Neurocutaneous Disorders

Neurocutaneous Disorders
Gilbert Vézina
A. James Barkovich
Neurocutaneous disorders (also known as phakomatoses) are characterized by multiple hamartomas and other congenital malformations affecting mainly structures of ectodermal origin, that is, the nervous system, the skin, the retina, and the globe and its contents; visceral organs are also involved but, in general, to a lesser extent. Classically, four diseases were included in this group: von Recklinghausen’s neurofibromatosis, tuberous sclerosis (Bourneville disease), retinocerebellar angiomatosis (von Hippel-Lindau disease), and encephalotrigeminal angiomatosis (Sturge-Weber disease). However, many other hereditary diseases (over 60) have subsequently been classified under the heading of neurocutaneous syndromes (1). A discussion of all of the neurocutaneous disorders that have been described is beyond the scope of this book. Instead, we will describe those that are most commonly seen in practice and likely to be seen in moderate- to large-sized outpatient and inpatient practices.
Many of the neurocutaneous disorders may be attributed to defective development of the neural crest, a multipotent cell population located between the neural and nonneural ectoderms at the lateral margins of the neural placode. Disorders that result from abnormal expression, migration, differentiation, or death of neural crest cells (NCCs) during embryonic development are termed neurocristopathies. NCCs migrate to nearly all tissues of the embryo; they form the neurons and glial cells of the peripheral nervous system, melanocytes of the skin, chromaffin tissue (adrenal gland, the carotid body), smooth muscle of the alimentary tract and of blood vessels, endothelial cells, adipocytes, fibroblasts, the sclera of the eye, cartilage, and membranous bone (2,3). Five categories of NCCs have been identified, based on their shared paths of migration and contribution to organs: cardiac, vagal, trunk, sacral, and cranial. Cranial NCCs give rise to a wide range of derivatives, including the cranial meninges, most of the facial tissues, cartilage and bone of the skull and face (including the dentin, dental pulp, and alveolar bone of the head), melanocytes, Schwann cells, smooth muscle cells/pericytes of the forebrain, and the intracranial vessels (2).
Several phakomatoses (and other inherited cancer predisposition syndromes) carry an increased genetic susceptibility to multiple primary malignancies, which is enhanced by sensitivity to ionizing radiation (4). The more common syndromes with radiation sensitivity that are relevant to diagnostic radiation exposure are listed in Table 6-1; care should be used to minimize exposure of patients with these disorders to radiation during diagnosis, treatment, and follow-up; MRI should be the favored imaging modality.
Table 6-1 Inherited Cancer Predisposition Syndromes in Which Exposure to Ionizing Radiation Should Be Minimized

Nijmegen breakage syndrome

Ataxia-telangiectasia

Nevoid basal cell nevus syndrome

Li-Fraumeni syndrome

Hereditary retinoblastoma

Neurofibromatosis type 1

Fanconi anemias

Severe combined immunodeficiency variants

Xeroderma pigmentosum

Modified from Kleinerman RA. Radiation-sensitive genetically susceptible pediatric sub-populations. Pediatr Radiol 2009;39(Suppl 1):S27-S31.

Neurofibromatosis Type 1
Neurofibromatosis type 1 (NF1), initially described by von Recklinghausen in 1882, is one of the most common autosomal dominant central nervous system (CNS) disorders; its worldwide incidence is approximately 1 per 2500 to 3000 individuals, without preference for race or sex (4,5,6,7,8). The genetic locus has been mapped to chromosome 17q11.2 (7). The NF1 gene produces a cytoplasmic protein called neurofibromin, which is enormous and appears to have functions in multiple intracellular processes. Neurofibromin is a negative regulator of the Rat sarcoma (RAS)/mitogen-activated protein kinase (MAPK) pathway (or Ras/MAKP pathway; also known as the RAS/RAF/MEK/ERK pathway). The Ras/MAKP pathway leads to expression of genes that encode proteins that regulate cell proliferation and survival, cell morphology determination, and organogenesis. Germ-line mutations in the RAS/RAF/MEK/ERK pathway give rise to a group of conditions now termed RASopathies (9), which are listed in Table 6-2.
In the CNS, neurofibromin is expressed primarily in neurons, Schwann cells, oligodendrocytes, and astrocytes (5,6). Understanding of the molecular pathogenesis of NF1 and the functions of the NF1 gene helps to explain the extensive clinical and imaging features of this syndrome and allows for the development of targeted therapies to improve the management of clinical problems associated with NF1 (10,11). The many functions of neurofibromin include the following:
  • It acts as a tumor suppressor gene that functions in part as a negative regulator of the RAS protooncogene (12) and of the mammalian target of rapamycin (mTOR) pathway (13).
  • It acts as a regulator of neural stem cell proliferation, survival, and astroglial differentiation, in addition to regulating neuroglial progenitor function (14,15). Neurofibromin is required for regulation of intracellular cyclic AMP (cAMP) generation in both neurons and astrocytes; abnormal levels of cAMP appear to be, at least in part, responsible for the abnormalities in glial and neuronal development evident in NF1 patients.
    Table 6-2 The Rasopathies

    NF1

    Noonan syndrome (NS)

    Costello syndrome

    Capillary malformation-arteriovenous malformation syndrome

    Cardiofaciocutaneous syndrome

    Legius syndrome

    NS with multiple lentigines (LEOPARD syndrome)

  • It regulates ERK signaling in GABA release, an important pathway involved in learning (and therefore in learning disabilities) (16).
  • It is involved in the maintenance of the vascular wall. Neurofibromin is expressed in the vascular endothelium and in vascular smooth muscle cells; loss of neurofibromin likely causes smooth muscle proliferation, possibly in response to nonspecific injury to the vascular wall (15), which can lead to vasculopathy (17).
  • It is involved in bone formation and remodeling. Neurofibromin is expressed in osteoblasts; it inhibits collagen synthesis, promotes mineralization, and regulates osteoclastogenesis (18).
  • It seems to be required for normal myelination by Schwann cells (18). In addition, the gene for oligodendrocyte myelin glycoprotein, a major myelin protein, is embedded within intron 27b of the NF1 gene (19). Therefore, it is not surprising that abnormalities of myelin/white matter are seen in patients with NF1.
Phenotypic expression of the disease is extremely variable, both clinically and radiologically; this variation has resulted in attempts to correlate phenotypes with underlying genetic factors (20). Overall, no genotype-phenotype relationships have been identified by mutational analyses of NF1 patients (21). Regulatory and epigenomic modifiers, possibly including environmental modifiers (at the level of the cellular milieu), unlinked to the NF1 locus, likely contribute to the variable expressivity of the disease (22,23). Diagnostic criteria are listed in Table 6-3.
Clinical Manifestations
Café au lait spots are the first manifestation of NF1 to develop; they are sometimes present at birth and usually develop at the age of 2 years (11). Freckling within the axilla will develop later in about two-thirds of patients (24,25,26) (Tables 6-3 and 6-4). Cutaneous neurofibromas begin to appear around the onset of puberty and increase in number throughout life. Lisch nodules, which are best seen by slit lamp examination, begin to appear in childhood and are present in almost all affected adults (24,25,26). A number of other features are characteristic of this disease, the most important from the neuroimaging standpoint being gliomas of the optic pathway and other intracranial astrocytomas, which may have a higher incidence in patients with optic pathway tumors (27,28), kyphoscoliosis, sphenoid wing dysplasia, vascular dysplasias, nerve sheath tumors, and macrocephaly. NF1 is associated with an increased incidence of tumors, with the frequency of brain tumors (other than optic glioma) being 1.5% to 2.0% and that of extra-CNS tumors (most commonly sarcomas, pheochromocytomas, and leukemia) being 3% to 5% (29). Megalencephaly is common; the cerebral enlargement is primarily attributable to an increase in cerebral white matter volume, with a smaller contribution from the gray matter (30). About 4% to 7% of patients have epilepsy, primarily related to intracranial masses and cytoarchitectural abnormalities (31).
Table 6-3 Criteria for Diagnosis of Type 1 Neurofibromatosis

The diagnosis of NF1 requires two or more of the following:

  1. Six or more café au lait spots over 5 mm in greatest diameter (over 15 mm in postpubertal individuals)

  2. Two or more neurofibromas of any type or one or more plexiform neurofibroma

  3. Freckling in the axillary or inguinal areas

  4. Optic glioma

  5. Two or more Lisch nodules (pigmented hamartomas of the iris)

  6. A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex

  7. A first-degree relative (parent, sibling, or offspring) with NF1

Adapted from Bhargava R, Au Yong KJ, Leonard N. Bannayan-Riley-Ruvalcaba syndrome: MRI neuroimaging features in a series of 7 patients. AJNR Am J Neuroradiol 2014;35(2):402-406.

Table 6-4 Incidence of Clinical Features of NF1

Feature

Incidence

Cutaneous lesions

>6 Café au lait spots

>95%

Axillary freckling

65%-85%

Cutaneous neurofibromas

Age 0-9 y

15%

Age 10-19 y

45%

Age 20-29 y

85%

Over age 30 y

95%

Lisch nodules

Age 0-4 y

20%

Age 5-9 y

40%

Age 10-19 y

80%

Over age 20 y

95%

Neurologic lesions

Plexiform neurofibromas

30%

Head and neck only

2%-4%

Malignant peripheral nerve tumors

2%-3%

Lifetime risk

10%

Cognitive deficits

Mental retardation

5%

Learning disabilities

50%

Scoliosis

10%-26%

Optic pathway gliomas

15%

Symptomatic

5%

Short stature

20%-30%

Macrocephaly

50%

Epilepsy

5%

Other systems

Pseudarthrosis of long bones

3%

Sphenoid wing dysplasia

1%

Renal artery stenosis

1%

Osteoporosis

up to 50%

Adapted from North K. Neurofibromatosis type 1. Am J Med Genet 2000; 97:119-127; North K, Joy P, Yuille D, et al. Cognitive function and academic performance in children with neurofibromatosis type 1. Dev Med Child Neurol 1995;37:427-436.

