The Phakomatoses

James G. Smirniotopou/os1 and Frances M. Murphy

From the Armed Forces Institute of Pathology (JGS), Georgetown University (FMM , JGS), and the Veterans' Affairs Medical Center (FMM), Washington, DC

The phakomatoses are a heterogeneous group actual Greek word for lentil bean, and "phakitha," of disorders primarily involving structures derived which is Greek for "" or "spot." Perhaps from the embryologic neuroectoderm. However, "phakithatosis," which suggests the cutaneous they commonly exhibit associated pathology in lesions () common in these disorders, tissues derived from all three germ cell layers, would have been too hard to pronounce. None of most notably ectoderm (skin) and these derivations truly suggests an inherited or (connective tissue). All the phakomatoses involve congenital nature to the disorder. the (CNS); some also In 1920, the Dutch ophthalmologist van der affect the peripheral nervous system. Most are Hoeve first used "phakoma" to describe two dif­ associated with cutaneous signs, and many have ferent benign ocular lesions. One occurred in visceral and connective tissue (mesodermal) (NF) where there are occa­ changes. Since the eye is functionally and devel­ sional patches of myelinated nerve fibers in the opmentally part of the CNS, it is not surprising retina (vs the unmyelinated nerves normal to the that ocular/retinal involvement is common in the retina) (2). These lesions of NF produce a slight phakomatoses. Although all of the phakomatoses yellowish-white thickening on the retina. The are congenital, the inheritance patterns vary. other lesion, characteristic of Some are autosomal dominant, some autosomal (TS), is a benign, slowly growing hamartomatous recessive, and some may be due to abnormal proliferation of retinal that forms a development of the , rather than a genetic raised, yellowish-white mass superficially resem­ defect. bling the myelinated patch of NF. The lesions of The term "phakoma" implies a benign growth TS resemble dried lentils ("phaki"), which usually of normal or nearly normal cells that are indige­ are small hemispheric pieces 3-5 mm in diame­ nous to the involved tissue; it may be likened to ter. Calling both these lesions "phakomas," van the term "." The word phakoma is der Hoeve then assumed that TS and NF were usually described as being derived from the Greek related diseases, and coined the term "phako­ "phakos"- a word whose meaning is erroneously matoses" as the umbrella or rubric for congenital generalized to include "mother spot" (birthmark?) disorders affecting the CNS with benign growths. and "lentil," as well as its true meaning which is Later, he enlarged this concept to include other "lens" or "eye" (1). However, similar sounding conditions characterized by CNS, cutaneous, and words that could have been used to form the often ocular involvement, eg, Sturge-Weber syn­ prefix for the "-oma" include "phaki," which is the drome (SWS) and von Hippel-Lindau disease. Although authorities debate the logic of this grouping, some 20 to 30 other disorders have The opinions and assertions presented herein are solely those of the authors, and do not necessa rily reflect the views of the Department of the now been classified as phakomatoses. This article Army and the Department of Defense. briefly reviews the clinical and imaging features 1 Address reprint requests to Editorial Office, Armed Forces Institute of the four most common and best described of of Pathology, Washington, DC 20306-6000. these disorders: encephalo-trigeminal-angioma­ Index terms: Phakomatoses; Pediatric neurorad iology tosis (Sturge-Weber syndrome); tuberous scle­

AJNR 13:725-746, Mar/ Apr 1992 0 195-6 108/ 92/ 1302-0725 rosis (Bourneville disease, Pringle disease); neu­ © American Society of Neuroradiology rofibromatosis type 1 (von Recklinghausen dis- 725 726 AJNR: 13, March/ April1992

A 8 Fig. 1. Sturge-Weber syndrome; gross photographs of the fa ce; two pa­ tients. A and B, Frontal (A) and right lateral (B) views of a young infant show a port-wine nevus involving all three divisions of the trigeminal nerve on the right and two divisions on the left. C, Frontal open mouth view of a young adult shows extensive port-wine nevus involving all three divisions of the trigeminal nerve, including the mucosa of the hard palate (arro w).

c ease, "peripheral" neurofibromatosis); and drome is the vascular lesion that involves the neurofibromatosis type 2 (bilateral acoustic neu­ territory of the trigeminal nerve (CN V) plus the roma, "central"neurofibromatosis). ipsilateral brain and . Typical patients exhibit a dark red or reddish-brown "port-wine" stain or nevus ("nevus flammeus") on the face in Sturge-Weber Syndrome the trigeminal territory {Fig. 1), a seizure disorder, Sturge-Weber syndrome (SWS) is a congenital and mental deficiency. From among many var­ disorder of the vasculature of the face, the men­ iants, Roach et al codified three basic forms of inges, the brain, and often the eye. It is sometimes SWS: type 1 (classic SWS) with both facial and called "encephalofacial" or "encephalotrigeminal" intracranial manifestations; type 2, with only the , because the hallmark of this syn- facial lesion, and no central changes; and type 3, AJNR: 13, March/ April 1992 727

