neuroimaging of phakomatoses · 2019-04-11 · enlarge the optic nerve and can involve any portion...

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euroimaging of Phakomatosesoris D.M. Lin, MD, PhD,* and Peter B. Barker, DPhil*,†

The phakomatoses are congenital disorders manifesting with central nervous system andcutaneous abnormalities. The structures predominantly affected are those of ectodermalorigin, including the skin, nervous system, and eyes. The 4 most common phakomatosesare neurofibromatosis (types 1 and 2), tuberous sclerosis, Sturge-Weber disease, and vonHippel-Lindau disease. Imaging of the brain and spine in these disorders plays an importantrole in diagnosis, as well as determining the extent of involvement and guiding surgicalinterventions. This article reviews the application of x-ray computed tomography andmagnetic resonance imaging to these disorders, as well as that of newer, “functional”imaging techniques such as positron emission tomography, magnetic resonance perfusionimaging, and spectroscopy.Semin Pediatr Neurol 13:48-62 © 2006 Elsevier Inc. All rights reserved.

KEYWORDS phakomatosis, neurocutaneous, neurofibromatosis, tuberous sclerosis, Sturge-Weber, von Hippel-Lindau, magnetic resonance imaging, spectroscopy, perfusion, com-puted tomography, brain, spine

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he phakomatoses, also known as neurocutaneous syn-dromes, consists of a group of disorders that tend to

evelop hamartomatous malformations and neoplasticrowths affecting the skin, the nervous system, and otherrgans. The more common phakomatoses include neurofi-romatosis (NF), tuberous sclerosis (TS), Sturge-Weber dis-ase (SW), and von Hippel-Lindau syndrome (VHL). Each ofhese has distinct clinical features and heterogeneous geneticrofiles, yet shares the common characteristics of abnormalevelopment of structures derived from ectodermal origin,uch as in the central nervous system (CNS) and skin.1 Ofote, even though these are collectively called neurocutane-us syndromes, VHL lacks cutaneous findings, which alsoay not always be present in other disorders (eg, NF2).mong these, SW is considered sporadic disease because noenetic abnormality has been identified to date.

These syndromes are typically diagnosed clinically by aumber of disease features, yet invariably in each there is apectrum of disease manifestation and severity, sometimesaking the diagnosis challenging. The genetic mutation has

een identified in most of these entities, providing a betternderstanding of the underlying pathophysiology through a

Russell H Morgan Department of Radiology and Radiological Science,Johns Hopkins University School of Medicine, Baltimore, MD; and

Kennedy Krieger Institute, Baltimore, MD.upported in part by NIH P41 RR15241 and USARA DAMD 170110713.ddress reprint requests to Doris D.M. Lin, MD, PhD, Department of Radi-

ology, Phipps B100, Johns Hopkins University School of Medicine, 600
iN Wolfe Street, Baltimore, MD 21287. E-mail: [email protected]
8 1071-9091/06/$-see front matter © 2006 Elsevier Inc. All rights reserved.doi:10.1016/j.spen.2006.01.011

umor suppressor mechanism,1 as well as a more preciseonfirmatory test and potentially a means of prenatal diagno-is. Neuroimaging plays an integral part of the clinical eval-ation by identifying lesions in the central nervous system. Itot only aids the initial diagnosis but is also fundamental inelineating the extent of central nervous system involvement,

n monitoring disease progression, and in providing an ana-omic roadmap for potential surgical intervention.

This article reviews the imaging findings in the more com-on phakomatoses, including NF types 1 and 2, TS, SW, andHL. The CNS manifestations on conventional computed

omography (CT) scans and magnetic resonance imagingMRI) are discussed as well as the role of other imaging tech-iques such as diffusion-weighted images, magnetic reso-ance (MR) perfusion, MR spectroscopy, and the nuclearedicine positron-emission tomography (PET) and singlehoton emission computed tomography (SPECT) tech-iques. These newer imaging modalities may contribute tohe understanding of the disease process by providing “phys-ologic” or “functional” information that complements thenatomic information present in conventional scans.

eurofibromatosisF1ype 1 neurofibromatosis, also called von Recklinghausen’sisease, is the most common phakomatosis that occurs aboutin 3,000 to 4,000.2 It is transmitted as an autosomal dom-

nant trait with the genetic defect localized to chromosome

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Neuroimaging of phakomatoses 49

7q11.2 encoding neurofibromin. Neurofibromin is a tumoruppressor that regulates Ras-guanosine triphosphate acti-ating protein and thereby controls cellular signal transduc-ion.3 Although it is hereditary, in 50% of the affected indi-

igure 1 A 6-year-old boy with NF1 and left proptosis. (A) Axial T2 andB) post-GdDTPA coronal T1-weighted images show extensive plexiformeurofibroma infiltrating the left face, periorbital soft tissue, masticatorpace, and parapharyngeal space. The mass is T2 bright with central darkreasandshowsheterogeneousyetavidcontrastenhancement. Inthiscase,he plexiform neurofibroma also involves the retrobulbar compartment,nd there is dysplasia of the left greater sphenoid wing. Both contributed tohemarkeddistortionof the leftorbit. (C)A22-year-oldmanwithNF1andeft arm pain. Three axial T2-weighted MR images through the lower cer-ical and upper thoracic spine show multiple plexiform neurofibromasnvolving the neural foramina, paraspinal, and prevertebral regions. The

asses in the middle section fill the bilateral neural foramina and causearked compression of the cord from both sides.