Cognitive impairment is found in 30% to 65% of children with NF1 and consists of a wide range of learning disabilities (most frequently problems with attention, perception, executive functioning, and academic achievement) (24,25,32,33,34). The most common neuropsychological manifestation of NF1 in childhood is a specific learning disability, defined as a major discrepancy between ability (intellect or aptitude) and achievement (performance) in patients with IQ scores in the normal range. Specific learning disability has been estimated to occur in 30% to 45% of children with NF1, which is more than three times the prevalence in the general population (33,34). The occurrence of cognitive deficits does not seem to be associated with the severity of other clinical features of the disease (33). In fact, a bimodal distribution of full-scale IQ scores is seen in children with NF1, suggesting that there are two populations of NF1 patients, those with and those without a degree of cognitive impairment. Multiple studies have attempted (with variable success) to establish a correlation between the presence of the characteristic T2 bright white matter/basal ganglia foci seen in NF1 children and the cognitive deficits evident in psychometric testing (33,35,36,37,38). The methodologies of these studies are complicated by the peculiar temporal evolution of the T2 bright foci: they are absent at birth; they appear in early childhood, and reach peak numbers around ages 7 to 12; and they essentially disappear by the end of the second decade of life. One of the most consistent markers of cognitive deficits between ages 8 and 18 years appears to be the presence of T2 bright foci in the thalami (33,35,36,37,38,39). Interestingly, long-term assessment of cognition in children with NF1 suggests that children with discrete hyperintense NF1 lesions show an increase in general cognitive function between childhood and adulthood, while the NF1 children without characteristic T2 lesions exhibit a stable cognitive profile (40); one wonders whether this suggests that the T2 hyperintensities are a result of impaired myelination.
Although learning disabilities are common in NF1, intellectual disability affects a much smaller proportion of patients. Some intellectually affected NF1 patients have been found to have deletions of the entire NF1 gene, leading to a distinctive phenotype that includes the development of a large number of neurofibromas and a distinctive facial appearance (41,42). Affected patients also appear to have a greater number of structural anomalies detected in their brains by MR studies. It is unclear whether this phenotype is the result of haploinsufficiency for the NF1 gene or whether a deletion of portions of contiguous genes contributes to the clinical picture (41,42).
Neurofibromas are found in the majority of NF1 individuals. They are benign perineural nerve sheath tumors that also involve the nerves themselves and are composed of Schwann cells, fibroblasts, perineural cells, and mast cells. NF1-deficient Schwann cells are considered to be the primary neoplastic cell in the tumor (43). Neurofibromas can be classified according to their appearance and location into four groups: cutaneous, subcutaneous, spinal, and plexiform (11). Cutaneous neurofibromas develop particularly during childhood and early adulthood and may number several thousand per patient in extreme cases. Subcutaneous neurofibromas present as palpable lesions with no risk of malignant transformation. Spinal neurofibromas can involve an individual or multiple nerve roots at any vertebral level; they often grow in a bilateral symmetric fashion. Plexiform neurofibromas (PNs) are locally aggressive congenital lesions found in up to 50% of individuals with NF1 and are usually present at birth. They arise from multiple nerve fascicles or plexi and tend to grow along the length of a nerve; they can be nodular or diffuse in appearance. Their growth rate is unpredictable; they grow most rapidly in early childhood, with a median growth rate of approximately 20% volume per year in children less than 8 years (11,44,45), and do no accelerate due to hormonal changes of puberty (46). Facial PNs causing disfigurement usually manifest early, within the first few years of life (46). PNs can be a source of neuropathic pain and neurologic dysfunction ranging from minor sensory alteration to complete myelopathy, and can undergo malignant transformation into a malignant peripheral nerve sheath tumor (MPNST). The lifetime risk of developing MPNST in NF1 patients is 8% to 13% (11,47,48,49); the risk of malignancy increases with age. MPNST usually present with localized motor deficits or pain and dysesthesias with or without evidence of a rapidly enlarging mass.
Because PNs have complex geometric forms, three-dimensional volumetric measurements are preferred for size evaluation; a 20% change in volume is the threshold criterion recommended to indicate a decrease or increase in tumor size (50). This 20% volume threshold is lower than what is used in the majority of brain tumor protocols (in which a 40% volume threshold, or 25% surface area, is usually used). Biologic agents have shown activity in PNs, causing delay in time to progression. Sirolimus (an inhibitor of the mammalian target of rapamycin (mTOR) pathway) (51), imatinib mesylate (Gleevec, a cMET blocking agent) (52), and MEK inhibitors (53) have shown demonstrable activity in their treatment.
Of note, patients with Legius syndrome, one of the RASopathies, have been mistakenly diagnosed in the past as having NF1. Patients with Legius syndrome present with café au lait spots and skin-fold freckling that are indistinguishable from NF1; however, they have no Lisch nodules, optic pathway gliomas (OPGs), neurofibromas, or MPNST (54).
Cranial and Intracranial Manifestations
Optic Pathway Gliomas
The most important primary brain abnormality in NF1 is the OPG (25,55,56). OPG is seen in 15% to 20% of individuals with NF1; almost all present before age 6 years. Less than one-half of these tumors cause vision loss; very few cause precocious puberty (57). Chiasmatic and retrochiasmatic lesions carry the highest risk for progression and visual loss (56,58,59); however, imaging features that predict development of symptomatic OPG have not been identified (60). Early identification of OPG by “screening MRI exams” (i.e., MRI exams in asymptomatic NF1 children) may lead to improved visual outcomes (58).
Figure 6-1 Optic pathway glioma in NF1. A. Contrast-enhanced sagittal T1-weighted image shows a mass (arrows) infiltrating the chiasm and the hypothalamus and extending into to the lower third ventricle. B. Axial T2-weighted image reveals posterior extension (arrows) of the OPG from the chiasm into the optic tracts to the level of the lateral geniculate body. C. Postcontrast axial T1-weighted image shows incomplete enhancement of the tumor within the optic tracts (arrows).
The tumor can be isolated to a single optic nerve or can involve both optic nerves; the chiasm and the optic tracts can also be involved (Figs. 6-1, 6-2, 6-3 and 6-4). Primary involvement of the optic nerve is more common in the NF1 population, while sporadic OPG (in patients without NF1) more commonly involves the chiasm and optic radiations (61). Irrespective of the distribution, the clinical course of NF1-associated OPG is more indolent than in the sporadic OPG (61,62).
Optic pathway tumors (and other tumors that arise commonly arise in the diencephalon, near the floor of the third ventricle in NF1 patients) are most commonly of low histological grade; most are pilocytic astrocytomas. In some NF1 patients, these tumors can spontaneously involute over time (Fig. 6-5) (63,64,65). Therefore, aggressive therapy is usually not indicated unless symptoms progress or radiologic evidence of progression is noted. Uncommonly, optic pathway tumors can be highly malignant, demanding a very aggressive treatment approach (59).
Tumors of the optic nerve infiltrate and expand the nerve, producing a fusiform mass. Two architectural forms can be distinguished. The intraneural form is a diffuse expansion of the optic nerve itself without significant subarachnoid tumor (Fig. 6-2C). The perineural form is tumor infiltration of the subarachnoid space (astrocytic proliferation), creating a rim of tumor around a relatively unaffected nerve; at times, both forms can coexist (Fig. 6-3B) (66,67). Postcontrast MR using fat suppression will distinguish the two architectural forms of optic nerve gliomas. When the nerve is diffusely infiltrated, enhancing tumor fills the optic nerve sheath, whereas infiltration of the subarachnoid spaces shows a rim of enhancing tumor around a minimally enhancing optic nerve. Marginal cases (characterized by development of mild thickening of the optic nerves or by transient or mild enhancement of the optic nerves) are commonly observed; it is not clear whether these truly warrant a diagnosis of OPG (60). Finally, optic nerve tortuosity (without abnormal thickening or enhancement) is commonly observed in NF1 and should not be mistaken for an optic nerve glioma (60,68).
Figure 6-2 Optic pathway glioma with extensive infiltration. A. Sagittal T1-weighted image shows a mass extending from the chiasm and hypothalamus (arrows) extending toward the mammillary bodies and the fornices. The pons is slightly enlarged and shows abnormal low T1 signal. B. Axial T2-weighted image shows T2 hyperintense tumor has infiltrated into the medial basal ganglia/internal capsules (white arrows) and the fornices (black arrow). The tumor has extended posteriorly to the level of the lateral geniculate bodies. C. Axial T2-weighted image at a lower level reveals diffuse tumor infiltration, manifested as hyperintensity of the pons and middle cerebellar peduncles (long white arrows). Both optic nerves (short white arrows) are enlarged with homogeneous low T2 signal.
Although tumors of the intraorbital optic nerves can be evaluated with CT, MR is the preferred imaging modality for evaluating the entire CNS in NF1 due to the increased information and lack of exposure of the child to ionizing radiation. Assessment of the precise diameter of the intraorbital optic nerves may be hampered by chemical shift artifact resulting from the location of the nerve adjacent to orbital fat, but use of fat-suppression techniques eliminates the chemical shift artifact and allows the nerve to be excellently evaluated, along with the intracranial optic nerves, optic chiasm, optic tract, and optic radiations. T1 and fatsuppressed T2-weighted axial and coronal sequences, using less than or equal to 3 mm slice thickness, should be obtained through the globes, optic nerves, and optic chiasm and followed by fat-suppressed contrastenhanced T1 axial and coronal images. A routine brain scan should follow to look for involvement of the optic tracts and other areas of the brain. Fluid-attenuated inversion recovery (FLAIR) and T2-weighted images show involvement of the optic tracts as high signal intensity extending posteriorly, often to the level of the lateral geniculate bodies; the internal capsules and adjacent basal ganglia are commonly infiltrated (Figs. 6-1 and 6-2). Further extension beyond the optic pathways can also be identified in some patients: superiorly into the hypothalamus, fornices, and septum pellucidum; laterally into the temporal lobes; posteriorly into the optic radiations; and inferiorly into the cerebral peduncles and the brainstem (Fig. 6-2). Rarely, tumor can extend into the lateral ventricles.
Figure 6-3 Optic nerve tumor with infiltration of the optic nerve sheath. A. Postcontrast axial T1-weighted image with fat suppression shows enlarged, enhancing the left optic nerve (long white arrow) and tumor infiltration into the dilated perineural spaces (low T1 signal bordered by a thin rim of enhancement [short white arrows]). The right optic nerve (black arrows) shows a smaller tumor. B. Oblique sagittal T2-weighted image of the left optic nerve with fat suppression reveals thickening and elongation of the nerve. The sheath around the nerve shows marked dilatation and hyperintense signal (white arrows).