and is not visualized at all on plain films. Angiog­ raphy may reveal the LV M, but is less sensitive than MR. The secondary changes of cortical atro­ phy and calcification can be identified on both MR and CT, and, after the age of two, on plain films. The inheritance pattern of SWS has been de­ scribed as both autosomal dominant and auto­ somal recessive. It may not necessarily be inher­ ited from either parent, but may result instead from an abnormal pattern of development. The Sturge-Weber Foundation now supports research efforts to collect peripheral blood specimens from a large number of affected individuals to discover an underlying causal genetic defect. Patients with SWS are often neurologically intact at birth; the diagnosis is suspected only because of the port-wine nevus. There is high of seizure activity (up to 90% ), which is often the presenting feature in a patient with a port-wine nevus. Focal or generalized seizures usually begin in the first year of life. Generalized seizure activity may be preceded by hypsarrhyth­ Fig. 2. Sturge-Weber syndrome; coronal brain section. The mia, which is characterized as "infantile spasms" right hemisphere is atrophic and the right lateral ventricle is or massive myoclonus (1). The growing infant enlarged. may then show developmental delay. Many pa­ tients will have homononymous hemianopsia similar to type 1, but without facial lesions (3). from involvement of the occipital lobe ipsilateral However, since facial port-wine nevi occur as to the PWS. Patients may also develop paresis or isolated findings in up to 90% of patients, type 2 plegia contralateral to the LV M. In the absence of patients without CNS findings should probably be normal stimuli from motor activity, the contralat­ considered a dermatologic curiosity, not a variant eral portion of the body may develop poorly or of SWS, even though the lesions may have similar become atrophic; neurological development may etiologies (4). Pathologically the vascular lesion fail to progress. However, many patients will of the face is a plethora of cutaneous vessels with initially achieve neurologic milestones, only to slowly flowing deoxygenated blood. They are lose them later as a consequence of the frequent small, thin-walled structures that resemble telan­ seizures, or as the regions of cerebral involvement giectatic capillaries or venules. become more extensive. The intracranial lesion of SWS is a leptomen­ The pathogenesis of SWS is unknown. Most ingeal vascular malformation (LV M) similar to the theories consider abnormal embryology at an facial lesion, and ipsilateral to it. The LV M also early stage, when there is a primordial vascular consists of simple vascular structures that lie mesenchyme for both the cephalic ectoderm and along the surface of the brain in the subarachnoid the underlying neural tube. Streeter described the space between the pia and the arachnoid mem­ progressive lamination of the cephalic vascul-ar branes. The cerebral cortex underlying the areas plexus into separate systems for the neural tube of LV M usually becomes dysfunctional, progres­ (the cerebral circulation), the dura and calvarium, sively atrophic (Fig. 2), and calcified. and the skin (6). If a defect occurred at this time The minimum clinical and diagnostic criteria (Streeter's stage 3-5, gestational weeks 4-8), the for SWS would require the presence of the intra­ lesion would be carried forward by differential cranial LVM, seen in Roach's types 1 and 3. The growth and morphogenesis, and present ante­ most sensitive test for revealing the intracranial riorly in the superficial structures of the skin and LY M appears to be magnetic resonance (MR) eye, and yet still affect the posterior (parieto­ imaging (5). The LV M itself is less commonly occipital) regions of the deep structures of the seen on computed tomography (CT) than on MR, meninges and cerebral hemispheres. One theory 728 AJNR: 13, March/ April1992 holds that the malformation results from a lack plexus seen ipsilateral to the facial and leptomen­ of vascular differentiation into arteries, capillaries, ingeal lesions. and veins as well as a lack of lamination into Because of poor venous drainage, the cerebral separate cerebral, dural, and cutaneous circulation in the affected areas becomes meta­ circulations. bolically insufficient over time. Rather than acute A simpler theory suggests that the primary infarction, there is slow, almost cell-by-cell, death defect in SWS occurs early during lamination, of the tissue, accompanied by the deposition of when there should normally be a persistent con­ calcium. The calcium deposits begin in the sub­ nection between the developing cortical veins cortical white matter, the middle layers of the (cerebral circulation) and the superior sagittal cerebral cortex (No. 2-4), and the walls of small sinus (dural/calvarial circulation). If the differen­ intracerebral vessels (7, 8). As the patient ages, tiation and separation of these two circulations and the hemodynamic compromise persists (or fails to maintain this communication, then the becomes more severe and extensive), there is a venous outflow from the cerebral cortex will be continued loss of tissue, until only a calcified impaired. The primitive vascular plexus will per­ shriveled layer of cerebral cortex remains (Fig. sist as a collateral pathway for venous drainage 4). After the cortex is reduced to a nonfunctional (Fig. 3). Such a derangement would usually be calcified mantle, the overlying LV M eventually unilateral , as is most common in SWS, since the regresses, since its source of blood-the capillar­ superior sagittal sinus and the superficial "bridg­ ies of the brain-are no longer perfused. ing" veins develop independently in the two hem­ Typically, the intracranial LV M and the paren­ ispheres. Absence of normal cortical venous chymal lesions of Sturge-Weber are unilateral and drainage could also lead to collateral venous flow supratentorial, overlying the parieto-occipital re­ from the cerebral cortex via the deep medullary gion. However, the area involved may extend veins to persistent simple vascular channels in from the posterior hemisphere anteriorly, to in­ the developing . The end result volve the temporal and even the frontal lobes. would be the enlarged "angiomatous" choroid Occasional cases show bilateral involvement of the posterior portions of both hemispheres. Some patients have lesions similar to SWS, but affecting only focal areas of the cerebral hemisphere and not involving the parieto-occipital regions. In the absence of any mental deficiency, ocular, or facial changes, these focal abnormalities should not be assumed to be variants of SWS. They may indeed represent other conditions, eg, meningioangiom­ atosis-which is more commonly focal, and is associated with NF, not SWS. Meningioangiom­ atosis is a proliferation of meningeal tissue, as well as blood vessels. It may cause superficial cerebral laminar calcifications just like SWS, but unlike the LVM of Sturge-Weber, meningioan­ giomatosis infiltrates into the underlying brain. Ocular lesions are seen in about one-third of SWS. They consist of a scleral vascular malfor­ mation akin to the lesions of the face and lepto­ meninges: multiple small thin-walled vascular spaces that affect the sclera of the eye (9). Ten to 30% of the patients are also born with buphth­ almos (literally "cow eye"), which is a large globe, often with increased tonicity. This is a form of Fig. 3. Sturge-Weber syndrom e; low-power photomicrograph congenital glaucoma. Almost invariably, the from a young patient. Multiple small vascular channels lie in the buphthalmos is ipsilateral to both the facial nevus subarachnoid space (arrows) between the arachnoid and the surface of the brain. This angiomatous malformation is limited to and the intracranial LV M. Although the sclera and the leptomeninges, and does not involve the brain itself. Atrophy choroid of the eye may have a capillary telangi­ and calcifications have not yet developed in this young patient. ectasia identical to the leptomeningeal angioma, AJNR: 13, March/April 1992 729

matomes in an irregular fashion. The same telan­ giectatic vascular change may extend from the skin to involve the linings of the paranasal si­ nuses, and may precipitate or aggravate epistaxis. Patients with SWS usually do not have thoracic or visceral findings. However, there can be an association of SWS with Klippel-Trenaunay syn­ drome (KTS) (angio-osteo-hypertropy-over­ growth of bone and vessels). The combined dis­ ease is then referred to as Klippel-Trenaunay­ Weber syndrome and exhibits the typical findings of KTS, facial and leptomeningeal vascular mal­ formations, and the secondary sequelae of cere­ Fig. 4. Sturge-Weber syndrome; low-power photomicrograph bral atrophy, calcification, and loss of somatic from an older patient. The cortex shows marked atrophic thinning function. and heavy calcification (small arrows). The blue-gray nodules are Imaging evaluation of suspected SWS includes mineralizations in the form of "calcospherites." Only a few dilated plain skull films, CT, angiography, MR and posi- vessels, remnants of the leptomeningeal angioma, remain in the subarachnoid space. X-rays passing along the line of the large arrow will create multiple parallel curvilinear densities called "tram­ track" calcifications (see Fig. 5). The angiomatous vessels are too small to explain the "tram-tracks." They are dwarfed in compari­ son to the size of the sulcus between the calcified banks of the two apposing gyri. the retina itself is usually unaffected. Therefore, patients with SWS usually do not have ocular blindness. The variable visual symptoms are usu­ ally related to atrophy and calcification of the occipital visual cortex. The cutaneous manifestations of SWS are usu­ ally limited to the telangiectatic vessels that pro­ duce the port-wine stain of the skin, and to secondary changes of fibrous and spongy thick­ ening of the skin. The port-wine color is due to the presence of deoxygenated blood within the vascular spaces. The color will blanch with finger pressure. Only 10% of patients with a facial port­ wine stain will have either ocular or pial angiomas and/or SWS (4). In both sporadic and SWS cases, the port-wine stain usually conforms roughly to the sensory dermatomes of the three branches of the trigeminal nerve. The risk of associated SWS is higher when the medial aspect of the upper eyelid is affected (a portion of the CN V1- ophthalmic nerve dermatome) and highest when the entire V 1 dermatome is affected, with or without extension to the other divisions. The risk is lowest when the only areas affected are inferior to the upper lid, ie, the lower portion of the ophthalmic division of the trigeminal nerve, or only the mandibular (V2) or maxillary (V3) trigem­ inal divisions (4). The stain does not always con­ Fig. 5. Sturge-Weber syndrome; plain skull radiograph dem­ form exactly to the trigeminal territory. It may onstrates classic occipito-parietal "tram-track" calcifications cross the midline and involve other sensory der- within the substance of the atrophic cerebral cortex (see Fig. 4). 730 AJNR: 13, March/ April 1992