Figure 3 A 7-year-old girl with NF1. (A) Axial T2-weigAxial T2 and (C) post-GdDTPA axial T1-weighted imacentral necrosis, and associated edema and mass effect o
Surgical pathology revealed a low-grade astrocytoma.
iduals, NF1 occurs sporadically because of spontaneousutation, and, in fact, it is the syndrome with the highestutation rate. Affected individuals manifest with cutaneous

café au lait” spots, skinfold freckling, and neurofibromas.isch nodules, harmartomas of the iris, may also be found.Neurofibromas are benign tumors arising from the nerve

heath and composed of a mixture of Schwann cells, perineu-al cells, and fibroblasts.4 The neurofibromas can be nodularnd discrete, or they can be diffuse, plexiform neurofibromasncasing and enlarging multiple nerve fascicles.5 The plexi-orm neurofibroma is quite infiltrative and vascular and mayccur in the deep spaces of the head and neck causing majorisfiguration or in the paraspinal regions, resulting in nerveompression and neurologic deficits (Fig 1). On MRI, theseasses are typically T1 hypointense and T2 hyperintense,ith a variable contrast-enhancement pattern.6 There is esti-ated to be a 10% risk of development of malignant periph-

ral nerve sheath tumors, often of the plexiform type, in NF1

igure 2 T2-weighted sagittal images of the lumbar spine showingultiple well-circumscribed neurofibromas (A) occupying the in-

radural extramedullary compartment of the spine and (B) expand-ng the neuroforamina.

age shows right optic nerve glioma with proptosis. (B)ow a right basal ganglia mass with rim enhancement,ventricles resulting in mild obstructive hydrocephalus.

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50 D.D.M. Lin and P.B. Barker

atients.7 Imaging findings of irregular contour and hetero-eneous enhancement are suggestive of invasive nature; how-ver, some of the malignant peripheral nerve sheath tumorsave a similar appearance to the benign ones. A few studiesuggested that F18-deoxyglucose positron-emission tomog-aphy (FDG-PET) may be useful in distinguishing the malig-ant from benign peripheral nerve sheath tumors.8-10 Multi-le spinal neurofibromas tend to occur in NF1 patients asumors in the intradural extramedullary, extradural, orixed compartments. They have a characteristic feature of aumbbell shape, expanding the neural foramina (Fig 2) andften exhibiting central dark signal on T2-weighted imageseflecting dense collagen formation on histopathology.

Intracranially, NF1 patients have the tendency of develop-ng neoplasms including optic pathway gliomas that are typ-cally of the juvenile pilocytic astrocytoma histology (Fig 3A)

igure 5 A 20-year-old woman with NF1.A) A sagittal T2-weighted image shows wid-ning of the thoracic spinal canal with scal-oping of the posterior vertebral bodiesaused by dural ectasia. (B) Sagittal and (C)xial T2-weighted images show outpouch-ng of the meninges, smooth pressure ero-ion of the posterior vertebral body, andidening of the left neural foramen becausef a large lateral meningocele.

s well as astrocytomas in other brain regions (Fig 3B and C).he incidence of CNS tumors in NF1 is about 1% to 5%.11

mong these, the optic nerve gliomas are most common.hey are slow-growing tumors that directly infiltrate andnlarge the optic nerve and can involve any portion of theptic pathway including the intraorbital optic nerves, chi-sm, optic tracts, lateral geniculate bodies, and optic radia-ions. The intraorbital and chiasmal optic gliomas may en-ance with gadolinium-diethylenetriamine penta-acetic acidGdDTPA) either avidly or mildly, whereas the extensionlong the lateral geniculate, optic tracts, and radiations typi-ally shows expansion and T2 prolongation without contrastnhancement. Visual acuity usually declines slowly and is theost common clinical presentation.12

A number of nonneoplastic abnormalities are often en-ountered in NF1. Mesenchymal dysplasia associated with

Figure 4 A boy with NF1. (A) An axialT2-weighted image shows bilateral op-tic nerve gliomas, which are larger onthe right. The distal internal carotid ar-tery flow voids are not well seen. (B) MRangiography of the circle of Willisshows stenosis of the distal internal ca-rotid arteries and complete occlusion atthe termini, with no flow in the rightmiddle cerebral artery and severe nar-rowing of the left middle cerebral ar-tery. Many collateralized lenticulostri-ate vessels are seen instead. (C) Axialtime-of-flight gradient-echo source im-ages of the MR angiogram again showthe moya-moya pattern of collateralvessels around the brainstem and in thebilateral basal ganglia regions.