Figure 6-4 Multivoxel spectroscopy of optic pathway tumor in NF1. A. Axial FLAIR image shows tumor infiltration in the chiasm/hypothalamus (long white arrow) and into the optic tracts (short white arrows). B. Color map of the choline to creatine ratio (Ch:Cr) from a long echo (TE = 270) multivoxel spectroscopy reveals the highest ratio of choline to creatine (red color) at the level of the chiasm/hypothalamus. Significant Ch:Cr elevation is also evident in the thalami bilaterally (yellow color). C. MR spectra from four different ROIs (numbered in image B). Highest (Ch:Cr) is evident in box 1, at the level of the chiasm/hypothalamus. Ch:Cr levels are elevated in the thalami (boxes 3, 4) compared to the putamen (box 2); this suggests the presence of microscopic tumor infiltration in the thalamus, despite the normal FLAIR signal.
Figure 6-5 Spontaneous partial involution of a diencephalic tumor. A and B. Axial T2 FLAIR (A) and contrast-enhanced T1 (B) images of a 5-year-old reveals a mass in the inferior left diencephalon with intense enhancement (long arrows, A, B); nonenhancing, presumed vacuolation is evident in the right globus pallidus (short arrow, A). C. Axial FLAIR image 3 years later (without intervening treatment) shows only a small T2 bright residual abnormality, immediately behind the anterior commissure (arrow), which could represent vacuolation or residual tumor (lesion did not enhance). T2 abnormality previously evident in the right globus pallidus shows near-complete resolution.
Care should be taken not to mistake enlarged subarachnoid spaces within the optic nerve sheaths (the result of ectasia of the dura surrounding the optic nerves) for optic nerve tumors. The enlarged perioptic spaces have signal intensity identical to cerebrospinal fluid (CSF) and do not enhance after contrast administration. Care should also be taken not to confuse extension of OPG into the optic tracts (and beyond) with the characteristic T2 bright foci encountered in pediatric patients with NF1 (see next section). Differentiation of the two pathologies can be very difficult; features of OPG infiltration include contiguity, mass effect, low T1 signal on precontrast images, enhancement after contrast administration, and significant elevations of choline (at MR spectroscopy) (Fig. 6-4) (69).
Other Gliomas and Tumor-Like Conditions
Astrocytomas are more common in NF1 than in the general population (25,48,55,70); they can arise anywhere in the CNS. Pilocytic astrocytomas (Figs. 6-6 and 6-7) are most common, but other low-grade (71) and higher-grade tumors (70,72) also occur. Almost any part of the CNS can be affected; outside of the optic pathway/diencephalon, the most common site is the brainstem (Fig. 6-7) (73). It is of interest to note that the brainstem tumors occurring in NF1 seem to differ biologically from brainstem tumors in other patients. In contrast to the predominance of pontine tumors in the general population, the medulla is the most common site of brainstem tumor origin in NF1, followed by the mesencephalon (particularly the periaqueductal region/tectum) and the pons. This difference in location may partly explain the indolent course and vastly better long-term outcome of most brainstem tumors in NF1 (73,74,75,76). Many tumors do not require therapeutic intervention (52); some may regress spontaneously (77). Thus, management of brainstem tumors in children with NF1 is generally not aggressive unless clinical progression is seen—isolated radiologic progression is considered less serious. Other common locations for astrocytomas in children with NF1 are the cerebellum (Fig. 6-6), the corpus callosum, and the cerebral hemispheres (Fig. 6-8) (48,55,78).
Chronic, nonprogressive enlargement of the pons, medulla, and middle cerebellar peduncles is occasionally observed in children with NF1 in association with, and likely the result of, extensive myelin vacuolation (Fig. 6-9). This hamartomatous enlargement should not be misdiagnosed as a brainstem glioma; differentiating features from infiltrating gliomas include normal or nearly normal signal in T1-weighted images, only modest (and usually heterogeneous) signal increase on T2 images, absence of contrast enhancement, and lack of progression on follow-up scans. The T2 signal abnormalities partly regress during adolescence, though the brainstem remains enlarged. For more discussion of brainstem tumors, see Chapter 7.
Figure 6-6 Development of a pilocytic astrocytoma in an area of extensive myelin vacuolation. A. Axial T2-weighted image of a 5-year-old child reveals multiple characteristic foci of T2 hyperintensity (arrows) in the deep cerebellar white matter and middle cerebellar peduncles. B and C. Axial T2-weighted (B) and postcontrast sagittal T1-weighted image (C) obtained 4 years later. A large rim-enhancing T2 hyperintense mass (arrows) has developed within the deep right cerebellar white matter, with surrounding edema.
Figure 6-7 Midbrain juvenile pilocytic astrocytoma in a 14-year-old with NF1. A. Postcontrast T1-weighted image shows a sharply marginated, intensely enhancing mass (white arrow) in the dorsal inferior midbrain. B. Axial FLAIR image demonstrates the well-circumscribed hyperintense mass (white arrow) to have minimal surrounding edema. C. Single voxel long echo (TE = 270) spectroscopy of the tumor reveals a very high Ch:Cr (3.49; normal < 1.5) and presence of lactate (double arrows). These MRS findings, worrisome for a malignant tumor, are commonly observed in pilocytic astrocytomas, the likely diagnosis in this patient. N-Acetylaspartate to creatine ratio (NAA:Cr) is decreased (1.68; normal > 2). The NAA:Cr is higher than expected for a glial neoplasm, likely secondary to contamination of the voxel by surrounding (normal) brain tissue as the voxel (2 × 2 × 2 cm size) is slightly larger than the tumor.
Figure 6-8 Grade 2 (fibrillary) glioma in the left temporal lobe of a 10-year-old with NF1. A. Axial T2-weighted image shows a tiny, hyperintense lesion (white arrow) in the white matter of the posterior left temporal lobe. B. Axial T2-weighted image a year later shows an ovoid, well-defined T2 bright focus in the same location (arrow), representing the enlarged tumor.
Hamartomatous enlargement of the hypothalamus is occasionally seen in children with NF1 (Fig. 6-10), usually not associated with precocious puberty or gelastic seizures (79). The lesion typically lies within the walls of the hypothalamus in the lower third ventricle (intrathalamic/sessile configuration). Like hypothalamic hamartomas in children without NF1, they are nearly isointense to gray matter on T1- and T2-weighted images and do not enhance (80); they should not be confused for a chiasmatic or hypothalamic glioma.
Figure 6-9 Probable hamartomatous enlargement of the brainstem. A. Sagittal T1-weighted image reveals diffuse enlargement of the pons and, especially, medulla (white arrows); the signal intensity is normal. B. Axial T2-weighted image shows enlargement and heterogeneously increased signal in the dorsal right pons and middle cerebellar peduncle, with slight mass effect on the fourth ventricle (arrow).
In a small but significant number of patients with NF1, hydrocephalus is present (81,82,83). The site of obstruction of CSF flow is usually the aqueduct of Sylvius, resulting from benign aqueductal stenosis, from extensive vacuolation of the tissues surrounding the aqueduct (see next section), or from tumors (astrocytomas or hamartomas) of the adjacent tectum or tegmentum of the mesencephalon. The diagnosis of a tectal glioma is relatively simple using MR. In contrast to benign aqueductal stenosis (in which the proximal aqueduct is dilated and the tectum displaced superiorly and thinned, see Chapter 8), gliomas enlarge the tectum and narrow (or completely obliterate) the aqueduct. Occasionally, the tectum may appear short and thick in aqueductal stenosis because of mass effect on the rostral aspect of the tectum by a dilated suprapineal recess (see Chapter 8). In these cases, the patient should be reevaluated after ventricular decompression.
Figure 6-10 Hypothalamic hamartoma in a 15-year-old boy with NF1. A. Sagittal T1-weighted image shows a gray matter intensity mass (short white arrows) in the floor of the third ventricle, posterior to the chiasm (long white arrow), and anterior to the mammillary bodies (black arrow). B. Coronal T2-weighted image reveals bilateral gray matter intensity mass (black arrows) in the floor and left lateral wall of the hypothalamus.
White Matter Abnormalities and Characteristic Hyperintense T2 Lesions
White matter abnormalities are evident in many NF1 children. Many patients have an increased volume of cerebral white matter, typically associated with a large midsagittal corpus callosum area (Fig. 6-11) (84,85); these findings are more pronounced in patients with macrocephaly (˜40% of those with NF1 (86)) and are associated with a lower overall IQ (87). Advanced MRI diffusion analysis of the white matter of NF1 patients reveals a decreased fractional anisotropy (FA) and an increased apparent diffusion coefficient (ADC). Radial diffusivity is disproportionately increased, suggesting that looser packing of axons, with or without myelination changes, may contribute to the increased volume of cerebral white matter (88). Abnormalities of apoptosis (leading to redundancy of fibers connecting the cerebral hemispheres) have also been postulated as an explanation of the increased white matter volume (87).
Figure 6-11 Sagittal T1-weighted image shows an abnormally thick corpus callosum (white arrows). The ventral pons (black arrows) is prominent.
MR imaging often reveals characteristic hyperintense T2 lesions in pediatric patients with NF1, located in the brainstem, cerebellar white matter, basal ganglia (especially the globus pallidus), thalamus, internal capsule, corpus callosum, and, occasionally, corona radiata (Figs. 6-12 and 6-13) (36,89,90) but not in the centrum semiovale or the subcortical white matter. These lesions are characteristically multiple; they have little or no mass effect (unless extensive confluence is evident, in which case mild mass effect may be detected, Fig. 6-9) and do not elicit vasogenic edema; their T1 signal appears iso- or slightly hypointense compared to uninvolved white matter; and they do not enhance after intravenous administration of paramagnetic contrast. Intermediate echo (TE = 144 ms) proton MR spectroscopy shows nearly normal N-acetylaspartate (NAA)/creatine (Cr) and moderately increased Cho/Cr (69). These lesions are rarely identified in the first 2 years of life but develop/become visible from late infancy to about age 12 years (Fig. 6-12) (89); new lesions almost never develop after age 15 years. The lesions start to regress starting late in the first decade of life (90,91) and slowly disappear; they are almost never seen in patients over the age of 20 years (Fig. 6-13). In the peak age group (6-12 years), they are seen in up to 90% of NF1 children (39,92,93). A pathologic analysis has shown that these regions contain areas of myelin vacuolation, where the layers of myelin become separated as they spiral around the axon (94). As might be expected, water diffusivity is increased in these areas of T2 hyperintensity to a greater degree than in other areas of the brain (95); anisotropy is normal, but transverse eigenvalues are increased (96). Multishell diffusion MRI studies have shown that the water contained in the T2 hyperintense lesions behaves as intracellular water that has obtained extracellular-like properties, thus supporting the intramyelinic edema appearance of vacuolation (97).
The discoveries that the oligodendrocyte myelin glycoprotein gene is imbedded within the NF1 gene (19) and that its protein product (neurofibromin) is required for Schwann cell myelination (18) further support dysgenesis of myelin as the cause of the white matter abnormalities in NF1. The vacuolization appears to develop, therefore, in regions where the myelin is inherently abnormal; presumably, the return of normal T2/FLAIR signal on subsequent exams reflects myelin repair or remyelination (98). The increased diffusivity of white matter (even normal-appearing white matter) in NF1 (99,100) further supports the concept of abnormal myelin as an underlying cause.