tron emission tomography (PET). Plain skull films widely spaced to be in the LVM itself, which has reveal indirect evidence of brain changes in SWS, vascular channels that are usually on the order ipsilateral to the facial lesion. There are multiple of hundreds of microns in diameter (140 units), curvilinear parallel densities along the posterior with occasional larger veins identified ( 10). The cortical surface of the atrophic hemisphere, called cerebral calcifications are parenchymal, in corti­ "tram-track" or "railroad track" calcifications (Fig. cal layers 2-4, as well as in the walls of small 5). The parallel calcifications represent apposed cortical arterioles. However, the arteriolar calcifi­ gyri. The intervening lucency is the cerebrospinal cations are only a minor component of the overall fluid-filled sulcus that is enlarged from gyral atro­ density. Cerebral cortical calcifications have phy. The radiographic calcifications are too rarely been reported at birth. In most patients, calcifications are first detected on plain films after age 1-2 years (earlier on CT), usually in the parieto-occipital area. As the disease progresses, the density and geographic extent of the calcifi­ cations increase. The skull develops asymmetrically and the calvarium thickens on the side of the lesion with increased diploic space, increased pneumatization of the paranasal sinuses, elevation of the petrous ridge, and elevation of the lesser wing of the sphenoid as ipsilateral compensatory changes due to the cerebral atrophy. This constellation of calvarial changes, called Dyke-Davidoff-Masson syndrome, is a nonspecific reactive or compen­ satory process that may occur from many differ­ ent causes of congenital or early acquired cerebral hemiatrophy (11). Angiography generally demonstrates abnormal circulation with an absence or paucity of normal Fig. 6. Sturge-Weber syndrome; 9-month-old infant. Noncon­ cortical veins in the affected area. There are slow trast CT demonstrates slight atrophy of the right hemisphere, widened sulci, and calcification within the deep cortex and sub­ flow/transit through the affected region, poor cortical white matter. opacification of the superior sagittal sinus, prom­ inence of the radially oriented medullary veins, and increased (yet slow) flow through the sub­ ependymal region into the deep central veins (12- 14). These findings are consistent with the con­ cept that the primary process in SWS is an abnormal cortical capillary venous drainage, with 1) persistence of the embryologic surface plexus as collateral venous drainage in the subarachnoid space, and 2) reversed flow from the cortex centripetally into the deep medullary veins to the choroid plexus. However, the angiographic ob­ servations have also been interpreted as consist­ ent with other theories of pathogenesis, eg, that SWS is primarily (rather than secondarily) a per­ sistence of the primordial vascular plexus. CT, and now MR, have supplanted plain films and angiography for the diagnosis and evaluation of patients suspected of having SWS (15-20). Because CT is about 1500 times more sensitive Fig. 7. Sturge-Weber syndrome. Noncontrast CT shows re­ to attenuation differences compared to plain markably dense calcifications bilaterally. The left lateral ventricle is enlarged, and the occipital cortex has been reduced to a calcified films, and will detect smaller amounts of cerebral shell. calcification in younger patients, CT is preferable AJNR: 13, March/ April 1992 731 to plain films in the early evaluation of suspected hemispheres may represent slowly flowing blood SWS (Figs. 6 and 7). Noncontrast CT will dem­ within the malformation in the subarachnoid onstrate the cerebral atrophy, the calvarial thick­ space; alternatively, the enhancement may be in ening, and the cortical calcifications. It may show the substance of the cerebral cortex, as a re­ subcortical white matter calcification. Contrast­ sponse to chronic injury from ischemia (Fig. 9) . enhanced CT may also demonstrate superficial Chamberlain et al also reported that MR revealed meningeal enhancement and enlargement of the areas of abnormal migration associated with LVS . choroid plexus ( 19). These were seen as areas of abnormally thick­ MR will also demonstrate the atrophy, calvarial ened cortex with few sulci (18). Elster et al have changes, and enlargement of the choroid plexus suggested that gradient images should be used (Fig. 8). Chamberlain et al (18) and Wasenko et to accentuate small regions of calcifications (15). al ( 17) reported that MR and CT were compli­ PET scanning has been used to assess cerebral mentary and relatively equal in making the diag­ metabolism in SWS. The affected area is typically nosis of SWS. However, Lipski et al (16) and hypometabolic. However, in the early stages, it Stimac et al (19) have emphasized the usefulness may have increased metabolism (21 ). Chugani et of the increased sensitivity when MR is performed al have also suggested that the sensitivity of PET with contrast enhancement. On MR, superficial may be helpful in planning surgical management enhancement along the surface of the cerebral directed at resecting the abnormal tissue (21). The lifespan and quality of life for patients with SWS has improved over the years. The neuro­ logic prognosis in these patients is dependent primarily on seizure control and whether or not the cerebral atrophy is limited or becomes more extensive as the patient ages. Seizure control is paramount, since the major morbidity results from the complications of . These com­ plications include accidental trauma during a sei­ zure, and damage from hypoxic/ischemic epi­ sodes. Seizure management is usually restricted to medical treatment. However, in situations where the deleterious effects of intractable sei­ zures dominate the picture, lobectomy and even hemispherectomy have been performed. Many patients do very well postoperatively and may even be cured after surgery. Because of the Fig. 8. Sturge-Weber syndrome. T2 MR shows left parieto­ plasticity of the cerebrum, their postoperative occipital atrophy with widened sulci. neurologic deficits may be much smaller than

Fig. 9. A and 8 , Sturge-Weber syn­ drome. A xial (A) and coronal (B) gadolin­ ium-enhanced Tl MR shows serpentine/gyr­ iform enhancement in the parieto-occipital area and an asymmetrically smaller left hem­ isphere.

