesis

Developmental

Impairment

1/M* 8 mo 1.7 yr 5.5 mo CPS/Gen Poor Left Severe delay

2/M 1.0 yr 16 yr 6 mo CPS/Gen Moderate Left Severe delay

3/F 1.7 yr 2.8 yr 3 mo CPS Poor-good (VNS) Right Severe delay

4/M 1.8 yr 1.8 yr 1.5 mo SPS, CPS Poor (VNS) Left Severe delay

5/M 5.4 yr 9.1 yr 7.1 yr CPS Moderate None Mild/moderate

6/F 6.4 yr 6.5 yr NA CPS/Gen Poor-good Left Mild/moderate delay

7/M 7.5 yr 7.5 yr 6 mo CPS/SPS Poor Right Mild/moderate delay

8/F 8.3 yr 8.3 yr 5 mo CPS/SPS/Gen Poor-good None Severe delay

9/M 9.8 yr 9.8 yr 2 wk CPS Poor-good Left Mild/moderate delay

10/M 10 yr 22 yr 22 mo CPS Good None Mild/moderate delay

11/F* 11 yr 27 yr 4 yr Drop/CPS/GTCS Poor-moderate Right Severe to mild/moderate delay

12/F 15 yr 15 yr NA Drop, P Poor Right Severe delay

13/M 26 yr 32 yr 18 mo CPS Moderate None Mild/moderate delay

14/M 21 yr 35 yr 2.5 mo SPS Good None Mild/moderate

Clinical data, including seizure control, presence of hemiparesis, and cognitive developmental delay, were obtained during most recent follow-up. Changes

(if present) during the disease course are indicated as initial status and then follow-up status.

* Patients underwent epilepsy surgery after their PET scans.

Abbreviations:

CPS = Complex partial seizures

Drop = Drop attacks

F = Female

Gen = Secondary generalized seizures

GTCS = Generalized tonic-clonic seizures

M = Male

mo = Month

NA = Not available

PET = Positron emission tomography

SPS = Simplex partial seizures

VNS = Vagal nerve stimulator

wk = Week

yr = Year

Hemiparesis and Developmental Impairment:Relationship to Frontal Hypometabolism

Nine patients (64%) manifested mild to severe hemipa-resis. The glucose positron emission tomography scans ofthese nine patients indicated hemispheric or extensive mul-tilobar hypometabolism, including superior frontal areascontralateral to the paretic extremities. In contrast, patientswith no overt hemiparesis never exhibited total hemi-spheric hypometabolism or hypometabolism in the supe-rior and middle frontal regions. In patient 8, withbilateral frontal hypometabolism and no hemiparesis, thehypometabolism included premotor areas, but the bilateralsensorimotor cortex was well preserved.

All patients demonstrated at least some degree of devel-opmental impairment, which was mild to moderate inseven patients (50%) initially. Positron emission tomogra-phy scans revealed total hemispheric functional abnormal-ity in only one patient with mild to moderate impairment.The bulk of the frontal lobes was relatively spared on bothsides. In contrast, bilateral frontal lobe hypometabolismwas always coupled with severe developmental impair-

ment (Fig 1). Patients with severe delay (n = 7) exhibitedeither unilateral total hemispheric (including frontal lobe)or unilateral/bilateral frontal metabolic abnormalities(mostly hypometabolism), in addition to multilobar in-volvement. None of the patients manifested severe devel-opmental impairment if good seizure control had beenmaintained during the entire course of their disease. In ad-dition, age at onset of first seizure did not differ signifi-cantly between patients with severe and mild to moderatedevelopmental impairment (P = 0.49).

Interestingly, two patients (patients 2 and 5) developedan autistic behavioral phenotype during the follow-upperiod. Both patients exhibited prominent bitemporal (al-though asymmetric) hypometabolism on positron emissiontomography (Fig 2), in addition to hypometabolism inother regions (Table 2).