Figure 6-12 Evolution of characteristic T2 bright signal abnormalities in pediatric NF1. A. Axial T2-weighted images through the posterior fossa of a 14-monthold reveals a few ill-defined foci of increased T2 signal within the deep cerebellar white matter in the middle cerebellar peduncles (arrows). B. Corresponding axial T2-weighted image in the same patient at age 3 years. There are now extensive foci of T2 abnormality within the deep cerebellar white matter, the middle cerebellar peduncles, and the pons (arrows). The volume of the involved tissue is mildly increased, resulting in mild distortion of the fourth ventricle.
In view of the frequency with which the characteristic T2 hyperintense foci are encountered in children with NF1, neither close imaging follow-up nor biopsy is indicated when they occur in the characteristic locations, are not significantly hypointense on T1-weighted images, and lack associated mass effect, edema, and enhancement. However, a growing astrocytoma of the basal ganglia, pons, or cerebellum, when small, may be indistinguishable from one of these lesions on noncontrast MR—especially in cases when there are numerous, confluent T2 hyperintense foci in expected locations. If a lesion has any suspicious characteristics, it is recommended that the patients have a follow-up contrast-enhanced MR scan, including diffusion-weighted imaging (DWI), perfusion imaging, or proton MR spectroscopy, 6 months to a year after the first study. A tumor will typically show progressive enlargement and mass effect on adjacent structures and often enhances (Fig. 6-6); it may also have locally reduced diffusion in its solid portion (95), have increased blood volume (101), and show elevated choline with decreased creatine and NAA on proton spectroscopy (69,102,103,104,105).
Figure 6-13 Partial resolution of basal ganglia signal abnormalities in NF1. A. Axial T2-weighted image at age 7 years shows multiple bilateral hyperintense abnormalities (white arrows) in the globi pallidi and internal capsules. B. Axial T2-weighted image 4 years later shows significant regression of the abnormalities.
T1 hyperintensity is observed in the globi pallidi of patients with NF1, with a different radiologic appearance than the characteristic T2 hyperintense foci: the hyperintensity on T1-weighted images develops after the T2 prolongation appears and persists after T2 prolongation disappears, a time course that suggests that the T1 shortening represents delayed or reactive formation of myelin (Fig. 6-14) (86,90,98,106). The distribution of the T1 bright signal can be diffuse within the T2 abnormality or be located along its periphery/rim. (Calculation of T1 values shows that the frontal white matter, caudate nuclei, putamina, and thalami also have some T1 shortening (86), but it is not apparent to visual inspection in these other areas.) In some patients, the T1 shortening is observed at the time of a first MRI, prior to exposure to gadolinium-based contract agents. However, many of the NF patients with appreciable T1 bright signal changes in the globus pallidus also have bright T1 signal in their dentate nuclei and have undergone multiple contrast-enhanced MRI exams; the T1 bright signal changes in some of these cases, therefore, may be a reflection of gadolinium deposition in the brain (107), rather than a reflection of an intrinsic abnormality of the myelin.
Figure 6-14 T1 and T2 prolongation in the basal ganglia in NF1 of an 18-year-old. A and B. Noncontrast sagittal T1- (A) and axial T2 (B)-weighted images show a lesion in the left globus pallidus with hyperintensity on both T1 and T2 images (arrows). There was no associated mineralization or calcification on susceptibilityweighted images or CT images (not shown).
The overwhelming majority of these characteristic T2 bright lesions resolve over time. However, as with all small, nonenhancing foci of T2 prolongation in the brain, the biological behavior of white matter lesions in NF1 cannot be predicted with complete accuracy by imaging alone. Benign-appearing lesions can degenerate into neoplasms (108), and neoplastic-looking lesions can shrink or disappear (63,64,65). Also remember that focal lesions developing in the cerebral cortex or in the subcortical or deep white matter do not represent characteristic T2 bright lesions of pediatric NF1 (Fig. 6-8) (93); if present, these should be followed by sequential imaging, as they may potentially represent lowgrade neoplasms.
Occasionally, the hippocampi of pediatric patients with NF1 can show diffusely increased signal on T2-weighted images, often with increased volume (Fig. 6-15); this finding can be unilateral or bilateral and is not progressive; it persists throughout childhood and adolescence (93), in contrast to the characteristic T2 lesions described above that regress during later childhood and adolescence. The nature of the hippocampal abnormality is not known. NF1-related hippocampal T2 changes should not be confused with hippocampal sclerosis (in which case the hippocampal volume is decreased) or with neoplastic infiltration.
Vascular Dysplasia
Dysplasia of the cerebral vasculature is increasingly recognized in children with NF1; it develops at a young age, with prevalence of up to 6% (109,110,111). The incidence in the symptomatic NF population appears to be higher, with a predicted range of 7% to 15% (112). The known significant incidence of vascular abnormalities in the cerebral vasculature and in other parts of the body makes vascular dysplasia a distinct clinical entity. Any child with NF1 who has seizures, mental retardation, paralysis, or severe headaches may have a vascular dysplasia, particularly in the absence of a brain tumor or hydrocephalus. However, clinically, a majority of NF1 patients with vascular dysplasia do not have focal deficits as a result of their arteriopathy by the time the dysplasia is diagnosed with MRI. Intracranial vascular dysplasias can result as a complication of irradiation for optic nerve or optic chiasm gliomas (presumably radiation arteritis in these cases; see discussion in Chapter 3).
Common vascular abnormalities include stenoses, occlusions, ectasia, moyamoya disease, and fusiform aneurysm formation. Most commonly, the dysplasia results from intimal and smooth muscle proliferation, with resultant stenosis or occlusion; they can progress overtime (Fig. 6-16) and may require revascularization surgery (109,111). The carotid (common or internal) artery, proximal middle cerebral artery, or proximal anterior cerebral artery is the most common site of involvement (Figs. 6-16 and 6-17). Moyamoya phenomenon with marked enlargement of the lenticulostriate arteries (which function as collateral vessels) is seen in many such patients (113). (Moyamoya is discussed further in Chapter 12.) Fusiform arterial dilation, cerebral aneurysms, and arteriovenous fistulas are also described, although less commonly (109,113,114).
Figure 6-15 High-resolution coronal FSE T2-weighted image reveals hyperintense T2 signal of both hippocampal formations (white arrows) (compare signal to that of adjacent temporal cortex). The right hippocampus is brighter and larger than the left.
Figure 6-16 Progressive NF1-related vasculopathy. A. Axial T2-weighted image at age 18 months shows normal-appearing signal voids in the basilar and proximal anterior and middle cerebral arteries—note the normal right MCA (arrow). B. Axial T2-weighted image 2 years later shows diminished size of the right MCA signal void (white arrow). C. Coronal reconstructed MIP image from a 3D TOF MRA reveals a lack of flow-related enhancement in the right MCA (arrows), consistent with an acquired complete occlusion (or very severe stenosis).
Vascular dysplasias can be difficult to detect on standard CT or MR images; with MR, close inspection of the arterial signal voids (Figs. 6-16 and 6-17), especially the distal carotid arteries and the circle of Willis (to detect narrowing of the cavernous or supraclinoid carotids and proximal middle and anterior cerebral arteries), is essential in patients with NF1 to avoid delays in clinical detection of these lesions; note that the intracranial vessels are poorly seen on FLAIR images, so acquisition and inspection of T2-weighted spin-echo images is strongly encouraged when imaging children with NF1, particularly those with declining function. As many vascular lesions are subtle and easily overlooked, some authors promote the routine use of MR angiography to better delineate intracranial vasculopathy (17). If vascular dysplasia is suspected, MR (or CT) angiography should be performed; conventional, catheter angiography is usually reserved for a presurgical workup. Angiography generally shows either severe stenosis or occlusion of the involved cerebral vessels (Fig. 6-17); arterial dysplastic lesions are also demonstrated.
Cranial Nerve Tumors
Cranial nerve tumors are uncommon in NF1, which mainly causes glial tumors and neurofibromas of peripheral nerves. Schwannomas are much more common in NF2 (see next section). The only cranial nerve that is frequently involved in NF1 is the optic nerve, which has been discussed above and is, in fact, a diencephalic white matter tract that has been misnamed as a cranial nerve. The other cranial nerves are rarely, if ever, involved. When schwannomas occur in patients with NF1, the possibility of “overlap” syndromes (syndromes with characteristics of both NF1 and NF2) is often raised (115,116). Although patients with features of both NF1 and NF2 clearly exist, the true incidence and implications of the overlap in affected patients are not known (117).
Figure 6-17 Vascular dysplasia in NF1. A. Axial T2-weighted image shows asymmetric appearance of the internal carotid arteries with absent flow void within the right posterior cavernous sinus (short arrow). The left optic nerve sheath is enlarged (long arrow). B. Lateral view of catheter angiography of the right common carotid artery shows dysplasia of the horizontal segment of the cavernous segment of the internal carotid artery with three focal areas of aneurysm formation (arrows); focal stenosis is evident next to the most distal aneurysm.
Calvarial and Orbital Abnormalities
Other cranial/intracranial manifestations of NF1 include deficiencies of the sphenoid wing and of the occipital bone along the lambdoid suture. Sphenoid bone dysplasia allows herniation of the temporal lobes into the orbit (Fig. 6-18). The pulsations of the temporal lobe may be transmitted through the globe, thus being visible externally as pulsatile exophthalmos (or enophthalmos secondary to atrophy of orbital contents). The globe may be dysplastic, enlarged (buphthalmos), or hypoplastic. Sphenoid wing deficiency is nearly always associated with PNs in the orbit or periorbital regions (Fig. 6-18). Recent work indicates that the abnormalities of the bony orbit may progress over time, suggesting that these are not simple dysplasias of bone, as previously postulated, but may in part result from erosions by the adjacent neurofibromas (Fig. 6-18) or optic nerve tumors (118,119). Occipital bone dysplasia is usually not clinically significant; it is easily recognized with CT imaging. With MR imaging, it presents as distortion and focal outward bulging of the cerebellar hemisphere deep to the bone defect; this can be confusing until the bone defect is recognized.
Figure 6-18 Dysplasia of the sphenoid wing with associated plexiform neurofibroma. A. Axial T2-weighted image shows an extensive neurofibroma (white arrows) infiltrating the superior orbit and the left temporal fossa (the V1 distribution). The greater wing of the sphenoid bone is dysmorphic, resulting in anterior extension of the contents of the left middle cranial fossa. B. Axial T2-weighted image at a slightly lower level shows the inferiorly displaced, proptotic left globe. Neurofibroma is also evident within an enlarged pterygopalatine fossa (V2 distribution, white arrows).