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F1 leads to defective connective tissue, ranging fromony abnormalities such as sphenoid wing dysplasia, vas-ular abnormalities such as intracranial aneurysm, steno-is, and moyamoya syndrome (Fig 4), to dural dysplasia.calloping of the posterior vertebrae may be seen withntraspinal tumors but more typically as an isolated find-ng related to dural ectasia. Weakness or defect of the

eninges in the spine gives rise to characteristic arachnoidysts or lateral meningoceles, which most commonly oc-ur in the thoracic region (Fig 5). Sphenoid wing dysplasiaccurs uncommonly, in about 1% of cases. This can resultn pulsatile exophthalmos related to transmission of cere-rospinal fluid pulsations through the bony defect anderniation of the temporal lobe (Fig 6).With the advent of MRI, it has been found that 60% to 90%

f NF1 individuals, without any neurologic symptoms, haveesions on long T2-weighted sequences.13-15 These lesionsave been coined the name “unidentified bright objects”UBOs) and are typically found bilaterally in the dentate nu-lei of the cerebellum, brainstem, basal ganglia, and thalami

igure 6 NF1. (A) Axial and (B) coro-al CT images of the orbit show a defect

n the right greater wing of the sphe-oid bone, resulting in asymmetric her-iation of the right temporal lobe caus-

ng proptosis of the right eye. Note alson enlarged left optic nerve because ofn optic nerve glioma. (C) A surface-endered 3-dimensional reconstructionf the skull shows and empty socketppearance on the right side and anpen bony defect. (Color version of fig-re is available online.)

n a symmetric or asymmetric fashion (Fig 7). Atypical loca-ion may also be found such as in the cerebral white matter.hey are not associated with any mass effect or enhancement.n pathology based on autopsy cases, these lesions corre-

pond to vacuolar changes in the myelin sheath.16 It is ofnterest that they often decrease in number and size betweenand 12 years of age, after which they gradually increase and

hen decrease again. The evolution may also shift in loca-ion.17 It has been noted that UBOs are found in only 29% ofF1 individuals older than 31 years. Even though these le-

ions do not cause neurologic symptoms, they have beenorrelated with learning disabilities.18-20 At times, UBOs mayave an atypical appearance (such as mass-like, associatedith apparent mass effect) or location that makes it difficult

o distinguish from an astrocytoma. A UBO should nevernhance with Gd, yet the typical low-grade glioma (astrocy-oma) also does not show any enhancement. In such cases,H-MR spectroscopy may be helpful. It has generally beenound that the metabolic profile in these UBOs is not veryifferent from that of a normal brain, suggesting that the

Figure 7 Two cases with NF1. (A)FLAIR images show typical distribu-tion of bright lesions (UBOs) in thecerebellar dentate, pons, cerebellarpeduncles, midbrain, globus pallidiand thalami. (B) UBO in a 22-month-old girl: T2-weighted images showingasymmetrically located, mass-like le-sion in the right middle cerebellar pe-duncle, which appears somewhat ex-panded.

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F2n contrast to NF1, there is minimal skin manifestation inndividuals affected by NF2, and the prevalence of NF2 is

uch lower, about 1 in 40,000. NF2 is characterized byilateral vestibular schwannomas (Fig 9),21,22 also known asentral form of neurofibromatosis or vestibular schwannomaeurofibromatosis. Diagnosis can be made on the basis of (a)ilateral vestibular masses, or (b) a positive family historyith either unilateral vestibular mass, or any 2 of meningio-as, gliomas, schwannomas, and congenital catatacts.23,24

he genetic defect has been localized to chromosome2q12.2.25,26 In 50% of the cases, however, the disease oc-urs as a result of spontaneous mutation.