Outcomes of Epilepsy Surgery

Three of 14 patients in this series underwent epilepsysurgery because of refractory seizures. Two patients (pa-tients 1 and 11) underwent surgery after glucose positron

Alkonyi et al: Bilateral Sturge-Weber Syndrome 445

Table 2. PET (hypometabolism, unless otherwise indicated) and MRI abnormalities of patients

Patient

Number/

Sex

Age at

PET

Scan

Place and

Year of

PET Scan

Time Difference

Between PET

and MRIBrain Glucose PET

Scan Findings

Brain MRI

FindingsRight Left Atrophy Angioma

1/M 8 mo CHM/1997 1 yr supFr, P, O, supT infFr, mid + infT Bilateral, generalized Bilateral, most

prominent in both P

(right > left), left Fr,

left supT, left supO,

both calcarine

region (right > left)

2/M 1.0 yr CHM/1995 NA P, O, supFr, supT Fr, infT NA NA

3/F 1.7 yr CHM/2010 1 yr Fr incr., (P) T, P, O, (Fr) Left T, P, O, and

right Fr

Left T, P, O, and right

Fr

4/M 1.8 yr CHM/2009 1 yr hemisphere Fr, O Bilateral (right > left) Bilateral, more

extensive on right

5/M 5.4 yr CHM/2002 1 mo T, P, O T, P Bilateral with

enlarged ventricles

Bilateral

6/F 6.4 yr CHM/1994 NA Hemisphere surgically

removed

P, postT, O NA NA

7/M 7.5 yr CHM/2001 2 days P (SM cortex) Hemisphere Left hemisphere

> right

No leptomeningeal

enhancement,

left choroid plexus

enlarged, (left P, O,

Fr angioma at age 1

yr)

8/F 8.3 yr CHM/2010 1 day Fr, (P), with

SM preserved

Hemisphere, with SM

preserved

Left hemisphere

and right Fr

Entire left hemisphere

and right Fr

9/M 9.8 yr CHM/2010 1 day T, P, O, (supFr) T Right hemisphere

(post. quadrant

predominance), left

T pole

Right post. quadrant,

left T

10/M 10 yr CHM/1995 5 yr P, latO P, O, supT Moderate in right

hemisphere,

moderate-severe in

left hemisphere,

bilateral ventricular

enlargement

Right Fr, P, O

11/F 11 yr UCLA/1989 NA P, O Fr, T, O NA NA

12/F 15 yr UCLA/1989 NA P, latO Hemisphere NA NA

13/M 26 yr UCLA/1991 4 yr P, O, infT P,O, infFr No significant atrophy Right Fr, T; smaller

ones on left + right

14/M 21 yr UCLA/1992 NA T, P, O (P) NA NA

Regions in parentheses indicate mild involvement.

Abbreviations:

CHM = Children’s Hospital of Michigan

F = Female

Fr = Frontal

incr. = Increased glucose metabolism

inf = Inferior

lat = Lateral

M = Male

mid = Middle

mo = Month

MRI = Magnetic resonance imaging

NA = Not available/not applicable

O = Occipital

P = Parietal

PET = Positron emission tomography

post. = Posterior

SM = Sensorimotor

sup = Superior

T = Temporal

UCLA = University of California at Los

Angeles

yr = Year

emission tomography scanning. Long-term follow-up in-formation was available for patient 11, who demonstratedmarked improvement in seizure control and significant de-velopmental improvement after a left hemispherectomy.Although only 5 months of follow-up were available forpatient 1, his life-threatening seizures ceased after surgery,

446 PEDIATRIC NEUROLOGY Vol. 44 No. 6

and he exhibited some developmental improvement(although he remained severely impaired). Patient 6 under-went a right hemispherectomy before positron emissiontomography scanning. Although the surgery resulted inthe cessation of her seizures, she remained moderatelyimpaired. Postsurgical positron emission tomography

Figure 1. Representative axial images of T1-weighted postgadoliniummagnetic resonance imaging (A) and glucose positron emission tomogra-phy images (B) of patient 4. This child exhibited poor seizure control, se-vere developmental impairment, and left hemiparesis at the time ofpositron emission tomography scanning. Magnetic resonance imaging in-dicated severe bilateral brain atrophy, with extensive bihemispheric lepto-meningeal angiomatosis and bilateral enlargement of the choroid plexus.The glucose metabolism of the entire right hemisphere was decreased.Moreover, the left frontal and occipital cortices were also hypometabolic,and only the temporal and parietal cortex exhibited preserved glucose me-tabolism on the left side (arrows). L = left; R = right.

revealed extensive hypometabolism, involving portions ofthe nonresected left occipital, parietal, and temporal lobes.