Neurofibromas and Plexiform Neurofibromas
Another cause of intracranial complications in NF1 is excessive growth of craniofacial PNs. They tend to progress along the nerve of origin (usually small, unidentified nerves) into the intracranial space, causing distortion and compression of the brain. They most commonly arise from branches of the trigeminal nerve, with occasional intracranial involvement to the level of the cavernous sinus. In the orbit, they act as masses, causing impaired ocular movements and exophthalmos (Fig. 6-19). Orbital neurofibromas commonly arise in the region of the orbital apex or superior orbital fissure (in the distribution of the first division of the trigeminal nerve); careful evaluation of the images often reveals extension into the cavernous sinus, nasopharynx, or pterygomaxillary fissure. The neck is another common location for neurofibromas, especially along the course of the vagal nerve, with an estimated occurrence of 25% to 30% in patients with NF1 (Fig. 6-20) (120). Neck masses, their appearance, and their differential diagnoses are discussed in Chapter 7.
Figure 6-19 Rapid progression of orbital plexiform neurofibroma. A. Axial fat-suppressed T2-weighted image of an 8-month-old reveals a dysplasia of the left greater wing of the sphenoid with resultant enlargement of the left middle cranial fossa. Mild soft tissue thickening is evident in the left cavernous sinus (black arrow) and in the lateral left orbital extraconal soft tissue (white arrows) indicative of a V1 distribution plexiform neurofibroma. The left globe is mildly proptotic. B and C. Corresponding axial fat-suppressed T2 (B) and contrast-enhanced T1 (C) images 2 years later show marked progression in the size of the plexiform neurofibroma within the cavernous sinus (black arrows) and in the pre- and postseptal soft tissues of the left orbit (white arrows). Left globe proptosis has significantly worsened.
Solitary neurofibromas have slightly greater signal intensity than does skeletal muscle on T1-weighted sequences. On T2-weighted sequences, the lesions have variable signal intensity. Most commonly, the periphery of the lesions tends to be of high T2 signal intensity with respect to muscle, whereas the center of the lesions is often of low signal intensity (121,122,123,124); this has been referred to as the “target sign” (Figs. 6-20 and 6-21) (125). The central area of decreased T2 intensity is probably related to the known dense central core of collagen within these lesions (122,123). Collagen has a low mobile proton density and therefore is of low signal intensity on T2-weighted images. Enhancement after administration of paramagnetic contrast is variable, although at least a portion of the tumor usually enhances (usually the central aspect, corresponding to the central T2 hypointense (“target”) components (see Fig. 6-24).
Figure 6-20 Slow progression of an extensive plexiform neurofibroma. A. Coronal inversion recovery fat-suppressed T2 image at age 5 years reveals several infiltrative T2 hyperintense masses (numbered 1 to 3, seen to connect on other images) in the paravertebral, deep cervical, and upper thoracic soft tissues typical of a plexiform neurofibroma. B. Corresponding coronal fat-suppressed T2 image 12 years later shows marked enlargement of the plexiform neurofibroma. The largest component measures approximately 40 mm in diameter. It has preserved central T2 dark/target characteristic (evident in all components of the mass); findings are not suggestive of a malignant transformation.
PNs tend to be of low attenuation on CT and generally show little enhancement after administration of intravenous contrast.
Spinal Manifestations
Scoliosis and Intramedullary Tumors
Abnormal curvature of the spinal column (scoliosis, kyphosis) is the most common skeletal abnormality reported in patients with NF1. In Holt’s series, it was present in 32% of affected children; the incidence increases with age (126). The abnormal curvature is usually minimal or mild in degree and can resemble idiopathic adolescent scoliosis. It can be severe, in which case dystrophic curves are commonly encountered, with potential for rapid progression (Fig. 6-22) (127). Dystrophic curves are associated with a high incidence of paraspinal or other internal neurofibroma next to the vertebra. Patients with paraspinal PNs have sixfold higher odds of developing spinal curvature abnormalities compared to patients without PNs (128). Dysplasia of the vertebral bodies is common, as are hypoplasia of the pedicles, transverse processes, and spinous processes; scalloping of the posterior aspects of the vertebral bodies; and hyperplastic bone changes (120,129). It is not certain whether these bony anomalies result from a primary mesodermal dysplasia or are secondary to the effects of nerve sheath tumors. Plain film radiography is essential to demonstrate the scoliosis optimally. CT is the optimal modality for demonstrating the changes of the individual vertebrae, as it shows superior bone detail. However, most of the bony changes are well visualized with high-quality MR studies.
Figure 6-21 Malignant nerve sheath tumor developing within a plexiform neurofibroma in a 15-year-old who recently experienced lower neck pain. A and B. Axial (A) and coronal (B) T2-weighted images with fat suppression reveals a mass in the right brachial plexus. Central target signs (black arrows) are evident in the more superficial aspects of the lesion, characteristic of plexiform neurofibroma. In the deeper portion of the mass, a larger confluent area (white arrows) without target sign is evident. Malignant nerve sheath tumor was confirmed by needle biopsy of this area.
Figure 6-22 Rapid progression of cervical kyphosis (without surgical intervention) in NF1. A. Sagittal T1-weighted image at age 10 years shows a focal kyphotic deformity in the mid cervical spine (black arrows) secondary to dysplasia and erosions of the adjacent cervical vertebrae. B. Postcontrast axial T1-weighted image with fat suppression through the midportion of the kyphosis reveals enhancing, infiltrating plexiform neurofibroma in the prevertebral space (short arrows), extending laterally into the right vertebral foramen (long arrow). The anterior aspect of the vertebral body is eroded (white arrowheads). The subarachnoid spaces (black arrowheads) along the posterior/right lateral aspect of the cord are enlarged secondary to the dural ectasia and kyphotic deformity. C. Sagittal T1-weighted image 6 years later reveals marked progression in kyphotic angulation.
When abnormal spinal curvature is present, the question often arises as to whether it results from the dysplastic bone of neurofibromatosis or from an intrinsic spinal cord lesion such as a tethered cord, syringomyelia, or a tumor. If an intrinsic spinal cord tumor is present in a patient with NF1, it is likely to be an astrocytoma (130). The appearance of intramedullary astrocytomas in children with NF1 is no different from that of other intramedullary astrocytomas (see Chapter 10). In the absence of any neurologic signs or symptoms, the incidence of an underlying spinal cord disorder is very low in children with dextroscoliosis (convexity of the curvature to the right). However, children with levoscoliosis, especially if it is rapidly progressive, associated with pain, or associated with neurologic deficits, have a significantly higher incidence of underlying spinal cord abnormalities (131). Imaging of scoliosis is discussed further in Chapter 9.
Dural Dysplasia and Meningoceles
Dural ectasia is identified in 75% of patients with posterior vertebral scalloping and in 25% of those with lateral scalloping. Lateral meningoceles are diverticula of the thecal sac (most commonly at the thoracic level) that extend laterally through widened neural foramina. Most authorities feel that the meningoceles result from a primary mesodermal dysplasia (129,132); the primary abnormality in affected patients may also be hypoplasia of the pedicles (which makes it possible for the dural sac to herniate laterally in response to spinal fluid pressure). Weakness in the meninges allows the thecal sac to be focally stretched in response to CSF pulsations. The protrusions from the thecal sac slowly erode the bony elements of the neural foramina, allowing the meningoceles to form. The thoracic region is thought to be primarily affected because of the lesser development of the paravertebral muscles and the relatively high pressure difference between the negative pressure of the thorax and the spinal CSF (133). The CT appearance of a lateral meningocele is that of a wide neural foramen with a CSF-attenuation dumbbell-shaped mass extending through it. The corresponding vertebral body is usually markedly scalloped (134). The MR appearance of these lesions is similar in that the neural foramen is markedly widened and the spinal canal is enlarged as a result of scalloping of the posterior vertebral body at the level of the meningocele (Fig. 6-23). The meningocele is isointense with CSF on all imaging sequences. Differentiation from neurofibromas can be made by noting the absence of the central low-intensity focus on the T2-weighted images (122). Neurofibromas are of higher signal intensity than CSF on T1-weighted images (compare Fig. 6-23 with Fig. 6-24).
Figure 6-23 Dural ectasia in NF1. A and B. Sagittal (A) and axial (B) T2-weighted images demonstrate scalloping of the posterior vertebral bodies at the lumbosacral junction (arrows, A). Bilateral anterior sacral meningoceles are evident (arrows, B). The largest on the left extends out of the spinal canal through a widened neural foramen (*).
Nerve Sheath and Other Soft Tissue Tumors
Intra- or paraspinous neurofibromas develop in a large number of patients with NF1, in all segments of the spine (48,135); in some families, neurofibromas are nearly entirely limited to the spine (136). Spinal nerve sheath tumors are less commonly symptomatic in NF1 (only 1%-2% are symptomatic (135)) than in NF2 (30%-40% symptomatic (137)). Scoliosis appears to be more common in NF1 patients with spinal neurofibromas than in those without (138). About 90% of these tumors are extradural, with more than half being intraforaminal (135). In contrast, most nerve sheath tumors in NF2 are intradural (139).
Figure 6-24 Extensive plexiform and spinal neurofibromas with cord compression in NF1. A. Coronal T2-weighted image of the lumbar spine and upper pelvis shows extensive plexiform neurofibroma (subcutaneous and muscular spaces). Intraspinal involvement is evident at the level of the kidneys (black arrow). B and C. Axial FSE T2-weighted image (B) and postcontrast axial SE T1-weighted image (C) through the upper lumbar spine show large bilateral neurofibromas (n) expanding the spinal canal and neural foramina; the intradural component of the right-sided neurofibroma displaces the thecal sac to the left (white arrow). Extensive plexiform neurofibromas infiltrate the retroperitoneum.
Most nerve sheath tumors in NF1 appear to be neurofibromas (121), with schwannomas uncommon. Although isolated spinal neurofibromas can be seen in patients unaffected by NF1, patients with von Recklinghausen disease can have neurofibromas of varying sizes at several levels throughout the spinal canal (55,122). However, in general, patients with NF1 have only a few (5,6) nerve sheath tumors, in contradistinction to patients with NF2, who typically have many (more than 10) spinal nerve schwannomas (see section on NF2 below).
The MR appearance of neurofibromas is that of masses that may be entirely within the spinal canal. When small, intradural neurofibromas appear as nodules of soft tissue along the nerves roots, most commonly identified along the cauda equina (Fig. 6-25). Larger intraspinal neurofibromas (which can be intra- or extrathecal) may displace the spinal cord or nerve roots of the cauda equina to the contralateral side of the canal (Fig. 6-24) and can cause canal enlargement. When bilateral neurofibromas are present at a single level, the cord can be compressed into a narrow, central band of tissue that is elongated in the anterior-posterior direction (Fig. 6-26). Furthermore, the lesions can extend outward from the spinal canal through neural foramina (Fig. 6-24) that are usually of enlarged secondary to pressure erosion of the bone (121,122).