Because of the prevalence of multiple intracranial and in-raspinal neoplasms, NF2 is also known as Multiple Inheritedchwannomas, Meningiomas, and Ependymomas Syn-rome.27 These are readily identified on contrast-enhancedRI.6 Schwannomas can be innumerable, showing as en-

ancing lesions involving multiple cranial nerves as well as

igure 9 A 21-year-old man with NF2 pre-enting with right ear deafness and right facialaralysis. (A) Axial and (B) coronal T1-weightedR images post GdDTPA show bilateral vestib-

lar schwannomas, which are larger on the rightide. The right-sided tumor has a large cerebel-opontine angle component, and both massesxtend into the internal auditory canals causingxpansion.

ithin the intradural compartment along the spinal nerveoots (Fig 10) and in the peripheral nerve sheath within thearaspinal regions (Fig 11A). Intraspinal schwannomas tendo grow as large dumbbell-shaped masses expanding the neu-al foramina, most commonly intradural extramedullary inocation but may be located extradurally or occupy bothompartments (Fig 11). They are characteristically bright on2-weighted images, with avid and homogeneous contrastnhancement (Fig 12) and at times a tendency of becomingystic. In contradistinction to neurofibromas, they do notave a malignant potential. Schwannomas displace but doot infiltrate the adjacent nerve roots; therefore, surgical re-ection is possible. Multiple meningiomas often occur in-racranially in the extra-axial compartment (Fig 13) and oc-asionally in the intraventricular location (Fig 14). They canlso be found in the spine as extramedullary masses. On a CTcan, they are slightly hyperdense, dural based, and may havessociated hyperostosis of the adjacent bone. On MRI, theyre typically isointense to gray matter on both T1- and T2-eighted images, with avid and homogeneous contrast en-ancement. In the general population, meningioma repre-

Figure 8 Brain lesions and associatedproton MR spectroscopic imaging find-ings in patients with NF1. (A) Glioma inthe splenium of the corpus callosumshows increased levels of Choline (Cho)consistent with a neoplasm. (B) UBO inthe midbrain just anterior to the quadri-geminal plate shows near normal metab-olite levels, in particular with no evidenceof increased Cho signal.

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ents a common extra-axial neoplasm most oftenncountered in older females, with its growth under the in-uence of estrogen. When meningioma occurs in a child, thessociation of NF2 should be considered. Finally, in NF2,here is a tendency of developing multiple ependymomashat typically present as intramedullary enhancing masses inhe spine (Fig 15) of the cellular histological type.28,29 Theyre well-circumscribed masses centrally located in the cord,sually exhibiting T1 isointensity and T2 hyperintensity rel-tive to the adjacent parenchyma, and are associated withtrong contrast enhancement.

Slso know as Bourneville disease, TS is characterized by a

riad of seizure, mental retardation, and facial angiofibromaadenoma sebaceum being a common misnomer). Seizuresffect more than 75% of TS patients, and there is also a highate of learning difficulties, cognitive impairment, and beha-orial problems.30-32 Similar to other phakomatoses, TS man-

igure 10 An 18-year-old female with NF2. Post-GdDTPA sagittal1 weighed image of the (A) cervicothoracic and (B) lumbar spinehow innumerable enhancing schwannomas along the surface of theord and nerve roots of the cauda equina.

igure 11 NF2. Post-GdDTPA axial T1-eighted images of the upper thoracic region

how (A) bilateral large extradural spinal schw-nnomas. Note multiple enhancing schwanno-as are also present in the posterior paraspinal

egions bilaterally. (B) In addition, there are en-ancing masses within the spinal canal in the

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fests as hamartomatous growths in multiple organ systemsncluding skin, heart, eye, kidneys, and lungs, in addition tonvolvement of the central nervous system. The prevalence isbout 1 in 6,000 to 10,000 births, with 60% to 70% cases ofporadic occurrence.33 It is an inherited disorder with anutosomal dominant trait. Chromosomal abnormality haseen localized to 9q34, encoding TSC1 or hamartin,34 and to6p13.3, encoding TSC2 or tuberin.35 Both gene productsorm a cytoplasmic protein heteromeric complex and act asumor suppressors affecting the regulation of cellular growth,dhesion, and migration.36,37

Intracranial findings clearly show malformations as a re-ult of perturbed proliferation, histogenesis, and migration ofeuronal and glial cells.38,39 The hamartomatous lesions cane found anywhere from the ependymal surface to the cortex,nd are composed of abnormal giant or balloon cells that mayxhibit features of astrocytes, neuronal cells, or intermediateorms. These lesions include subependymal nodules, corticalnd subcortical tubers, and subependymal giant-cell astrocy-oma.40,41 All 3 forms are considered the major features in theevised diagnostic criteria from the Tuberous Sclerosis Com-lex Consensus Conference in 1998,42 making imaging an

mportant part of establishing the clinical diagnosis. In theevised criteria, 2 major features or 1 major plus 2 minoreatures are diagnostic; fulfilling 1 major and 1 minor features considered probable TS. In addition to these typical find-ngs, white-matter signal abnormalities reflecting “migrationines” can be seen as bands of myelination defect or glio-is.43,44