Discussion

This study, to the best of our knowledge, is the first to fo-cus on the neuroimaging correlates of neurodevelopmentaloutcomes in a series of patients with bilateral Sturge-Weber syndrome. The findings demonstrate that, althoughthe general clinical outcome is often poor in these patients,a significant portion (approximately 50%) of this groupachieved relatively good seizure control with or withoutsurgery, developed good gross motor function, and mostimportantly, escaped severe developmental impairmentduring the course of their disease. Our findings suggestthat the relatively good outcomes in these patients arelikely attributable to their common asymmetric lobar func-tional involvement, allowing at least one side of the brain tosupport neurocognitive functions. In contrast, bilateralfrontal lobe involvement appears to be a critical imagingmarker of both developmental and motor outcomes,whereas bitemporal hypometabolism may comprise a riskfactor for autistic features. Therefore, functional neuroi-maging with positron emission tomography can be partic-ularly important in providing prognostic information about

children with bilateral Sturge-Weber syndrome. In addi-tion, because epilepsy surgery can be considered in somepatients with bilateral Sturge-Weber syndrome (as success-fully performed in three of 14 patients in our cohort), glu-cose positron emission tomography can also be used toevaluate the functional integrity of the nonresected hemi-sphere before surgery.

The long-term clinical prognosis varies considerablyamong patients with Sturge-Weber syndrome [7,16], andpredicting long-term outcomes during the early course ofthe disease is challenging even in unilateral Sturge-Weber syndrome. Previous studies, however, shed somelight on the potential clinical or imaging markers of unfa-vorable outcomes. An early onset of seizures and intracta-ble epilepsy were associated with developmentaldeterioration and the need for special education, renderingepilepsy a crucial factor in developmental impairment [16].With respect to brain damage, as assessed by neuroimag-ing, the degree of cortical atrophy appeared to be stronglyassociated with overall clinical severity [9]. In addition,simple clinical markers, such as hemiparesis, may differen-tiate between patients with and without impaired adaptivefunctioning, a good indicator of everyday functioning [6].Most neuroimaging and neuropsychologic studies havefocused on the majority of Sturge-Weber syndromepatients with unilateral intracranial damage.

No studies to date, to the best of our knowledge, have fo-cused exclusively on the imaging and clinical characteris-tics of bilateral Sturge-Weber syndrome. However, someclinical and prognostic differences between patients withbilateral and unilateral brain involvement were outlined.Bilateral hemispheric involvement was demonstrated torender patients more susceptible to seizures, and the onsetof seizures may occur earlier in patients with Sturge-Webersyndrome and bilateral leptomeningeal angiomatosis thanin those with unilateral lesions [5]. Indeed, the lack of ep-ilepsy is very rare within this subset of patients withSturge-Weber syndrome. Notably, all patients in our serieshad a history of seizures. The rare absence of seizures inbilateral Sturge-Weber syndrome (and also in cases withunilateral involvement) is likely associated with good intel-lectual functioning [5]. In contrast, the developmental sta-tus and educability of the majority of patients with bilateralcerebral involvement and concomitant seizures vary con-siderably, but are almost invariably impaired. Our dataare in accordance with this concept, although we couldnot detect an obvious relationship between early-onsetseizures and more severe developmental impairment.Whether this relationship exists in bilateral Sturge-Webersyndrome could probably be determined by investigatingeven larger series in a longitudinal setting (which wouldbe difficult to accomplish unless a broad, multicenter studyis performed). Nevertheless, in a large study of patientswith Sturge-Weber syndrome (including unilateral and bi-lateral cases), mental retardation and a requirement for spe-cial education tended to decrease with increasing age atseizure onset [17]. In addition, earlier positron emission

Alkonyi et al: Bilateral Sturge-Weber Syndrome 447

Figure 2. Axial image planes of the glucose positron emission tomogra-phy scan of patient 5, whose developmental impairment was mild to mod-erate. He subsequently developed autistic behavioral features. Hispositron emission tomography scan demonstrated bilateral (more severeon the right than on the left) temporal hypometabolism (arrows) and bilat-eral parietal and right occipital hypometabolism.

tomography studies suggested that chronic seizure activityplays a role in the progression of cortical metabolic abnor-malities in children with epilepsy (related or not related toSturge-Weber syndrome) [18,19].