Outside the spinal canal, neurofibromas show a slightly greater signal intensity than skeletal muscle on T1-weighted sequences and high intensity periphery with variable intensity center on T2-weighted sequences (121,122,123), sometimes resulting in the aforementioned “target sign” (Fig. 6-24) (125). On CT, the paraspinal neurofibromas have low attenuation when compared to muscle.
Malignant Peripheral Nerve Sheath Tumor
It is well established that malignant peripheral nerve sheath tumors (MPNST, also known as neurofibrosarcomas) occur in NF1; most arise within preexisting PNs (48,49,55). The MR features of benign and malignant nerve sheath tumors are not always sufficiently different to distinguish them. Both can be large and relatively well circumscribed, and neither commonly invades adjacent structures. Serial MRI demonstrating localized, disproportional change in appearance/size of areas within a PN is highly suggestive of localized malignant transformation; a threshold value of 5 cm is frequently used (140,141). Other MR findings indicative of a MPNST (Fig. 6-21) include irregular tumor shape, poor demarcation from surrounding tissues, evidence of necrosis, intratumoral lobulation, presence of high-signal-intensity foci on T1-weighted images (corresponding to intratumoral hemorrhage) and lack of target sign. ADC values tend to be lower than for benign peripheral nerve sheath tumors. Heterogeneous enhancement and a lower proportion of enhanced area have been documented (122,125,142). Of note, marked heterogeneity can be seen in benign tumors as well (124), so this is not a specific imaging sign.
Figure 6-25 Multiple small intraspinal neurofibromas. A. Sagittal T2-weighted image shows multiple small nodular soft tissue intensity foci (white arrows) in the subarachnoid space. B. Axial postcontrast T1-weighted image shows that the lesion (arrow) at the sacral level enhances.
Figure 6-26 Bilateral C1-C2 spinal neurofibromas with spinal cord compression in NF1. Axial T2-weighted image shows neurofibromas (white arrows) that compress the thecal sac and spinal cord (small white arrowheads). An intradural neurofibroma component is evident on the right (large white arrowhead). (* denotes odontoid process of C2).
Currently, 18F-fluorodeoxyglucose (FDG) PET imaging seems to be the best way to differentiate benign from malignant nerve sheath tumors; malignant tumors show significantly higher uptake of FDG than do benign tumors (143). A SUV max greater than 3.5 is indicative of malignant transformation in a PN (140,141).
Neurofibromatosis Type 2
Clinical Manifestations
Neurofibromatosis type 2 (NF2) has also been called neurofibromatosis with bilateral acoustic schwannomas. NF2 is a separate disease altogether from NF1. NF2 is associated with mutations of chromosome 22 (critical region in about 6 megabases within 22q12.2 (144)). The product of the NF2 gene is called merlin (Meosin-ersin-raxidin-like protein, also called schwannomin); it is a tumor suppressor gene that is believed to control interactions between affected cells and surrounding structures in the extracellular matrix, largely by regulating essential signal transcription pathways, including growth stimuli to cell cycle progression (145). Mutated merlin inhibits cell adhesion, which is important for regulating cell growth, and is more soluble than normal protein, making its interaction with the cytoskeleton unstable (146,147). A correlation has been identified between the type of mutation of the NF2 gene and the phenotype of the affected patients in that nonsense and frame shift mutations cause more severe disease (younger age at onset and diagnosis, more tumors) than missense mutations or mild deletions (148,149).
NF2 is autosomal dominant, with an estimated incidence of 1 in 25,000 to 33,000 births (47). About 50% of cases represent new mutations, and as many as one-third are mosaic for the underlying disease causing mutation (150). The major feature of NF2 is the presence in nearly all affected individuals of bilateral vestibular schwannomas (Figs. 6-27 and 6-28). When detected very early, before the age of 1 year, bilateral vestibular schwannomas have a propensity to remain asymptomatic until the second decade of life (151). Other tumors of the central nervous system, particularly meningiomas and other schwannomas (Figs. 6-29 and 6-30), may be present as well. (Most children with meningiomas do not have NF2; however, 72% of pediatric meningiomas harbor deletions of the NF2 gene (152).) Although tumors begin to develop in children, symptoms are often delayed until early adulthood (late teens or 20s) when the tumors become large enough to cause symptoms. In contrast to the situation in adults, hearing loss is an uncommon presentation in childhood; seizures (caused by meningiomas) and facial nerve palsy are much more common presenting symptoms, as are neurologic symptoms related to brainstem and/or spinal cord tumors (150,153,154). Tumor load tends to be extensive when presentation is during childhood; cranial meningiomas are seen in 60% of cases, cranial schwannomas (other than vestibular) in 36%, and spinal schwannomas and meningiomas each in 80% (154). NF2-associated intracranial tumors show substantial variability in growth rate and pattern. The most common growth pattern is saltatory, characterized by periods of growth and quiescence; linear growth and exponential growth are less common (155).
Figure 6-27 Small bilateral acoustic schwannomas in NF2. A. Postcontrast axial T1-weighted image shows bilateral enhancing masses (arrows) filling the internal auditory canals. On the right, the mass extends into the vestibule (arrowhead). B. Axial steady-state acquisition T2-weighted image (FIESTA) shows replacement of hyperintense CSF signal in the interval auditory canals by the hypointense schwannomas (arrows) and a filling defect in the right vestibule (arrowhead) from intralabyrinthine tumor extension.
Cutaneous manifestations are much less frequent than in NF1: only about 25% of affected patients will have café au lait spots, and, when present, the spots are pale and few in number (<5) (137,156); only 1% will meet NIH criteria for NF1 (157). Cutaneous nerve sheath tumors (predominantly schwannomas) are seen in about 65% of affected patients but are minimal in size and few in number (137). When present, however, cutaneous schwannomas tend to develop during the first decade of life, before the cranial nerve schwannomas, which typically do not develop until the age of 10 to 15 years (156,158,159). Subcapsular cataracts are present in more than half of patients and may be present during childhood (137,160). Therefore, skin tumors and cataracts are valuable clues in the early detection of children with NF2 (156,158,159). The established diagnostic criteria for NF2 are listed in Table 6-5 (47). It should be noted that these criteria do not work well in children or in patients without a family history of NF2 (as many as 50% of affected patients (150,161)). Indeed, less than 20% of patients with NF2 are diagnosed during childhood (159). However, early diagnosis has important implications, as age at diagnosis is the strongest single predictor of relative risk of mortality and is a useful index for patient counseling and clinical management (162).
Figure 6-28 Bilateral acoustic schwannomas and cerebellar hamartomas in an adolescent with NF2. A and B. Postcontrast axial T1 (A) and axial fat-suppressed fast spin-echo T2 (B) images demonstrate bilateral nerve VIII schwannomas (arrows, A); the larger leftsided lesion expands the internal auditory canal and extends into the cerebellopontine angle cistern, compressing the middle cerebellar peduncle. Multiple nonenhancing T2 bright lesions are evident in the cerebellar hemispheres (arrows, B), with associated retraction deformities; appearance is consistent with that of hamartomas.
Some authors have noted that NF2 can be subdivided into two large groups (163). Type 1, also called Gardner’s form of NF2, is the mildest form of the disease with late onset. Patients have slowly growing eighth cranial nerve schwannomas and not more than one other tumor (meningioma or schwannoma). Type 2, also called Wishart’s form of NF2 or the Wishart-Lee-Abbott form, is a more severe form characterized by early onset and the presence of multiple tumors, including schwannomas, meningiomas, ependymomas, and sometimes astrocytomas. Patients with type 2 NF2 have a higher incidence of cataracts and skin tumors, as well as CNS tumors, than do those with type 1 NF2 (137). These subgroups have proved useful for prognostic purposes; however, the reader should remember that, as with nearly all such groupings, many patients with NF2 have intermediate severity of the disease and may not fall neatly into either form.
Figure 6-29 NF2 with multiple schwannomas. A. Postcontrast axial T1-weighted image of NF2 patient reveals bilateral trigeminal schwannomas. The left-sided schwannoma is limited to the cisternal portion of the nerve (white arrow), while the right-sided one involves the cisternal portion (small black 5) and the trigeminal ganglion (large black 5). B. Postcontrast axial T1-weighted image shows bilateral eighth nerve schwannomas (white arrows), schwannoma of the left temporal branch of the third division of the fifth cranial nerve (white arrowhead), and the large schwannoma involving the right trigeminal ganglion (black 5). C. Postcontrast axial T1-weighted image at a slightly more inferior level shows, in addition to the fifth nerve tumors (black 5) described in (B), a ninth nerve schwannoma (white arrow) in the cerebellomedullary cistern. D. Postcontrast coronal T1-weighted image shows the large right-sided fifth nerve schwannoma (white arrows) extending through and expanding the right foramen ovale.
The mainstay of management of NF2 is surgical removal of symptomatic cranial and spinal tumors. However, there are recent reports of slowing of the growth of vestibular schwannomas with therapies targeted to the intracellular signaling pathways involved in NF2 tumorigenesis (47,164). The antiangiogenic agent bevacizumab, an inhibitor of the VEGF-pathway, is highly efficacious in shrinking the lesions, with resulting improvement of hearing (138,165).
Imaging of Intracranial Manifestations
As a result of the absence of cutaneous and ocular manifestations, patients with NF2 may not develop any clinical manifestations of the disease until the second, third, or even fourth decade of life (137,158). Moreover, it may fall upon the radiologist to make the diagnosis of NF2 in affected patients. The characteristic intracranial abnormalities are schwannomas of the vestibular (Figs. 6-27, 6-28, 6-30) and other cranial nerves (most commonly the oculomotor and the trigeminal nerves, Fig. 6-29) and meningiomas (often multiple, Fig. 6-30).
Figure 6-30 NF2 with bilateral acoustic neuromas and multiple meningiomas. Postcontrast coronal T1-weighted image shows bilateral enlargement of the cranial nerve VIII within the internal auditory canal and the cerebellopontine angles, compressing the brainstem (*). Meningiomas are demonstrated above the left petrous bone (short arrow), within the lateral ventricles (long arrow), and over the right cerebral convexity, with associated blistering of the parietal bone (double arrows).
Two-thirds of the NF2 patients harbor meningiomas. The tumors are most frequently located at the convexity and along the falx cerebri, followed by the skull base and the lateral ventricles. Growth of meningioma tends to be faster in younger individuals (under 30 years of age) and when the meningioma elicits adjacent brain edema (166).
Table 6-5 Criteria for Diagnosis of Neurofibromatosis Type 2