A B 732 AJNR: 13, March/ April 1992

expected (22). Accidental trauma related to men­ tal handicaps can also occur. Cosmetic treatment to remove the stigma of the facial angioma in­ cludes laser therapy for ablation, opaque makeup, and opaque tattooing. In summary, the CNS manifestations of SWS include 1) loss of cerebral cortical tissue (atrophy), commensurate loss of visual, motor and sensory function, and mental impairment; 2) secondary changes in the calvarium; 3) electrical hyperex­ citability and seizures; and, 4) progressive depo­ sition of calcium in the affected cortex and sub­ cortical white matter. These are all due to im­ paired venous drainage from the cerebral cortical capillaries, which also allows a primitive vascular plexus to persist in the subarachnoid space. Deoxygenated blood in a similar plexus of vessels in the skin of the face, usually in the trigeminal Fig. 10. Tuberous sclerosis. Preoperative photograph of a 7- year-old boy demonstrates multiple reddish papular masses on distribution, gives the skin a port-wine dis­ the face in a bimalar "butterfly" distribution. Histologically these coloration. are angiofibromas, composed of vascular spaces and . Tuberous Sclerosis Tuberous sclerosis (TS) is an autosomal dom­ inant disorder, with no racial or sexual predilec­ tion. The rate of spontaneous ap­ proaches 60%, thus many affected individuals will have no family history nor affected first­ degree relatives. The incidence of TS has been reported to be as high as 1 in 10,000 live births. However, the prevalence in the adult population is lower, about 1 in 20,000 (23, 24). The genetic abnormality has been reported to be a deletion from chromosome 9, although other chromo­ somes, including 11, have also been implicated (25, 26). The suspect chromosomes probably contain "tumor suppressor ." The deletion may then predispose the patient to the develop­ ment of various tumorous growths, some of which are "," others true (usually be­ nign) neoplasms. von Recklinghausen was the Fig. 11. Tuberous sclerosis; gross brain surface. Multiple gyri are enlarged focally (asterisks) by "potato-like" cortical tubers. first to describe patients with tuberous sclerosis These are hamartomas. (1862), but the eponym commonly applied is "Bourneville" disease, after the French physician occurs in less than one-third of all TS cases, and who studied and published the cases of several some patients have none of the three classic affected individuals. TS is sometimes called features (27). Past reports have particularly over­ "cerebral sclerosis," as well as "epiloia," a neolo­ estimated the incidence of mental deficiency by gism contracted from the two most common including large numbers of institutionalized features of this disorder: epilepsy and anoia patients. (mindlessness). - Gomez divided the diagnostic features of TS TS was originally defined by Vogt' s clinical into primary and secondary criteria (27). The triad of adenoma sebaceum, epilepsy, and mental presence of one primary criterion permits a firm deficiency. However the modern definition of TS diagnosis of TS (modified from Gomez) (27): does not require that all three elements of the adenoma sebaceum (facial angiofibroma); ungual classic triad be present. Indeed the complete triad fibroma; cerebral cortical tuber; subependymal AJNR: 13, March/April1992 733 nodule (hamartoma); and fibrous forehead , the ocular phakoma of TS may plaque. be multiple and bilateral, and may contain calci­ A firm diagnosis of TS can also be made when fications that are detectable clinically, by ultra­ the patient exhibits two or more of these second­ sound and by CT. The phakoma of TS is most ary features: infantile spasms (hypsarrhythmia); often an asymptomatic lesion, but can cause loss hypopigmented macules; shagreen patch; retinal of vision. hamartoma (phakoma); bilateral renal cysts or The brain lesions in TS are almost always angiomyolipomas; cardiac rhabdomyoma; and benign hamartomas. They have been variously first degree relative with TS. described as low-grade benign neoplasms, clus­ In addition to these clinical criteria there are ters of heterotopic within the white mat­ also primary imaging criteria for the diagnosis of ter, and regions of gliosis or abnormal TS. A definitive diagnosis can be established (destruction/) (28-30). Bender and Yu­ when CT / MR identify either multiple subepen­ nis suggest that the same cellular components dymal nodules (especially with calcification) or are present in all the parenchymal brain lesions when multiple cortical abnormalities with calcifi­ in TS, that they represent a combination of both cation and subcortical white matter edema are neuronal and astrocytic features, and that they noted. A presumptive diagnosis of TS can be result from disordered migration and differentia­ made when imaging reveals an intraventricular tion (30). The gross lesions only vary in location tumor consistent with a subependymal giant cell (peripheral or deep) and size (nodule or tumor). , focal wedge-shaped calcifications The hamartomas occur in two prominent loca­ in the cerebral or cerebellar cortex, or multiple tions: on the surface as superficial cerebral cor­ cortical/subcortical foci of edema. Once the di­ tical "tubers" (Fig. 11) and as deep subependymal agnosis of TS is established by clinical or patho­ nodules (SEN). Fewer than 20% of patients also logic means, an attempt should be made to eval­ have cerebellar tubers. The histology of the ha­ uate all the first-degree relatives to determine the martomas is similar in both locations. They con­ family pedigree, identify those at risk for having tain unusual large cells, along with gliosis (astro­ the disease, and establish a protocol for serial cytosis) and demyelination (28). The large cells follow-up evaluation of the affected individuals. may show both neuronal and astrocytic differ­ The cutaneous manifestations of TS include entiation (29). The cortical tubers are typically the facial angiofibroma or "adenoma sebaceum" large and pale compared to the surrounding nor­ (Fig. 10); localized subepidermal fibrous skin mal gyri. The tubers may contain giant neurons thickening-the "shagreen patch" nail-bed an­ and lack the normal six-layered lamination of the giofibroma (subungual/periungual fibroma); and cortical gray matter. The gliosis and absence of hypomelanotic macules of diverse size and shape, myelin present in the cortical tubers may extend including the characteristic "ash-leaf spot." The into the underlying subcortical white matter. most common finding is the hypomelanotic ma­ The subependymal nodules (Fig. 12) are typi­ cule, which is present in over 90% of patients cally located along the lateral borders of the examined thoroughly with an ultraviolet lamp. ventricles, in the striothalamic groove between Adenoma sebaceum may be absent in the major-· the caudate nucleus and the thalamus. Multiple ity of patients (up to 53%) (27). adjacent subependymal nodules resemble drip­ The ocular findings of TS are dominated by ping wax, hence the nickname "candle gutterings" the hallmark lesion of one or more benign retinal for the pneumoencephalographic appearance of masses, the original "phakoma" of van der Hoeve. these lesions. Occasionally SEN are found in the These lesions are small, slightly raised usually frontal horns and the third ventricle. yellow-white plaques, that may be smooth or SEN are histologically benign masses of pri­ nodular with a "regularly irregular" surface pat­ marily astrocytic proliferation with mixed multi­ tern, like a mulberry. They may present in chil­ nucleated giant astrocytes and large spindle cells. dren as leukokoria. The phakomas are benign These cells may be arranged around blood vessels proliferations of astrocytes, without necrosis, in a pattern that is easily mistaken for the peri­ hemorrhage, or dissemination. They must be dif­ vascular pseudorosettes of an (28). ferentiated from nonneoplastic causes of leuko­ The SEN are sharply circumscribed, do not koria such as Coats disease and persistent hyper­ spread through the periventricular tissue, and are plastic primary vitreous, as well as from neo­ covered by an intact layer of . Miner­ plastic masses, notably retinoblastoma. Like alization, regions of piloid astrocytes, and promi- 734 AJNR: 13, March/ April 1992