Previous studies indicated that more extensive braindamage is associated with more severe neurocognitive def-icit in patients with Sturge-Weber syndrome. The extent ofcortical damage, thalamic hypometabolism, and whitematter loss ipsilateral to the angioma were strong predic-tors of impaired cognitive function in unilateral Sturge-Weber syndrome [10,11,15]. In addition, the results ofour recent objective voxelwise analysis identifiedipsilateral prefrontal white matter areas with anisotropyvalues correlating with the full-scale intelligence quotientsof patients with unilateral angiomatosis [20]. Importantly,the severe early damage of one hemisphere may facilitatefunctional reorganization in the intact contralateral hemi-sphere [15]. In case of bilateral intracranial involvement,this process is most likely significantly hindered, which ex-plains the worse overall clinical picture in these patients.However, most patients with one frontal lobe maintaininggood metabolic activity can avoid severe developmentalimpairment, suggesting that at least the partial reorganiza-tion of critical cognitive functions can occur in these chil-dren. Moreover, regarding the deleterious effects ofbilateral homotopic functional damage of the brain inSturge-Weber syndrome, two patients with bitemporal in-volvement developed autism. Concordantly, previous stud-ies of childhood autism demonstrated the bilateraldysfunction of temporal regions involved in language andsocial perception [21]. In addition, the functional impair-ment of medial and lateral temporal regions, along withother brain regions, was implicated in a subgroup of chil-dren with facial port wine stains and autism, but without in-tracranial angioma [22].

Our finding of cortical hypometabolism involving supe-rior frontal areas or even the whole hemisphere in patientswith some degree of hemiparesis is in concordance witha recent study demonstrating more diffuse cortical injury,extending to frontal areas, in hemiparetic children, regard-less of the unilateral or bilateral localization of the angioma[6]. That study suggested that hemiparesis may be a simplemarker of adaptive functioning while also indicating fron-

448 PEDIATRIC NEUROLOGY Vol. 44 No. 6

tal lobe involvement. Based on our data, however, we em-phasize that the preserved function of the sensorimotorcortex (even in the presence of bifrontal damage) could re-sult in normal gross motor functions. Nevertheless, moreanterior frontal injuries may account for fine motor dys-function [20].

Although our limited magnetic resonance imaging data(in some instances, based on reports many years apart) pre-clude any definitive statement about the clinical correlates ofmagnetic resonance imaging abnormalities, magnetic reso-nance imaging scans, including postcontrast sequences,are clearly capable of identifying bilateral structural braindamage in Sturge-Weber syndrome. As indicated in Table2, magnetic resonance imaging abnormalities (volume lossor angioma), similar to positron emission tomography ab-normalities, were almost invariably more severe in onehemisphere. Because many of the available magnetic reso-nance imaging scans were performed far in time from thepositron emission tomography scans, an exact concordanceormismatch between thesemodalities needs to be addressedin coregistration studies. Nevertheless, an earlier study indi-cated that areas of glucose hypometabolism extended be-yond computed tomography abnormalities in patients withSturge-Weber syndrome [14]. In the present series, magneticresonance imaging and positron emission tomography wereperformed within days of each other in patients 7-9. In allthree cases, positron emission tomography provided infor-mation to supplement that from magnetic resonance imag-ing. In patient 7, no leptomeningeal enhancement wasdetected, despite bilateral atrophy; positron emission to-mography revealed very focal hypometabolism on the rightside, indicating functional integrity in much of that hemi-sphere. In patient 8, positron emission tomography demon-strated the preservation of the sensory-motor cortex,whereas in patient 9, temporal lobe hypometabolism ex-tended beyond temporal pole atrophy seen on magnetic res-onance imaging.

In opposition to the traditional concept that bihemi-spheric disease precludes epilepsy surgery in Sturge-Weber syndrome, successful hemispherectomies or focalresections with good long-term seizure control and im-proved development were reported in a few cases[12,13]. Our experience, although limited, also supportsthe importance of considering epilepsy surgery, even inbilateral Sturge-Weber syndrome with intractable seizures.Because data indicate that the persistence of devastatingseizures contributes to neurocognitive decline [23,24],early removal of the epileptic focus may be beneficial interms of seizure control and neurocognitive development.Because brain involvement is typically asymmetric inthese patients, glucose positron emission tomographymay play a critical role in evaluating the functionalintegrity of the unresected hemisphere.