Definite:

  1. Bilateral vestibular schwannomas.

  2. A parent, first-degree relative, or offspring with NF2 and a unilateral eighth nerve tumor at less than age 30 y or two of the following:

    • Neurofibroma

    • Meningioma

    • Glioma

    • Schwannoma

    • Juvenile posterior subcapsular lenticular opacities/juvenile posterior cortical cataract

Presumptive or probable:

  1. A unilateral vestibular schwannoma diagnosed before the age of 30 y, plus at least one of the following:

    • Meningioma

    • Glioma

    • Schwannoma

    • Juvenile posterior subcapsular lenticular opacities/juvenile posterior cortical cataract

  2. Two or more meningiomas and a unilateral vestibular schwannoma and age <30 y or one of the following:

    • Glioma

    • Neurofibroma

    • Schwannoma

    • Juvenile posterior subcapsular lenticular opacities/juvenile posterior cortical cataract

Adapted from Blakeley JO, Plotkin SR. Therapeutic advances for the tumors associated with neurofibromatosis type 1, type 2, and schwannomatosis. Neuro Oncol 2016;18(5):624-638.

The imaging characteristics of schwannomas and meningiomas are described in Chapter 7. If bilateral acoustic tumors are present or a diagnosis of NF2 is suspected for other reasons, the imaging procedure of choice should be contrast-enhanced MR of the entire brain and spine, with thin (≤3 mm) postcontrast T1 sections and high-resolution, submillimeter heavily T2-weighted sequences (FIESTA/CISS) through the posterior fossa. Schwannomas and meningiomas both enhance brightly after the infusion of intravenous contrast; smaller lesions may not be apparent on precontrast scans (90,137).
An important point is that schwannomas and meningiomas are unusual tumors in children and young adults (under age 30 years). If a meningioma or schwannoma is seen in a young patient, a contrast-enhanced MR scan should be obtained through the brain to look for other asymptomatic schwannomas or meningiomas that may aid in establishing the diagnosis of NF2. Regularly repeated contrast-enhanced MR scans are recommended for patients in whom the disease is established, as new tumors continue to develop throughout life and surgical or gamma knife therapy is necessary when they grow large enough to cause hydrocephalus or symptoms. Repeated exams or genetic testing may also be useful when isolated meningiomas or schwannomas are detected in young children. The authors have seen multiple children with “isolated” meningiomas who have bilateral acoustic schwannomas 5 to 8 years later.
Malformative cerebral and cerebellar parenchymal lesions are commonly identified in NF2 patients. In the cerebrum, nonspecific T2 hyperintense lesions in the cortex and white matter, cortical dysplasias (presenting as T2 hyperintensities, often wedge shaped), transmantle sign, abnormal cortical mineralization (T2 hypointense), and focal enlargement of Virchow-Robin spaces are observed. Cerebellar dysplasias are also seen (Fig. 6-28B). Most of the observed parenchymal lesions appear to be manifestations of an underlying disorder of neuronal migration, including glioma hamartomas (167).
Imaging of Spinal Manifestations
The characteristic spinal manifestations of NF2 are multiple paraspinal nerve sheath tumors (mostly schwannomas with some neurofibromas), intraspinal meningiomas, and intramedullary spinal cord tumors (137,148,154). Spinal tumors affect close to 75% of patients (137,153,154). A lower age of diagnosis and a higher number of intracranial meningiomas and schwannomas appear to be significant risk factors for development of spinal tumors (168). Intraspinal and paraspinal nerve sheath tumors are very common in patients with NF2 (121,137) and can nearly always be detected with proper imaging technique in patients beyond the age of 15 years. Because they have more extramedullary spinal tumors, patients with NF2 more frequently develop symptoms of cord compression than do patients with NF1. Coronal imaging optimally shows the nerve root tumors and their relation to the spinal cord. Nerve sheath tumors may be intramedullary, extramedullary intraspinal, or extraspinal or may involve both the intraspinal and extraspinal compartments in addition to the intervening neural foramen (Fig. 6-31). The tumors are usually isointense to neural tissue on T1-weighted images and hyperintense (usually) on T2-weighted images and enhance uniformly after intravenous administration of paramagnetic contrast (Fig. 6-31). As with NF1, axial images are helpful in evaluating any deformity of the cord and the relationship of the tumors to the cord.
Intrinsic spinal cord tumors and syringohydromyelia occur with an increased incidence in NF2 (48,130). The most common intrinsic cord tumors are ependymomas, although astrocytomas and intramedullary schwannomas can be seen (148). Ependymomas and astrocytomas of the spinal cord are sometimes difficult to distinguish by CT and MR; the presence of a centrally located, contrast-enhancing tumor with sharply marginated borders favors a diagnosis of ependymoma over astrocytoma. Ependymomas can be solitary (most often involving the conus medullaris and filum terminale), or multiple, occurring at all levels of the neural axis. Contrast-enhanced MR is the imaging modality of choice. Without the administration of contrast, ependymomas of the spinal cord may be difficult to differentiate from multiloculated syringohydromyelia. Further characteristics of intramedullary neoplasms are described in Chapter 10.
Figure 6-31 Multiple spinal schwannomas in a patient with the schwannomatosis variant of NF2. A and B. Sagittal postcontrast T1-weighted images show multiple enhancing intra- and extramedullary masses, mostly intramedullary (black arrows) in A and mostly extramedullary (white arrows) in B. C. Coronal T2-weighted image shows multiple enlarged nerves (small white arrows) exiting bilateral neural foramina in the cervical spine. On T2-weighted images, it is difficult to separate schwannomas from lymph nodes (large white arrow) of the neck when away from the neural foramina, so contrast administration is essential. D. Contrast-enhanced axial T1-weighted image in the midlumbar region shows a large enhancing mass (long arrow) occupying the lateral aspect of the spinal canal in the left, enlarging the neural foramen, and extending deep to the psoas muscle. Normal enhancing nerve ganglion is evident on the right side (short arrow).
Meningiomas are common in the intraspinal as well as intracranial compartment in NF2 (48). As in patients without neurofibromatosis (see Chapter 10), spinal meningiomas are most common in the thoracic region. They are intradural, extramedullary masses that displace the spinal cord as they grow. These dural-based masses will sometimes cause pressure erosion of the adjacent bone. They can be identified as extramedullary, intradural masses on CT with intrathecal or IV contrast. MR is the preferred diagnostic modality; sagittal and coronal images are essential to visualize the extent of the tumor and its relationship to the spinal cord and neural foramina. These lesions are usually isointense with cord on both T1- and T2-weighted images. They uniformly enhance after contrast infusion (169,170,171).
Syringohydromyelia has been described in association with NF1 and NF2. The syrinx is almost always a secondary phenomenon, resulting from either a primary tumor of the spinal cord or an intradural, extramedullary mass, such as a meningioma or neurofibroma, that alters the CSF dynamics of the surrounding spinal subarachnoid space (see Chapter 9) (172,173). The syrinx will often disappear after removal of the tumor (173,174). The cause of the syrinx cavity resulting from primary spinal cord lesions is less clear. The syrinx most likely results from altered CSF dynamics; however, in some patients, the syrinx may be caused by fluid secreted into the spinal cord and central canal by the tumor (175). If syringohydromyelia is seen in neurofibromatosis (either NF1 or NF2) and no extramedullary mass can be seen, a thin section, contrast-enhanced MR of the spinal cord should be performed to rule out an intramedullary lesion. Syringohydromyelia is discussed in more detail in Chapter 9.
Schwannomatosis
Schwannomatosis is the third major form of neurofibromatosis. It is a rare disorder with an incidence of 0.58 per 1,000,000 persons and a reported peak incidence between the ages of 30 and 60 years; very few pediatric cases have been reported (176,177). It is characterized by a predisposition for the development of multiple schwannomas in the absence of bilateral vestibular schwannomas; meningiomas are less common (5%). Schwannomas commonly affect the spine and peripheral nerves; large cranial nerve schwannomas are uncommon. Anatomically limited disease, presumably due to genetic mosaicism, is seen in approximately 30% of patients. Unilateral vestibular schwannomas have been reported (47).
The genetics of schwannomatosis is complex and incompletely understood; more than 90% of sporadic cases and approximately 50% of familial cases have no currently identifiable genetic mutation (176,178). Most cases are sporadic, likely representing new mutations. The inherited form constitutes 15% to 25% of cases and is of autosomal dominant transmission. Germ-line involvement of the SMARCB1 gene plays a role in tumorigenesis of schwannomatosis; in addition to schwannomas, patients with SMARCB1 germ-line mutations are at a higher risk for specific malignancies including MPNST, rhabdoid-type tumors of the kidneys, and atypical teratoid rhabdoid tumors (176,178).
Schwannomas arise from schwann cells and grow eccentrically with respect to the underlying nerve. This is in sharp contrast with neurofibromas, which are located centrally within the affected nerve. Schwannomas reveal a single cell type with two distinct histologic patterns termed “Antony A” and “Antony B” regions; compared to Antony A regions, Antony B regions are less cellular and show more disorganized matrix and common cystic degeneration.
Imaging findings include multiple discrete, well-defined, rounded to oval lesions situated in the spinal canal (extramedullary) or along the course of peripheral nerves, paraspinous nerve roots, or cranial nerves. Spinal tumors are seen in about 75% of cases, most frequent in the lumbar spine, followed by the thoracic spine and the cervical spine (Fig. 6-31). Peripheral schwannomas are present in about 90% of cases (177). Lesions tend to be slightly hypo- to isodense to skeletal muscle on CT, with varying contrast enhancement. On MR, lesions are typically low to intermediate signal on unenhanced T1-weighted sequences and T2 hyperintense; they show heterogeneous, often intense enhancement after IV contrast administration. Heterogeneous appearance may result from cystic degeneration, hyalinization, and calcification. The target sign identified in PNs is usually absent (178).
Tuberous Sclerosis Complex
Clinical Manifestations
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease that is characterized by the presence of tumor-like lesions (hamartomas) in multiple organ systems. Two separate genes have been identified that are mutated or deleted in patients with tuberous sclerosis. The TSC1 gene is localized to chromosome 9q34 (179,180) and codes for a protein called hamartin; the TSC2 gene has been localized to chromosome 16p13.3 (181,182) and codes for a protein called tuberin. Mutations can be identified in 75% to 85% of TSC patients (21,183,184,185,186). Hamartin and tuberin interact physically in vivo, a fact that clarifies how mutations in two different genes result in the common phenotype (187,188). These proteins form a heterodimer that functions as a suppressor of factors of cell growth by inhibiting the mammalian target of rapamicin (mTOR) kinase cascade. MTOR is active in transduction of factors such as amino acids, neurotransmitters, glucose, and growth factors into normal growth and homeostasis. Overactivation of mTOR, however, may result in organized or disorganized cellular overgrowth and differentiation, resulting on overgrowth syndromes or neoplasia (186,189,190,191,192); mutation of either protein seems to lead to both increased protein translation and cell size enlargement (193). Overall, about 75% of TSC mutations are spontaneous (186); however, before concluding that an affected child has a new mutation, it is necessary to examine both parents thoroughly, including Wood light examination, neuroimaging, and, if possible, chromosomal analysis from multiple tissues including germ cells (194). A 2% to 3% risk of recurrence in future pregnancies remains even if both parents seem unaffected (194).
TSC2 mutations are about five times more common than are mutations of TSC1 (186). TSC1 mutations are slightly less common in sporadic TSC cases (those with no family history, about two-thirds of all patients) and are somewhat more common (15%-50%) in familial cases (21). It is of interest that the TSC2 gene is located only 48 base pairs of DNA from the gene for adult-onset polycystic kidney disease (PKD1). When patients have a continuous deletion of both TSC2 and PKD1, they have a particularly severe phenotype with very early onset of PKD and early renal failure (195).
Overall, compared to those with TSC1 mutations, the TSC2 group is associated with more and larger tubers, more radial migration lines (RML), more subependymal nodules (SENs), higher risk of intellectual impairment, and higher frequency of seizures, renal disease, and facial angiofibromas (166,185,196,197). However, as with all disorders, the outcome depends upon the effect of the mutation upon the function of the protein product in affected pathways (in this case, mTOR); therefore, some TSC2 mutations have relatively mild phenotypes, likely due to small effects upon tuberin function (192).
Classically, TSC has been characterized by the clinical triad of mental retardation, epilepsy, and characteristic skin lesions known as adenomata sebaceum (198). The term adenoma sebaceum is used to describe a nodular rash of brownish red color that is disseminated over the face, typically originating in the nasolabial folds and eventually spreading to cover the nose and the middle of the cheeks in the infraorbital region. Epilepsy is the leading cause of morbidity in children with TSC and arises in 75% to 90% of children (199). Half of affected patients have normal intelligence.
Almost any organ of the body can be affected (200). As a result, more sophisticated criteria for clinical diagnosis of the disorder have been established and are listed in Table 6-6 (201). Increasing awareness of the condition has resulted in a revision of the estimated incidence from approximately 1 in 100,000 patients (198,202,203) to 1 in 6000 live births (204,205). No racial or sexual predilection has been detected. The intracranial abnormalities of tuberous sclerosis are postulated to result from an abnormal expression of genes within the neuroprogenitor cells of the developing brain (206,207). As a consequence, these stem cells do not differentiate, develop, or migrate properly (208). The result is the presence of dysplastic, disorganized cells in the ventricular zone, subventricular zones, the cortex, and along the radial glia coursing between them (19,206,209).
Approximately half of TSC patients develop intractable epilepsy (199). Infantile spasms or myoclonic seizures that begin in infancy or early childhood are the presenting symptom of tuberous sclerosis in approximately 80% of patients; indeed, a significant number (10%) of infants presenting with infantile spasms have tuberous sclerosis (210). The infantile spasms evolve into other seizure types, most commonly symptomatic generalized epilepsy (˜60%), partial epilepsy (˜20%), or a mixture of partial and generalized epilepsy (˜20%) (211). The seizures often decrease in frequency with increasing age (212), particularly when the epilepsy is partial (213). Patients with TSC can have nearly any type of seizure; therefore, the diagnosis of tuberous sclerosis should be considered in any child with epilepsy. The incidence of intellectual disability is about 50% (214); approximately two-thirds will be moderately to severely disabled, and one-third only mildly to moderately affected. Cognitive impairment in TSC is a multifactorial condition; a link exists between cognitive disabilities and lesion load (based on the proportion of brain volume occupied by tubers and on the number of RML (215)), age at seizure onset, and history of infantile spasms (216); however, these factors explain only part of the intelligence quotient variability (186).
Table 6-6 Diagnostic Criteria for Tuberous Sclerosis Complex (Revised 1998)