The MR appearance of these major lesions varies withge.38,45 In the perinatal to early infancy periods, they are besteen as T1 bright lesions, including the white-matter lineslong the trail of radial glia and migrating neurons (Fig 16).ater in life, the subependymal nodules are often calcifiednd may be depicted on T1-weighted images as isointensityo mild hyperintensity and mild T2 hypointensity. Corticalnd subcortical tubers as well as white-matter migration linesre best seen on long TR sequences, particularly fluid-atten-ated inversion recovery (FLAIR).Subependymal nodules represent disorganized glial and

euronal elements and can be found lining the ependymalargin and protruding into the ventricular system, yielding

n appearance of “candle guttering” (Fig 17). Even thoughhese nodules show signal intensity similar to gray matter,

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hey are slightly hyperintense on FLAIR, probably reflectingncreased water content.46 Not infrequently, these nodulesalcify, best seen on CT scans, but also found on MRI, causingephasing or loss of signal intensity, particularly on suscep-ibility weighted images. Some of these nodules enhance

igure 13 NF2 patient with (A) bilateral seventh and eighth nerveomplex masses representing vestibular schwannomas and a lobularxtra-axial enhancing mass reflecting a meningioma along the rightreater wing of the sphenoid that extends intraorbitally resulting inproptotic right eye.

igure 14 A 14-year-old girl with NF2 shows (A) bilateral intra-analicular vestibular schwannomas and (B) an intensely enhancing
ntraventricular meningioma in the right lateral ventricular trigone. l
ith GdDTPA without indicating any increased neoplasticotential. There is a 5% to 14% estimated risk of developing

ntracranial neoplasm–giant-cell astrocytoma (Fig 18) fromhe subependymal nodule that is located at the foramen of

onro, often resulting in obstructive hydrocephalus. Histo-ogically, this again represents a mixture of varied glioneuro-al phenotypes with dysplastic-appearing giant cells.4 It is aiscrete, low-grade neoplasm of World Health Organizationlass I amenable to surgical resection. Subcortical and corti-al tubers similarly represent a disorganized cluster of glion-uronal elements, with variable degrees of differentiation,nd have a strong association with epilepsy, particularlyanifesting as infantile spasms and generalized tonic-clonic

eizures. They typically show areas of hyperintensity on longR sequences located in the subcortical white matter, with-

Figure 12 NF2 patient with radioculopa-thy. (A) Axial T2-weighted and (B) axialpost-GdDTPA T1-weighted images show adumbbell-shaped T2 hyperintense masswith intense enhancement, characteristic ofa schwannoma. In this case, the mass is ex-tradural in location, expanding the left neu-ral foramen and causing flattening of the the-cal sac on the left side.

igure 15 NF2. (A) Sagittal T2 and (B) post-GdDTPA sagittal T1-eighted images of the cervical and thoracic spine show multiple

ntramedullary masses, most concentrated in the cervical region,eflecting multiple ependymomas. A number of additional enhanc-ng lesions along the surface of the cord and cauda equina are most
ikely intradural schwannomas.

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ut associated mass effect or enhancement.38,40,44 They maylso calcify (Fig 19). The associated white-matter signal ab-ormality at times shows a linear or wedge-shaped trackxtending from the ventricular surface. This is thought to

igure 16 TS. A 5-day-old male infantho had multiple cardiac masses previ-usly detected in utero. (A) An axial T1-eighted image reveals a large soft-tissueass abutting the left ventricle and dis-

lacing the heart to the right side. (B) Axial1-weighted images show multiple linearyperintense lesions along the subcorticalhite matter reflecting cortical/subcortical

ubers as well as small round lesions alonghe ependymal surface representing sub-pendymal nodules. Note that a morerominent lesion near the right foramen ofonro in the middle section is suggestive

f a subependymal giant-cell astrocytoma.ome of the white matter linear lines (eg, inhe right frontal and left parietal regions)re elongated and approximating the ven-ricles, characteristic of migration lines.

igure 17 A 7-year-old girl with TS. (A) FLAIR images show mul-iple hyperintense cortical and subcortical tubers. In addition, sev-ral small subependymal hamartomas are present, showing slightLAIR and T2 hypointensity likely reflecting calcification. (B) Axial1-weighted images before and after GdDTPA show that the sub-pendymal hamartomas are T1 hyperintense without additional en-

cancement, which is also consistent with calcific deposits.

epresent the trail of radial glial cells during the migrationnd proliferation process.