Some limitations of the present study must be noted.First, the distinction between unilateral and bilateral intra-cranial involvement is often ambiguous. Advanced neuro-imaging techniques may depict brain abnormalities missed

by other modalities [25,26]. Importantly, we included onlythose patients in this study whose bilateral brain damagewas confirmed by positron emission tomography andanother imaging method (computed tomography ormagnetic resonance imaging). Because cases of Sturge-Weber syndrome and bilateral intracranial involvementare very rare, a reasonable number of patients could be col-lected only over a long period (24 years). Thus, we couldnot obtain more formal and uniform quantitative neuropsy-chologic data in all cases, and we could qualitatively corre-late cortical glucose metabolic abnormalities only withrather gross categories of developmental impairment andseizure control. Importantly, the frequency, types, and se-verity of seizures, as well as the occurrence of stroke-likeepisodes (which were not systematically analyzed in thisstudy), may also contribute to the variable outcomes of pa-tients with bilateral Sturge-Weber syndrome. In addition,the broad age range of the studied patients and the lackof long-term outcome data in some cases comprised furtherlimitations.

This study was partly supported by grant R01 NS041922 from the Na-

tional Institutes of Health to C.J. The authors thank the Sturge-Weber

Foundation for referring patients to us. The authors are grateful to the fam-

ilies and children who participated in the study.

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jor predictor of cognitive function in Sturge-Weber syndrome. Arch Neu-

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multimodality imaging study of children with Sturge-Weber syndrome.

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[14] Chugani HT, Mazziotta JC, Phelps ME. Sturge-Weber syn-

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mography. J Pediatr 1989;114:244-53.

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relation between clinical course and FDG PET findings. Neurology 2001;

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[16] Sujansky E, Conradi S. Outcome of Sturge-Weber syndrome in

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Alkonyi et al: Bilateral Sturge-Weber Syndrome 449

VI. SUMMARY OF THESIS

1. The ipsilateral thalamus is impaired metabolically in unilateral SWS, and severity of

thalamic damage is associated with the extent of cortical injury.

2. In children with left hemispheric angiomatosis, the metabolic and microstructural damage

of the thalamus (measured by FDG PET and DTI, respectively) can be a simple, but robust,

independent imaging marker of neurocognitive outcome.

3. Microstructural WM abnormalities occur not only ipsilateral, but to a certain extent,

contralateral to the angioma in patients with unilateral SWS.

4. Nevertheless, cognitive function (IQ) and fine motor function of the hand opposite to the

angioma appears to be associated with microstructural damage of focal ipsilateral WM areas.

5. A paradoxical pattern of (mostly frontal) cortical glucose hypermetabolism is common

among young patients with SWS. Focal increases of cortical metabolism occur shortly after or

before the first clinical seizures.

6. Cortical hypermetabolism is invariably transient and predicts subsequent metabolic

deterioration of the affected cortex.

7. Intractable epilepsy requiring epilepsy surgery is more frequent in children with initial

cortical hypermetabolism than in those without, which suggests that this metabolic abnormality

could be an imaging marker for drug resistant epilepsy.

8. The leptomeningeal angioma region of SWS patients shows increased 11C-leucine uptake,

which is mainly driven by increased amino acid transport.

9. Higher leucine uptake is associated with more severe glucose hypometabolism in the

angioma region.

10. Increased leucine transport and protein synthesis rates in the angioma regions suggest

proliferative activity, likely related to active vascular remodeling. The presence of active

vascular proliferation in the angioma tissue is also supported by our histopathology data.

76  

11. Neurocognitive outcome in the subset of patients with bilateral intracranial involvement

depends on the extent and localization of brain injury. Early seizure onset does not necessarily

result in severe clinical outcome in these patients.

12. Total hemispheric or bilateral frontal brain damage appears to be coupled with unfavorable

cognitive and seizure outcome; bitemporal lesion is often associated with autistic phenotype.