their major morbidity through mechanical ob­ struction of the lateral ventricle(s) and hydro­ cephalus. They do not seed the , do not spread hematogenously, and do not spread through the white matter tracts. They may, however, be firmly embedded in the adja­ cent caudate nucleus. Complete resection may be curative, but surgical zeal is often tempered by the deep location of the lesion, and the pa­ tient's other clinical problems. Though histologi­ cally benign and slow growing, the SGCA directly (6/40) or indirectly (4/40) accounts for 25% of deaths due to TS (33). TS patients may also have prominent cardiac, pulmonary, renal, and occasionally hepatic in­ volvement. Multiple renal angiomyolipomas (Fig. 13) and/or benign cysts occur in about one-half to three-quarters of patients with confirmed TS; conversely, less than half (perhaps as few as 20%) of all patients with an angiomyolipoma meet the diagnostic criteria for TS (34, 35). The angiomyo­ lipoma is a benign hamartomatous mass com­ posed of blood vessels, smooth muscle, and ma­ ture adult fat. Angiographically and even histo­ logically, this disorganized arrangement of tissues is easily mistaken for a malignant. process, espe­ cially a or renal cell carcinoma (34-38). Both the cysts and the angiomyolipomas tend to be multiple and bilateral in TS. Whereas the sporadic angiomyolipoma is almost always a large solitary mass in a woman of reproductive age, the angiomyolipomas of TS are usually Fig. 12. Tuberous sclerosis. Axial brain section displays mul­ small, multiple, and bilateral. Although the angie­ tiple subependymal nodules (SEN) that arise along the striothal­ amic groove and protrude into the lumina of the lateral ventricles. myolipomas of TS shows a female predominance they also present in affected males. The solitary nent thick-walled capillaries are also common renal angiomyolipoma may be indistinguishable features. Histologically, the giant astrocytes of from other solid tumors. However, the imaging the SEN may be mistaken for the large anaplastic characteristics include: multiplicity and bilateral­ cells of , as well as for the plump ity, hyperechogenicity on ultrasound, fatty den­ cells of a "gemistocytic" astrocytoma. sity on CT, and a "whorled" nephrogram and Approximately 5%-15% of individuals with TS pseudoaneurysms, but no shunting, on arteriog­ will develop brain neoplasia, almost invariably raphy. The renal cystic disease of TS does not subependymal giant-cell astrocytoma (SGCA). have radiologic differential features. Although This neoplasm is occasionally mistaken for an renal cell carcinoma has been reported to have ependymoma, spongioblastoma, giant-cell glio­ an association with TS, it may not be a true blastoma, or ganglion cell tumor, but has immu­ component of the classic syndrome since less nohistochemical (GF AP) staining characteristics than 10 cases of this association have been re­ that point to the as the cell of origin ported, and many of those patients had atypical (30-32). The SGCA is a slowly growing benign features of the disease (39). Patients may also mass. It most commonly arises from the subep­ develop angiomyolipomas in the liver. endymal surface of the caudate nucleus near to The lung involvement in TS consists of a the foramen of Monro. Most authors agree that periarterial proliferation of smooth muscle in the the SGCA probably arises from a preexisting interstitium of the lung parenchyma, predomi­ (hamartomatous) SEN (31). These growths cause nantly, though not exclusively, in female patients. AJNR: 13, March/ April 1992 735

The pulmonary disease in TS superficially re­ sembles sporadic pulmonary lymphangioleiomy­ omatosis (LLM) (42). However, important differ­ ences suggest it is probably a distinct entity. These include: the absence of primary smooth muscle deposition in the lymph nodes, the rarity of chylothorax (which is seen in 50% of LLM), the lack of abdominal lymphatic involvement, and the presentation of the disease in some male TS patients (LLM is exclusively female) (41 , 43). However, some have suggested that LLM and even renal sporadic angiomyolipomas, actually represent formes fruste of TS. The association of LLM and angiomyolipomas in the same patient, yet without other stigmata to indicate TS, further complicates this argument (44). The cardiac lesion in TS is the rhabdomyoma. These are benign lesions that may affect the patient through ventricular obstruction, but do not metastasize. One or more small cardiac rhab­ domyomas are noted in 25%-49% of patients with TS (33, 45). Cardiac rhabdomyoma is one of the secondary characteristics of TS; and ap­ proximately one-half of them occur in patients meeting other diagnostic criteria for TS. Plain radiographs may detect calcification in the SEN, in the cortical tubers, and in the cere- . bellum, especially when it is particularly dense (46-48). Skull films may also demonstrate super­ ficial calvarial densities that are bone islands­ condensations of cortical bone within the diploe. CT and MR are both sensitive and specific tests for the diagnosis of TS (49-54). In a study of 60 couples, Roach et al reported that although MR was more sensitive in finding multiple lesions, CT

Fig. 13. Tuberous sclerosis. Longitudinal section of the kidney displays a 6-cm angiomyolipoma arising in the upper pole, and innumerable smaller angiomyolipomas studding the kidney (arrows).

This leads to pulmonary and reor­ ganization of the parenchyma into cystic spaces, which may rupture to produce pneumothorax (40, 41). This pulmonary involvement produces a coarse reticulation or "honeycomb" pattern. Despite the interstitial thickening, the lung vol­ ume is increased, and the diaphragms may be Fig. 14. Tuberous sclerosis. Noncontrast CT dem onstrates flattened. In addition, secondary signs of cor multiple nodular calcifications that are anchored along the caudate pulmonale and pneumothorax may be present. nucleus and protrude into the ventricular lum en. 736 AJNR: 13, March/April1992

A B . c Fig. 15. Tuberous sclerosis. A , Contrast-enhanced CT demonstrates multiple poorly calcified subependymal nodules and an enlarged gyrus with a central hypodensity (arrow) representing a cortical tuber. B, Axial Tl MR shows a corresponding hypoin­ tensity (arrow) within the abnormal gyrus. Coronal Tl MR (C) and T2 MR (D) show multiple cortical tubers (arrows indicate one tuber) that have central hypointensity on the Tl MR and centrally hyperintensity on the T2 MR (the "gyral core").

D was more specific in diagnosing TS. Although the patients with a clinical diagnosis of TS; only two clinical diagnosis in any particular individual patients had entirely normal MR images (52). On rarely requires imaging confirmation, both CT CT, the SEN only rarely demonstrate enhance­ and MR may be needed for genetic counseling ment with iodinated contrast. An enhancing le­ (55-58). sion is presumed to represent the development CT easily depicts the subependymal nodules, of a neoplasm, the SGCA (49, 60). However, even in very young patients, when they are non­ Martin et at described GD-DTP A enhancement in calcified and isodense to brain. The calcification 11 SEN that did not enhance on CT, and six of in SEN (Figs. 14 and 15) can vary from a ho­ their 10 patients had enhancing nodules. They mogeneous confluent density to multiple punc­ interpreted their data to suggest that enhance­ tate foci of hyperdensity. Detection of the nodules ment indicated "active lesions" that are preneo­ can be difficult on MR . SEN are not always focal plastic (53). signal voids, rather, the intensity changes of Kingsley et al noted cortical and/or white mat­ gliosis and demyelination (prolongation of both ter changes in 55% of their patients studied by T1 and T2) may compete with the effects of CT. Some of these abnormalities were detected diffuse calcification (shortening of both T1 and primarily because of calcification (49). MR (es­ T2), which can make the SEN difficult to identify pecially in the coronal plane) (Figs. 15C and 15D) (58, 59). Nixon et al identified SEN in 17/19 reveals the cortical tubers as enlarged gyri, with AJNR: 13, March/ April1992 737