Variable forms of congenital anomaly have been reportedn association with TS, ranging from transmantle cortical dys-lasia and corpus callosum dysgenesis to findings of schizen-ephaly and hemimegalencephaly.38,47 Infratentorial abnor-alities can also be found (Fig 20), including cerebellar folia

r nodular white-matter calcifications, cerebellar hemispherend vermis agenesis or hypoplasia, enlargement of the cere-ellar hemisphere, and brainstem and fourth ventricle sub-pendymal nodules and tubers.39

Proton MR spectroscopy of cortical tubers and subependy-al nodules show decreased N-acetylaspartate/creatine

NAA/Cr) and increased myoinositol/Cr ratios. This patternas thought to reflect expression of immature neurons andlia or gliosis as a result of disturbed cell migration and dif-erentiation in TS.48,49 In addition to these similar findings,nother study correlated the detection of lactate to the re-ions of epileptic foci on electroencephalography (EEG) in 6atients.50 On diffusion-weighted imaging, cortical tubershow significantly increased apparent diffusion coefficientADC) values compared with normal controls.51,52 Further-ore, in a study of 4 TS patients who had unifocal interictal

pikes on EEG and magneticoencephalography, ADC wasignificantly higher in the 4 epileptogenic tubers than 18onepileptogenic ones, which in turn showed significantlyigher ADC compared with that in a normal-appearing cor-ex.53 These findings are yet to be confirmed in a larger seriespreferably with correlation of surgical outcomes). However,t would be of significant value if noninvasive imaging tech-iques can depict the primary epileptogenic focus in thoseatients being considered for surgical seizure management.Perfusion-weighted MR images in a child of multiple cal-

ified tubers in the subcortical white matter shows decreased

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verall perfusion compared with adjacent normal-appearinghite matter, and in some of the core of the calcified tubers,

here is virtually absent perfusion (Fig 21). Perfusion deficitn the tubers is confirmed in multiple prior radionuclidePECT and PET studies.54,55 A more specific radionuclidegent, alpha-[11C]methyl-L-tryptophan ([11C]AMT) assess-ng serotonin uptake was found to be useful in discriminatinghe epileptogenic from nonepileptogenic foci in TS patients.lthough multiple tubers show decreased glucose metabo-

ism on FDG-PET, there was a differential pattern of11C]AMT uptake; the tubers with increased uptake had aigh correlation with the epileptogenic foci detected on ictalEG.56 Moreover, resection of the high [11C]AMT-uptake

ubers allowed achievement of seizure-free outcome in chil-ren with TS, suggesting that AMT-PET can provide an ex-ellent test for presurgical patient selection and seizure local-zation.57

WW, also known as trigemino-encephalo-angiomatosis, isharacterized by a cutaneous port-wine stain typically in thephthalmic division of the trigeminal nerve distribution andntracranial leptomeningeal angiomatosis ipsilaterally.58

here are often ocular abnormalities as well, including con-

Figure 18 TS. (A) Noncontrast-enhanced head CT scforamen of Monro representing a subependymal giancalcified subependymal nodules. (B) FLAIR image showsA post-GdDTPA T1-weighted axial image shows avidastrocytoma. There is no hydrocephalus in this case.

enital glaucoma and choroidal angioma, affecting the sameide as the cutaneous capillary angioma. SW is relatively rare,ccurring in about 1 in 40,000. Although there are familialases, thus far no genetic link has been identified, and SW ishought to occur sporadically.59,60 Common neurologic man-festations in affected individuals include seizure, develop-

ental delay, cognitive impairment, visual field defect, head-che, and stroke-like symptoms.

The presence of facial port-wine stain at birth raises theuspicion of the diagnosis, but port-wine stain itself is a com-on cutaneous finding, and only 8% of individuals withort-wine stain have intracranial involvement that is charac-eristic of SW.61 Clinically, the expression of SW is variable.n 1992, Roach62 provided a classification scheme based onhe varying degrees of involvement as follows: type 1, classicnd the most common form, manifesting both facial andeptomeningeal angiomatosis with or without glaucoma; type, facial angioma and possible glaucoma, without intracranial

nvolvement; and type 3, leptomeningeal angioma but noacial angioma or ocular manifestation of disease.

Conventional MRI and CT scans have been useful in aidinghe diagnosis of SW and showing the extent of intracranialnvolvement.63 A CT scan best shows the classic tram-trackalcification of the cortex (Fig 22A), whereas MRI with con-rast provides the most sensitive means of depicting lepto-

ws a partially calcified intraventricular mass near thestrocytoma. Additional punctate calcifications reflectle cortical and subcortical tubers to best advantage. (C)

ast enhancement in the foramen of Monro giant-cell

Figure 19 A 7-year-old girl with TSpresenting with infantile spasm andautism. (A) Axial T2, (B) axial FLAIR,and (C) post-GdDTPA axial T1-weighted images show multiple calci-fied subcortical tubers that appeardark because of the dephasing effect.Additional noncalcified tubers can beseen in (A) and (B) in the subcorticalwhite matter and centrum semiovale.There is no associated edema, mass