13. Good seizure control and only mild/moderate developmental impairment may be achieved

in about half of the bilateral SWS patients, with or without resective surgery.

77  

VII. BIBLIOGRAPHY

• Articles related to thesis:

Alkonyi B, Chugani HT, Karia S, Behen ME and Juhász C: Clinical outcome in bilateral

Sturge-Weber syndrome. [Pediatric Neurology. 2011 Jun;44(6):443-9]

Impact factor (IF) (2009): 1.497

Alkonyi B, Chugani HT and Juhász C: Transient focal cortical increase of interictal glucose

metabolism in Sturge-Weber syndrome: Implications for epileptogenesis. Epilepsia.2011 Apr

11.; doi: 10.1111/j.1528-1167.2011.03066.x. Epub ahead of print

IF (2009): 4.052

Alkonyi B, Chugani HT, Muzik O, Chugani DC, Sundaram SK, Kupsky WJ, Batista CE and

Juhász C: Increased L-[1-11C]leucine uptake in the leptomeningeal angioma of Sturge-Weber

syndrome: a PET study. J Neuroimaging. 2011 Jan 11. doi: 10.1111/j.1552-

6569.2010.00565.x. Epub ahead of print

IF (2009): 1.719

Alkonyi B, Govindan RM, Chugani HT, Behen ME, Jeong J and Juhász C: Focal white matter

abnormalities related to neurocognitive dysfunction: An objective diffusion tensor imaging

study of children with Sturge-Weber syndrome. Pediatr Res. Jan;69(1):74-9.

IF (2009): 2.604

Alkonyi B, Harry T. Chugani, Michael E. Behen, Stacey Halverson, Emily Helder, Malek I.

Makki and Csaba Juhász: The role of the thalamus in neuro-cognitive dysfunction in early

unilateral hemispheric injury: A multimodality imaging study of children with Sturge-Weber

syndrome. Eur J Paediatr Neurol. 2010 Sep;14(5):425-33.

IF (2009): 2.007

• Articles not related to thesis:

78  

Alkonyi B, Barger GR, Mittal S, Muzik O, Chugani DC, Bahl G, Robinette NL, Kupsky WJ,

and Juhasz C: Accurate differentiation of recurrent gliomas from radiation necrosis by kinetic

analysis of α-[11C]methyl-L-tryptophan PET. [under review in Neuro-Oncology]

Alkonyi B, Juhász C, Muzik O, Behen ME, Jeong JW and Chugani HT: Thalamocortical

connectivity in healthy children: asymmetries and robust developmental changes between age

8 and 17. AJNR Am J Neuroradiol. 2011 May;32(5):962-9.

IF (2009): 3.296

Alkonyi B, Juhász C, Muzik O, Asano E, Saporta A, Shah A, Chugani HT:

Quantitative brain surface mapping of an electrophysiologic/metabolic mismatch in human

neocortical epilepsy. Epilepsy Res. 2009 Nov; 87(1):77-87.

IF (2009): 2.479

Trauninger A, Alkonyi B, Kovács N, Komoly S, Pfund Z: Methylprednisolone therapy for

short-term prevention of SUNCT syndrome. Cephalalgia. 2010 Jun;30(6):735-39.

IF (2009): 3.686

Auer T, Janszky J, Schwarcz A, Dóczi T, Trauninger A, Alkonyi B, Komoly S, Pfund Z:

Attack-related brainstem activation in a patient with SUNCT syndrome: an ictal fMRI study.

Headache. 2009 Jun; 49(6): 909-12.

IF (2009): 2.786

Fehér G, Koltai K, Alkonyi B, Papp E, Keszthelyi Z, Kesmarky G, Toth K: Clopidogrel

resistance: Role of body mass and concomitant medications. Int J Cardiol. 2007 Aug 21;

120(2): 188-92.

IF (2007): 2.878

Fehér G, Koltai K, Papp E, Alkonyi B, Solyom A, Kenyeres P, Kesmarky G, Czopf L, Toth

K: Aspirin resistance: possible roles of cardiovascular risk factors, previous disease history,

concomitant medications and haemorrheological variables. Drugs Aging. 2006;23(7):559-67.