abnormal signal intensity (50, 52, 54). Nixon et Neurofibromatoses al described two important features of TS on MR: the "gyral core" seen on T1 W or inversion recov­ Although at least eight variants of neurofibro­ ery images and the "sulcal island" seen on T2W matosis have been proposed, the National Insti­ scans (52). On T2W, cortical tubers typically tutes of Health (NIH) Consensus Development appear as bright zones in the cortex, the subcor­ Conference has, so far, defined only two distinct tical white matter, or both the gray and white types: NF-1 (von Recklinghausen or "peripheral" matter. The sulcal island appearance is produced neurofibromatosis); and, NF-2 (bilateral acoustic when the isointense gray matter is highlighted by or "central" neurofibromatosis) (61 , 62). Together, the bright white matter, an appearance that can these two are the most common of the phako­ be mimicked by vasogenic edema. The term matoses. They are hereditary disorders charac­ "gyral core" describes an area of T1 W hypoin­ terized by multiple CNS and peripheral nervous tensity in the white matter within the center of system growths, most commonly nerve sheath an expanded gyrus with isointense gray matter. tumors. Both types have an autosomal dominant In the Mayo clinic report of 19 patients, 10 had pattern of inheritance. Though they are not sex­ cortical lesions, all of which were better delineated linked, the associated neoplasms clearly have on MR: one had only a "gyral core," four had only hormonal sensitivity, since symptoms are rare "sulcal islands," and the other five had both (52). Gray matter heterotopias in the white matter may be isointense to cortical gray matter. Foci of gliosis and/or abnormal myelin may appear as linear hyperintensities, often extending from a SEN to a cortical tuber (54). This linear area may have faint hyperdensity (calcification) on CT, and suggest a migration/maturation etiology for the lesions of TS. MR and CT enhancement do not occur within either the heterotopias or the cortical tubers (48, 53). In TS, true neoplasms almost always present as intraventricular masses in or near to the fora­ men of Monro (Figs. 16 and 17). They are usually large, heterogeneous, contain one or more focal areas of dense calcification, and are associated with obstructive enlargement of the lateral ven­ tricles. This neoplasm invariably enhances on A both CT and MR (50, 53). On CT, enhancement was a good differential feature favoring SGCA over a hamartomatous nodule. However, nodular periventricular enhancement is less specific on MR, since some nonneoplastic "nodules" may also enhance. The distinction between a SEN and a small, early SGCA is then difficult. Some patients with TS have a shortened life­ span, which accounts for the difference between the birth incidence of 1/10,000 and the reduced prevalence of about 1/20,000. The common causes of death include status epilepticus, renal failure from extensive angiomyolipomas (Figs. 18 and 19), cardiac failure or hem­ orrhage from CNS lesions/or their surgical com­ plications, pulmonary complications from lung Fig. 16. Tuberous sclerosis. Gadolinium-enhanced T l MR in involvement (Fig. 20), and bronchopneumonia the axial (A) and sagittal (B) planes shows a large enhancing subependym al giant cell astrocytoma near the foramen of Monro. (23). TS patients may also suffer major morbidity The hamartomatous subependymal tubers (arrow) are all far from the accidental and anoxic effects of seizures. smaller and, in this patient, do not enhance. 738 AJNR: 13, March/ April 1992

is considerable overlap in the manifestations of these two forms of neurofibromatosis, some ex­ trapolations of data from the older literature to the new definitions, although necessary for a thorough review, may not be entirely accurate. In addition, NF-2 is not really a "­ tosis" at all, since it is usually characterized by multiple and other tumors, not multiple . Unfortunately, the dis­ tinction between these two different nerve sheath tumors is frequently avoided, making interpreta­ tion of the published literature difficult and confusing.

Neurofibromatosis Type I Neurofibromatosis type 1 (NF -1) is an autoso­ mal dominant disorder without racial or sexual Fig. 17. Tuberous sclerosis; contrast-enhanced CT. The large, predilection. In some female patients gestational lobulated, heterogeneously enhancing mass at the foramen of hormones may exacerbate the disease (63). NF- Monro causes obstructive hydrocephalus. The multiple small periventricular calcifications indicate that this patient has tuberous 1 is the disorder commonly referred to by the sclerosis and that the large lesion is a subependymal giant cell eponym "von Recklinghausen disease." NF-1 is astrocytoma. the most common single disorder, with a reported incidence of approximately 1/2,000- 3,000 live births (64). The manifestations of NF- 1 are linked to a gene located on the proximal portion of the long arm of (65, 66). Approximately one-half of the patients lack a family history, and are presumed to arise from spontaneous mutation. The NIH Consensus Com­ mittee has defined diagnostic criteria for NF-1 . A firm diagnosis of NF-1 may be made when a patient exhibits two or more of the following (61 ): 1) six or more cafe au Ia it macules, >5 mm

Fig. 18. Tuberous sclerosis. Abdominal CT reveals multiple renal angiomyolipomas as hypodense masses that have low at­ tenuation values near but not equal to those of the retroperitoneal fat. before puberty, and exacerbations occur in fe­ male patients during pregnancy. NF-1 and NF-2 are now recognized as genetically distinct dis­ eases caused by genetic abnormalities at two different loci. They share many phenotypic sim­ ilarities and in the past were considered to be part Fig. 19. Tuberous sclerosis; abdominal CT. The large hypo­ dense mass in the right lobe of the liver (black arrow) and the of a spectrum of a single disease entity. To avoid slightly hypodense mass (white arrow) growing from the upper further confusion, these two diseases will be dis­ pole of the left kidney are both angiomyolipomas. The denser cussed separately whenever possible. Since there renal mass has a smaller component of fat. AJNR: 13, March/ April 1992 739

To be considered as hamartomas these lesions should be without mass effect, have no spreading pattern (ie, no vasogenic edema), and should not have contrast enhancement or signs of hemor­ rhage. However, the globus pallidus lesions have been noted to have both T1 hyperintensities (in more than half the cases) and mild mass effect (67 , 73). Mirowitz et al suggested that the T1 hyperintensities may represent regions of in­ creased myelination, perhaps due to heterotopic Schwann cells, or even melanin (73). Although heterotopias within the CNS have been documented in the spinal cord and brain

Fig. 20. Tuberous sclerosis. Chest radiograph shows a "hon­ eycomb" pattern of coarse interstitial markings produced by the reorganization of the lung parenchyma from pulmonary lymphan­ gioleiomyomatosis. The radiographic appearance is due to the formation of multiple cysts, each surrounded by compacted lung tissue forming the walls between the cysts. Lymphangioleiomy­ omatosis is an infiltration of smooth muscle along the small pulmonary vessels and bronchi. There is no evidence of chylothorax. Fig. 21. Neurofibromatosis type 1. Photograph of the skin shows several areas of macular hyperpigmentation (cafe-au-fait spots), and multiple small, innocuous-appearing cutaneous before puberty, > 15 mm after puberty (Fig. 21 ); neurofibromas. 2) two or more neurofibromas (Fig. 22); 3) one or more plexiform neurofibromas (Figs. 23 and 24); 4) axillary or inguinal freckling; 5) optic ; 6) two or more iris hamartomas (Lisch nodules); 7) one or more distinctive bone lesions (eg, sphenoid dysplasia (Fig. 25), pseudoarthrosis (Fig. 29), thinning of long bone cortex); and 8) a first degree relative who also meets these criteria for NF-1. Patients with NF-1 develop a multitude of in­ tracranial lesions, both hamartomatous and neo­ plastic, including (Fig. 26) and paren­ chymal . T2-weighted MR shows multiple bright foci in the brain stem, cerebellar white matter, dentate nucleus, basal ganglia, periven­ tricular white matter, optic nerve, and optic path­ ways (67 -71 ). Although histologic verification is justifiably lacking, most authors feel that the T2 hyperintensities represent either abnormal mye­ Fig. 22. Neurofibromatosis type 1. Photograph of the skin lination or some hamartomatous change (Fig. 27) shows innumerable cutaneous neurofibromas-"fibroma (67' 68, 72). molluscum." 740 AJNR: 13, March/ April 1992