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eningeal enhancement that is considered the hallmark ofhe disease (Fig 22B), in addition to cortical atrophy.64,65 Theeptomeningeal angiomatosis represents embryonic venouslexus that is normally present during 4 to 8 weeks of fetal

ife. The failure of regression and lack of development oformal cortical veins results in ineffective venous drainage,enous stasis and hypertension, and subsequent ischemia ofhe underlying brain.58 In the early stage of disease, involve-ent is most frequently seen in the parietal and occipital

obes, sometimes followed by temporal and frontal lobes re-ulting in hemiatrophy of the brain. Bilateral involvementccurs in about 15% of cases.66 Post–contrast T1-weightedLAIR images have been advocated to better depict lepto-eningeal disease.67 It was found that these images show

eptomeingeal enhancement with greater conspicuity com-ared with the conventional post–contrast T1-weightedpin-echo images, probably by suppressing the vascular sig-als (Fig 23). In addition to pial angiomatosis that showsnhancement, there are frequently choroidal glomi andransmedullary venous angiomas that likely form a collateralenous drainage pathway because the cortical venous systems dysplastic. These transmedullary veins and surface angio-

igure 20 Wedge-shaped cerebellar hamartomas shown on (A) T2nd (B) FLAIR images in a 7-year-old girl with TS.

igure 21 Dynamic contrast-enhancedusceptibility weighted MR perfusion inuberous sclerosis. Multiple calcifiedubcortical tubers are best depicted onusceptibility weighted (T2*-weightedradient echo) sequence, whereas non-alcified tubers are seen on FLAIR. Theight-hand panel of signal intensity ver-us time plot shows decreased perfusionithin the subcortical tubers (white box

nd plot) or nearly absent perfusion (yel-ow box and plot). (Color version of fig-re is available online.)

atosis can be exquisitely depicted using long echo timeusceptibility weighted gradient-echo MRI or high-resolu-ion MR venography (Fig 24). This sequence uses the intrin-ic contrast of venous blood that is rich in deoxyhemoglobinhat appears dark in the background of the brain parenchymaecause of T2* dephasing effect.68,69 By use of this particularequence, there has been a report of earlier detection of evolv-ng leptomeningeal angiomatosis in an infant with SW beforet is evident on post–contrast T1-weighted images.70

Nuclear medicine studies including PET and SPECT haveraditionally been used to assess functional hypoperfusion inW as a result of anomalous venous development. Cerebralerfusion imaging using Technetium-99m hexamethylpro-yleneamineoxime SPECT have shown hypoperfusion in therea of vascular malformation that is at times more extensiveompared with abnormalities depicted on CT scans andRI.71,72 It is suggested that functional measures may beore sensitive for the early diagnosis of the disease because

everal cases showed that the perfusion (estimated by usingPECT) and metabolism (assessed by using FDG-SPECT)lterations were evident before the development of structural

igure 22 A 15-year-old boy with SW. (A) A noncontrast-en-anced CT scan shows tram-track calcification of the left parietal-ccipital cortex. (B) A post-GdDTPA T1-weighted MR image showseptomeningeal enhancement in the similar region.

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bnormalities.73 Reductions in perfusion and glucose metab-lism also corresponded to the patterns of neurologic deteri-ration in these patients.74 In addition, a relationship washown between seizure frequency, lifetime number of sei-ures, and hemispheric area of asymmetric cortical metabo-ism. More recently, perfusion deficits in SW have also beenxamined by using dynamic contrast MR perfusion tech-ique (Fig 25), similar to that typically used in evaluatingcute cerebral infarction.75 This allows a simple yet compre-ensive examination in the same MR study that is used toelineate structural abnormality in SW patients, to avoid theisk of ionizing radiation, and to provide information onbnormalities caused by either the arterial or venous phase.

Proton MR spectroscopy depicts abnormalities of metabo-ites, providing an independent functional assessment ofhese patients. Typically in older SW children correspondingo the region of cerebral atrophy, a decreased NAA is identi-

igure 23 Post-GdDTPA FLAIR images in a 2-year-old boy withW show enlarged choroid glomi on both sides as well as leptomen-ngeal enhancement in the bilateral occipital regions. Also noted inhis case is the left frontal osseous thickening.

Figure 25 A dynamic contrast enhanced susceptibilitysponding to marked cortcial atrophy and leptomeninhypoperfusion (shown as prolonged mean transit time, Mis in seconds (range 0 to 40), with increasing MTT rep
change of the inverse transverse ralaxation time T2*. (Color ve
ed suggesting neuronal dysfunction or loss (Fig 26).56,76 Athe early stage of disease and (eg, during the first few years ofife), however, the NAA level has been found to be normal,hereas choline is slightly elevated, perhaps reflecting ab-ormal development or myelination.75