IF (2006): 2.200

Cumulative impact factor: 29.2

79  

First author articles: 17.7

• Book Chapter:

Csaba Juhász, Bálint Alkonyi and Harry T. Chugani: Imaging brain structure and function in

Sturge-Weber syndrome. In: Roach ÉS, Bodensteiner JB. eds.: Sturge-Weber syndrome. The

Sturge-Weber Foundation, NJ, 2010.

• Congress abstracts related to thesis (first author if not otherwise indicated):

White matter perfusion abnormalities in Sturge-Weber syndrome: relation to cortical glucose

metabolism and seizure severity

[poster] (2011 Annual Meeeting of the American Academy of Neurology, Honolulu, HI, USA,

April, 20111)

Focal white matter diffusion abnormalities in children with Sturge-Weber syndrome: Relation

to neurocognitive dysfunction

[poster] (2010 Child Neurology Society Annual Meeting, Providence, RI, USA, October,

2010)

Increased L-[1-11C]leucine Uptake in the Angioma Associated with Cortical Hypometabolism

in Children with Sturge-Weber Syndrome: a PET Study

[poster] (Molecular Neuroimaging Symposium, National Institutes of Health, Bethesda,

Maryland, USA, May, 2010)

Image of the month (July 2010 in SNM Molecular Imaging Center of Excellence website)

reprinted from J Nucl Med. 2010;51:827,830.

Metabolic and diffusion abnormalities of the thalamus and their cognitive correlates in

unilateral Sturge-Weber syndrome

[poster] (2010 Annual Meeeting of the American Academy of Neurology, Toronto, Canada,

April, 2010)

80  

• Congress abstracts not related to thesis (first author if not otherwise indicated):

Juhász C, Alkonyi B, Hu J, Xuan Y, Chugani HT: Neurometabolic abnormalities and

epileptogenesis in Sturge-Weber syndrome

[abstract accepted for poster presentation at the 2011 Child Neurology Society Annual

Meeting, Providence, RI, USA, October, 2011]

Differentiation of recurrent gliomas from radiation necrosis by kinetic analysis of α-

[11C]methyl-L-tryptophan PET

[platform presentation] (2011 Annual Meeeting of the American Academy of Neurology,

Honolulu, HI, USA, April, 2011)

Metabolic and molecular imaging characteristics of epileptogenic dysembryoplastic

neuroepithelial tumors (DNETs) [poster] (2010 Annual Meeting of The American Epilepsy

Society, San Diego, TX, USA, December, 2010)

Muzik O, Pai D, Alkonyi B, Juhász C, Hua J: Performance evaluation of an integrative

software environment for analysis of multi-modality neuroimaging data [platform presentation]

(SNM 57th Annual Meeting, Salt Lake City, Utah, USA, June, 2010.)

Focal cerebral increases of α-[11C]methyl-L-tryptophan (AMT) uptake suggest activation of

the kynurenine pathway in multiple sclerosis: a PET study

[poster] (2010 Annual Meeting of the American Academy of Neurology, Toronto, Canada,

April, 2010)

Quantitative brain surface mapping of cortical hypometabolism in neocortical epilepsy [poster]

(2009 Annual Meeting of the American Epilepsy Society, Boston, MA, USA, December,

2009)

Complementary MR imaging examinations in headaches of trigeminal nerve origin [platform

presentation] (Conference of the Hungarian Society of Headache, Siófok, Hungary, 2008)

81  

An ictal fMRI study of a patient with SUNCT syndrome

[platform presentation] (Conference of the Hungarian Society of Headache, Siófok, Hungary,

2007)

• Citable abstracts based on congress presentations:

Bálint Alkonyi, Geoffrey R. Barger, Sandeep Mittal, Otto Muzik, Gautam Bahl, Pulak K.