(with and without neurofibromatosis), their pres­ Plain radiographs and other studies may reveal ence in the NF -1 basal ganglia as the cause of erosion or dilatation of the optic canal. However, the hyperintensities has not yet been pathologi­ in NF-1, the optic canal may be enlarged by cally confirmed (72). As many as 10% of patients dysplasia alone (75). with NF -1 will develop a parenchymal CNS Patients with NF-1 may also have other orbital glioma, the majority of them . In lesions including enlarged optic canals, sphenoid contradistinction, the patients with central neu­ dysplasia (Figs. 25 and 26) (5%-10%), Lisch rofibromatosis (NF -2) develop gliomas that are nodules, and plexiform neurofibromas (10%- (67, 74, 75). 35%) of the face, eyelid, and intraorbital nerves Optic nerve gliomas occur in 15%-40% of (64, 75, 82). Iris hamartomas (Lisch nodules), are patients with NF-1 (64, 67, 68, 71).1n NF-1, these small (2-3 mm), often translucent, hemispheric are almost invariably low-grade pilocytic astro­ (lentil-like?) raised lesions that can be missed on cytomas (Fig. 26). These neoplasms are fre­ routine ophthalmoscopy. Slit-lamp examination quently very indolent, so that conservative man­ to verify (or exclude) the presence of Lisch nod­ agement without surgery or irradiation has been ules may be helpful in confirming the diagnosis suggested in cases where vision is preserved, the of NF -1 . Plexiform neurofibromas tend to be lesion is limited to the orbit, and it does not infiltrating masses, producing thickening of the involve the chiasm (76-78). However, the man­ tissue and abnormal contrast enhancement (82). agement of optic gliomas in NF -1 is controversial·, The extensive plexiform neurofibromas that oc­ with some authors recommending surgery, or cur in the orbit and on the face may displace the biopsy followed by irradiation (79-81 ). These globe (nonpulsatile proptosis) or produce thick­ recommendations are difficult to adhere to when ened baggy folds of overgrown skin, creating an MR commonly reveals signal abnormalities in the appearance suggesting elephant hide. (The origi­ optic pathways that could represent spread of the nal "Elephant Man" probably did not have neu­ neoplasm (even in patients without documented rofibromatosis. It has been suggested that he optic glioma) (67, 68). actually had a newly described process called On imaging studies, optic gliomas appear ".") either as a focal mass on the optic nerve, or more A distinction should be made between the two frequently as a fusiform or diffuse enlargement common benign nerve sheath tumors: the of the nerve over a long segment (67, 75). T2- and the neurofibroma. This distinc­ weighted MR will show abnormally high signal in tion may be a difficult problem that is only the affected areas of the optic nerve, and, in compounded when one considers the complexi­ 30%-80% of cases, may reveal posterior exten­ ties of the neurofibromatoses (83, 84). Neurofi­ sion of these signal changes into the chiasm, the bromas are uncommon sporadic tumors, and are optic tracts, and the optic radiations (67, 68). seen most often in association with NF -1, not

Fig. 23. Neurofibromatosis type 1 . Photograph of the face shows an extensive plexiform neurofibroma involving the orbit, eyelid, and the side of the face, with massive overgrowth and redundancy of the skin and soft-tissues. Fig. 24. Neurofibromatosis type 1. Coronal T2 MR shows a plexiform neurofibroma of the left orbit, the overlying skin, and the soft tissues. The neurofibroma (arrows) is hyperintense compared to both brain and the adjacent tissues. Fig. 25. Neurofib'romatosis type 1. Frontal skull radiograph shows extensive dysplasia on the left, with severe hypoplasia of the sphenoid bone, enlarged superior orbital fissure, and hypoplastic petrous bone. AJNR: 13, March/April1992 741

Fig. 26. Neurofibromatosis type 1. Axial CT (A) and Tl MR (B) demonstrate a dys­ plasia of the left sphenoid bone with defi­ ciency of a large portion of the medial aspect of the greater wing. The temporal lobe (ar­ rowheads) has herniated into the orbit, pro­ ducing proptosis. Plexiform neurofibroma (arrows) has infiltrated the eyelid and orbit. Optic gliomas enlarge both optic nerves.

A B

Fig. 27. Neurofibromatosis type 1; axial CT (A) and axial T2 MR (B). The lesions of the basal ganglia and deep white matter appear hypodense on CT and hyperintense on MR. MR also shows additional smaller lesions (arrow) not clearly seen on the CT. These lesions have been described as areas of gliosis or absent/ abnormal myelination. As such, they should not have mass effect nor show contrast enhancement. Similar le­ sions are also seen in the posterior fossa white matter, and may progress and regress on serial studies in children. However, they are distinctly rare in adult patients with NF- 1.

A B

NF-2 (84, 85). Conversely, schwannomas are the nant schwannoma" or "neurofibrosarcoma." At principal tumor of NF -2, not NF -1. Halliday et at least 50% of all malignant nerve sheath tumors reported that only 2/42 sporadic nerve sheath occur in patients with NF -1. The incidence of tumors were neurofibromas; the other forty were malignant nerve sheath tumors in von Reckling­ schwannomas (85). In Halliday's series none of hausen patients is at least 5% (87). seven patients with NF -2 had a pure neurofi­ Patients with NF-1 may present with myriad broma, although one patient had both a schwan­ other features outside the brain and skin. These noma and a "mixed" tumor. Conversely, all 14 have been extensively reviewed elsewhere (94, patients with NF-1 had spinal neurofibromas ex­ 95). The calvaria frequently show congenital dys­ clusively (Fig. 28) (85). Although NF -1 patients plasia of the sphenoid bone, which may lead to do not develop acoustic schwannomas, they may herniation of the temporal lobe into the orbit with develop dysplastic enlargement of the internal pulsatile exophthalmos. There may be nontu­ auditory canals (86). The mechanism of enlarge­ morous enlargement of the internal auditory and ment may be analogous to the expansion of the optic canals and a curious benign bony defect subarachnoid space noted in the spine (see along the course of the lambdoid suture, near its below). junction with the temporal (petrous) bone. Most malignant tumors of nerve sheath deri­ Spinal changes vary from mild to the vation have features that overlap the traditional characteristic, acutely angled cervical , boundaries between schwannoma and neurofi­ which is one of the "distinctive bone lesions" cited broma. Therefore, the less specific term "malig­ in the diagnostic criteria (96). Dysplastic enlarge­ nant " is preferable to "malig- ment of the subarachnoid space may cause ero- 742 AJNR: 13, March/April 1992

sexual predilection (98, 99). Female patients may experience exacerbations during pregnancy (1 00). The NIH Consensus Committee has defined diagnostic criteria for NF-2, which are met if the patient has one bf the following (modified from Ref. 61): 1) bilateral masses of the eighth cranial nerve (biopsy not needed) (Figs. 30 and 31 ); and 2) a first-degree relative with NF-2 and either a single eighth nerve mass or any two of the follow­ ing-schwannoma, neurofibroma, , glioma, or juvenile posterior subcapsular lens opacity. With or without NF-2, the cells in some of these neoplasms ( and schwanno­ Fig. 28. Neurofibromatosis type 1. Metrizamide CT myelogram mas) exhibit deletions from chromosome 22; it demonstrates a moderately large, freely communicating left-sided was suggested in 1986 and established in 1987, lateral thoracic meningocele. that loss of genetic material on this chromosome was an inherited familial trait in "bilateral acoustic neurofibromatosis" ( 101, 102). Patients who are heterozygous for the NF gene are at risk for developing acoustic schwannomas, meningio­ mas, ependymomas, intracranial non tumoral cal­ cification, and, less commonly, neurofibromas (85, 99, 103). Acoustic schwannomas are the hallmark of NF-2. In the absence of this congenital syndrome, acoustic schwannomas present as solitary lesions in the fifth decade; with NF-2 they present as