HLlso known as retinocerebellar angiomatosis, VHL is inher-

ted as an autosomal dominant trait with variable pen-trance.77,78 The incidence is about 1 in 36,000.79 The abnor-ality has been localized to chromosome 3p25-p26,80 which

ncodes a tumor suppressor as a regulator of hypoxia-induc-ble genes.81 Although most affected individuals inherit thebnormality, 20% are caused by a spontaneous mutation.he symptoms usually manifest in the second to third decadef life. In VHL, patients present with congenital capillaryngiomatous harmartomas in the CNS, including cerebellar

igure 24 Susceptibility weighted image, or 3-dimensional bloodxygen level dependent (BOLD) venography, shows abnomal lep-omeningeal angioma along the right temporal lobe in a 17-year-oldale with SW. This sequence prominently depicts numerous small

ortical and deep veins in the brain.

ted MR perfusion in a 4-year-old girl with SW. Corre-giomatosis in the left parietal lobe, there is markedd venous stasis (magenta box and plot). The MTT scale

ng slower flow. In the y-axis, delta R2* represents the

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Figure 26 Magnetic resonance spectroscopic imaging (MRSI) of the same girl as in Figure 25. Corresponding toatrophic left parietal lobe, there is reduction of all metabolites (Cho, choline), in part reflecting volume averaging with
adjacent CSF. In addition, the NAA is markedly diminished reflecting neuronal loss or dysfunction.
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igure 27 A 23-year-old woman with VHL presenting with head-che. (A) Axial T2-weighted and (B) post-GdDTPA T1-weightedmages show a left cerebellar cystic mass with an enhancing muralodule, associated with surrounding vasogenic edema, compres-ion of the left dorsolateral pons, and effacement of the fourth ven-ricle. (C) Axial T2-weighted and (D) post-GdDTPA T1-weightedmages at the level of the C1-2 junction show another mixed cysticnd solid mass in the right aspect of the cord. Both tumors were
emangioblastomas. p
igure 28 A 30-year-old man with VHL. (A) A post-GdDTPAagittal T1 weighted image shows multiple enhancing hemangio-lastomas in the cerebellum and within the cord. (B) An axial2-weighted image shows a peripherally located intramedullaryystic hemangioblastoma expanding the cord. Multiple cysticasses are present in the kidneys. (C) Magnified view of the

onus shows a cystic hemangioblastoma with a central enhancingolid nodule and another small solidly enhancing one in the
roximal filum.

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emangioblastomas (44%-72%), spinal hemangioblastomas13%-50%), and retinal angiomas (25%-60%).77 Outside theNS, there is also multisystem involvement including renalysts that have a high incidence of developing into clear-cellenal cell carcinomas, pancreatic cysts and neuroendocrineumors, pheochromocytomas, and epididymal or broad lig-ment papillary cystadenomas.

In the CNS, hemangioblastoma occurs most frequently inhe cerebellum.77,82 It arises from endothelial origin and isery vascular. Initially, hemangioblastoma shows solid en-ancement and appears pial based and is therefore peripher-lly located in the cerebellum. When large, its appearance isost often cystic with an enhancing mural nodule (Fig 27),

nd the natural history of progression shows a faster rate ofystic expansion than growth of the causative solid tumor,ventually resulting in pressure effect and clinical symp-oms.83,84 At times, hemorrhage or prominent serpiginousascular flow voids can be found associated with the tumor.lthough solitary cerebellar hamangioblastoma can occur inny individual, multiplicity suggests the syndrome of VHL.mall tumors are often seen as solidly enhancing nodules thatay be difficult to distinguish from metastatic disease.Hemangioblastoma also occurs in the brainstem with a

imilar appearance, and in the spine as intramedullary le-ions. Because of the peripheral, pial-based location, at times,t is difficult to classify tumor location as intramedullary orxtramedullary. Focal expansile T2 hyperintense mass witholid enhancement (25%) or cystic with an enhancing nodules the typical appearance (Fig 28). There may also be associ-ted syrinx within the cord.84

igure 29 A 38-year-old woman with VHL, presenting with left-ided tinnitus and hearing loss. (A) An axial CT image of the leftemporal bone and (B) coronal CT image of both sides show aoft-tissue mass centered in the left cerebellopontine angle causingytic destruction of the petrous temporal bone. The soft-tissue masslso extends to the tympanic cavity. The mass was resected withistology revealing endolymphatic sac tumor.

Although rare, endolymphatic sac tumors occur with 1

igher frequency in VHL individuals, affecting about 10% ofatients.85,86 This is a very vascular and locally aggressiveumor that arises from the endolymphatic sac, which oftenauses lytic erosion of the petrous temporal bone resulting inensorineural hearing loss, disequilibrium, and aural fullnessFig 29).85,87,88

ummaryn summary, neuroimaging plays an important role in theiagnosis of the phakomatoses. Conventional, morphologic

maging techniques such as CT scans and MRI documentNS involvement including lesion size, distribution, and lo-ation; newer “functional” imaging techniques (for instanceased on perfusion or metabolism) offer further insights intoisease pathophysiology.

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