Chakraborty and Csaba Juhasz: Differentiation of recurrent gliomas from radiation necrosis by

kinetic analysis of α-[11C]methyl-L-tryptophan PET. Neurology 2011;76 (Suppl 4) A182. IF

(2009): 8.172

Bálint Alkonyi, Yanwei Miao, Jiani Hu, Harry T. Chugani and Csaba Juhasz: White matter

perfusion abnormalities in Sturge-Weber syndrome: Relation to cortical glucose metabolism

and seizure severity. Neurology 2011;76 (Suppl 4) A301. IF (2009): 8.172

Sandeep Mittal, Ian M. Zitron, William J. Kupsky, Bálint Alkonyi, Sandeep Sood and Csaba

Juhász: Cytokine-mediated inflammation in epileptogenic dysembryoplastic neuroepithelial

tumors. Neuro-Oncology 2010;12 (suppl 4): iv32. IF (2009): 4.984

Bálint Alkonyi, Rajkumar M. Govindan, Harry T. Chugani, Michael E. Behen, Jeong-Won

Jeong, Csaba Juhász: Focal White Matter Diffusion Abnormalities in Children with Sturge-

Weber Syndrome: Relation to Neurocognitive Dysfunction. Ann Neurol 68 Oct 2010 (Suppl

14) S 104. IF(2009): 9.317

Otto Muzik, Darshan Pai, Bálint Alkonyi, Csaba Juhász, Jing Hua: Performance evaluation of

an integrative software environment for analysis of multi-modality neuroimaging data.

J Nucl Med. 2010; 51 (Suppl 2) 82P. IF (2009): 6.424

Bálint Alkonyi, Harry T. Chugani, Otto Muzik, Diane C. Chugani, Senthil K. Sundaram,

William J. Kupsky, Carlos Batista and Csaba Juhász: Increased L-[1-11C]leucine Uptake in the

Angioma Associated with Cortical Hypometabolism in Children with Sturge-Weber

Syndrome: a PET Study.

82  

J Nucl Med. 2010;51:827. IF (2009): 6.424

Bálint Alkonyi, James Y. Garbern, Diane C. Chugani, Otto Muzik, Pulak Chakraborty and

Csaba Juhász: Focal cerebral increases of α-[11C]methyl-L-tryptophan uptake suggest

activation of the kynurenine pathway in multiple sclerosis: a PET study.

Neurology 74 March 2, 2010 (Suppl 2) A238. IF (2009): 8.172

Bálint Alkonyi, Harry T. Chugani, Michael E. Behen, Stacey Halverson, Emily Helder, Malek

I. Makki and Csaba Juhász: Metabolic and diffusion abnormalities of the thalamus and their

cognitive correlates in unilateral Sturge-Weber syndrome.

Neurology 74 March 2, 2010 (Suppl 2) A230. IF (2009): 8.172

Bálint Alkonyi, C. Juhasz, O. Muzik, E. Asano, A. Saporta, A. Shah and H. T. Chugani:

Quantitatvive brain surface mapping of cortical hypometabolism in neocortical epilepsy.

Epilepsia 50 Nov, 2009 (Suppl 11) pp. 427-428. IF (2009): 4.052

Gergely Fehér, Katalin Koltai, Előd Papp, Zsuzsanna Keszthelyi, Bálint Alkonyi, Péter

Kenyeres, Hajnalka Rapp, Gábor Késmárky and Kálmán Tóth: Acetylsalicylic acid and

clopidogrel resistance: Possible role of risk factors, medication and hemorheological variables.

Atherosclerosis Supplements 7 (3):398.

83  

84  

VIII. ACKNOWLEDGEMENTS

I am grateful first of all to Dr. Csaba Juhász who has been the leader of my research studies for

more than two years. Our close collaboration, his scientific experience, optimistic attitude and

helpfulness were indispensable for achieving the results presented here. I am truthfully

thankful to Dr. Zoltán Pfund, who made it possible for me to join an exquisite research group

in the United States. His earlier personal experience, which he shared with me, was indeed

useful during the time spent in the US and also during my earlier clinical work as a resident.

The families with a child suffering from Sturge-Weber syndrome, who participated in

our research studies for the hope of eventually finding the cure, deserve special gratitude.

I also thank Prof. Sámuel Komoly for the support he gave me and the clinical

knowledge he shared with me during residency. I would like to thank everybody (especially

Dr. Harry T. Chugani, the chief of the PET Center and Pediatric Neurology at the Children`s

Hospital of Michigan, as well as several postdoctoral fellows at the CHM PET Center) who

contributed to my work with their help, support or suggestions.

I am grateful to my parents, sister and fiancée for supporting, helping and loving me not

only during this exciting but sometimes difficult period but all through my life.