Fig. 29. Neurofibromatosis type 1. Plain radiograph shows bilateral masses in the second and third decades pseudoarthroses at the junctions of the middle and distal thirds of (104). Acoustic schwannomas almost invariably the radius and the ulna. These have persisted, despite prolonged arise either within the internal auditory canal or orthopedic fixation. at its orifice, the porous acousticus. Deformity sions of the adjacent bone, such as nontumorous enlargement of the neural foramina (Fig. 28) and posterior scalloping of the vertebral bodies (most prominent in the lumbar area). Multiple arachnoid cysts may develop and protrude along the course of the exiting nerve roots, especially in the tho­ racic spine, becoming lateral thoracic meningo­ celes (Fig. 28). Lateral meningoceles are one of the common causes of a mass in the thorax in NF-1 ; discovery of a lateral meningocele should prompt search for other stigmata of neurofibro­ matosis, since the lateral meningocele arises spo­ radically in fewer than V3 of cases (94, 97). Other distinctive osseous lesions include focal over­ growth of a digit, ray, or an entire limb, pediatric tibial bowing, and pseudoarthrosis (Fig. 29). Fig. 30. Neurofibromatosis type 2; gross photograph. The bil ~ teral acoustic schwannomas cause dramatic distortion, dis­ placement, and compression of the pons and cerebellar hemi­ Neurofibromatosis Type 2 spheres. These tumors grow very slowly, allowing the brain to mold itself around them. The cut surface of the tumors is heter­ Neurofibromatosis type 2 (NF-2) is also an ogeneous with focal areas of hemorrhage (arrowheads), indicating autosomal dominant disorder without racial or rich vascularity. AJNR: 13, March/ April1992 743

Fig. 31 . Neurofibromatosis type 2; gad­ olinium-enhanced Tl MR. T he axial (A) and coronal (B) images demonstrate m ultiple in­ tracranial neoplasms. The smaller posterior fossa schwannoma shows homogeneous en­ hancement, whereas the larger schwannoma has become heterogeneous. The right para­ sagittal meningioma and the left parietal convexity meningioma both compress the underlying brain. Both demonstrate the "dural tail" sign, a nonspecific feature seen with many neoplasms that irritate or infil­ trate the meninges, including both meningi­ omas and schwannomas (see arrow in A).

A B and/or enlargement of the internal auditory canal now be confidently diagnosed or excluded using is noted on routine CT in more than 70% of cases gadolinium-enhanced MR (93). (89, 90). Schwannomas have a biphasic histologic The MR appearance of peripheral nerve sheath composition characterized by dense areas (Antoni tumors is nonspecific; they tend to be smooth, A tissue) and looser areas (Antoni B tissue). As well-demarcated masses that are mildly hetero­ they enlarge and age, schwannomas tend to be­ geneous with increased signal intensity that pro­ come heterogenous masses, both grossly and on gresses from intermediate, through moderate, to imaging, because of cystic degeneration and clearly bright, as the pulse sequence is changed hemorrhage (72, 84, 89, 104). from T1-weighted, through "proton-density," to Schwannomas are the principle neoplasms of T2-weighting (92). NF -2, centrally and peripherally. They tend to In addition to acoustic schwannomas, patients show prominent contrast enhancement, which with NF-2 may develop intracranial meningiomas may be homogeneous when the tumor is small (often multiple), and schwannomas involving and heterogeneous when the tumor is large (88). other cranial nerves (67). Schwannomas are more vascular than neurofi­ Patients with NF -2 also develop intracranial bromas, so both hemorrhage and "cystic change" meningiomas (Fig. 31) that may be multiple. The are more common than in neurofibromas (Figs. NF -2 meningiomas present in the lateral ventricle 24, 30). However, on non contrast CT, there is more commonly than do sporadic meningiomas tendency for both neoplasms to be hypodense (16% vs 5%) (103). Meningiomas in childhood compared to skeletal muscle, and hypodense to are particularly suspicious fo r NF-2 (105). The isodense to brain (88, 89, 90). In NF-2, schwan­ NF -2 meningiomas have typical histology and nomas also develop in the dorsal (sensory) nerve radiologic appearance, differing only in their mul­ roots of the spinal cord. Intramedullary spinal tiplicity, and perhaps in presenting in younger cord schwannomas may develop primarily, or patients who are examined because of symptoms through secondary extension into the cord from related to other features of the disease. The a site of origin in the nerve root (98). multiple meningiomas may be few and large, or Because they are relatively vascular neoplasms appear as a diffusion of small masses, producing without a blood-brain-barrier, the vast majority a nodular studding along the dural surfaces. The of acoustic schwannomas will enhance on both meningiomas are usually dural based, homoge­ CT and MR scans performed after contrast infu­ neous, and hyperdense to brain before contrast; sion (91). Small intracanalicular acoustic schwan­ enhancement is usually homogeneous. On MR, nomas, which formerly required gas or positive­ meningiomas may appear relatively isointense contrast CT -cisternography for identificatj~n, can <::ompared to brain, but may nonetheless be iden- 744 AJNR: 13, March/ April 1992

tified by secondary displacement of adjacent Acknowledgments brain or associated calvarial hyperostosis. Menin­ We want to express our thanks to Steve Kruger, Wendy giomas enhance brightly after gadolinium infu­ Baker, and Clarice Williams for assistance in preparing this sion, but are perhaps a little less intense than manuscript. schwannomas. In summary, NF-1 (von Recklinghausen Dis­ References ease) is characterized by pathology of the nervous system including the neurons (heterotopias), as­ 1. Dorland's Illustrated Medical Dictionary. 26th ed. Philadelphia: W.B. trocytes (optic nerve gliomas), and multiple neu­ Saunders, 1981 2. FitzGerald MJT. Visual pathways and visual cortex. Neuroanatomy, rofibromas of the spinal and peripheral nerves. basic and applied. London:Bailliere Tindall, 1985:chap 29 These patients also have prominent cutaneous 3. Roach ES. Diagnosis and Management of Neurocutaneous Syn­ lesions, most notably cafe au lait spots and neu­ dromes. Semin Neurol 1988;8:83- 96 4. Enjolras 0, Rich MC, Merlan JJ. Facial port-wine stains and Sturge­ rofibromas of or under the skin. They are also at Weber syndrome. Pediatrics 1985;76:48-51 significant risk for various musculoskeletal prob­ 5. Sperner J, Schmauser I, Bittner R, et al. MR-imaging findings in lems. In contrast, patients with NF-2, are prone children with Sturge-Weber syndrome. Neuropediatrics to develop neoplasia not of astrocytes and neu­ 1990;21:146-152 6. Streeter GL. The development of the venous sinuses of the dura rons, but of other cells. They develop multiple mater in the human embryo. Am J Anat 1915;18:145-178 schwannomas (of the cranial and spinal nerves), 7. Wohlwill FJ, Yakovlev Pl. Histopathology of meningo-facial angiom­ meningiomas (intracranial), and ependyomas (not atosis (Sturge-Weber's disease). J Neuropathol Exp Neurol astrocytomas) (62, 74, 103). When the histology 1957;16:341-364 8. Welch K , Naheedy MH, Abroms IF, Strand RD. 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