Major Features

Facial angiofibromas or forehead plaque

Nontraumatic ungual or periungual fibromas

Hypomelanotic macules (more than three)

Shagreen patch (connective tissue nevus)

Multiple retinal nodular hamartomas

Cortical tubera

Subependymal nodule

Subependymal giant cell astrocytoma

Cardiac rhabdomyoma, single or multiple

Lymphangioleiomyomatosisb

Renal angiomyolipomab

Minor Features

Multiple randomly distributed enamel pits in dental enamel

Hamartomatous rectal polypsc

Bone cystsd

Affected first-degree relative

Cerebral white matter radial migration linesa,d

Gingival fibromas

Nonrenal hamartomac

Retinal achromic patch

“Confetti” skin lesions

Multiple renal cystsc

Definite TSC: Either two major features or one major plus two minor features

Probable TSC: One major plus one minor feature

Possible TSC: Either one major feature or two or more minor features

a When cerebral cortical dysplasia and cerebral white matter migration tracts occur together, they should be counted as one rather than two features of tuberous sclerosis.b When both lymphangioleiomyomatosis and renal angiomyolipomas are present, other features of tuberous sclerosis should be present before a definite diagnosis is assigned.c Histological confirmation is suggested.d Radiologic confirmation is sufficient.

TSC, tuberous sclerosis complex.

From Roach E, Gomez M, Northrup H. Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol 1998;13:624-628.

Figure 6-32 In utero MRI of a fetus with tuberous sclerosis. A. Coronal single-shot half-Fourier RARE image through the fetal brain shows a cortical tuber (black arrowheads) extending from the right frontal cortex through the cerebral mantle to the superolateral surface of the right lateral ventricle. A subependymal hamartoma (black arrow) is also present. B. Coronal image through the parietal lobe and chest shows a large cardiac rhabdomyoma (R) in addition to a parietal tuber (black arrow).
Neuroimaging often plays an important role in making the diagnosis of TSC (217,218); characteristic abnormalities are present on neuroimaging studies in more than 95% of affected patients (218). These CNS abnormalities are present from before the time of birth (Fig. 6-32), whereas the cutaneous malformations, such as adenomata sebaceum, may not develop until much later in childhood. Current recommendations are for cranial imaging every 1 to 3 years until the age of 25 years (and every 3-6 months if a giant cell tumor is present) and renal ultrasound every 1 to 3 years at all ages (because renal angiomyolipomas may enlarge at a concerning rate) (219,220).
Cutaneous Manifestations
Although not radiologically apparent, cutaneous adenomata sebaceum are a characteristic component of tuberous sclerosis, and the imager should have a general knowledge of their clinical characteristics, which were described in the previous section. These lesions, which are histologically classified as angiofibromas, usually develop between ages of 1 and 5 years. Angiofibromas also occur in other areas of the body, most commonly the trunk, gingiva, and periungual regions; in these regions, they develop later (typically after age 5 years) and may continue to develop throughout life (221). Depigmented nevi in the form of oval areas with irregular margins (ash-leaf spots) occur on the trunk and extremities and are as common as angiofibromas. Depigmented nevi appear sooner than the adenoma sebaceum; indeed, they are often present at birth and are frequently the cutaneous lesions that lead to a diagnosis of tuberous sclerosis in children with seizures (222). In lightskinned children, the depigmented nevi may be demonstrable only under an ultraviolet light. Café au lait spots are occasionally seen in patients with tuberous sclerosis, but their incidence is similar to that in the general population; their presence in isolation should not suggest a diagnosis of phakomatosis (223). Rarely, patients may develop lesions of the scalp that induce hyperostosis of the underlying calvarium; histologically, these seem to be epidermal inclusion cysts. The other common cutaneous lesions of tuberous sclerosis, shagreen patches and subungual fibromas, do not usually appear until after puberty and will not be discussed here.
Ocular Manifestations
Ocular findings are common in tuberous sclerosis. The most common of these is the retinal hamartoma, an astrocytic proliferation that is seen on or near the optic disc in 15% of affected patients (198,202). Retinal hamartomas are usually present in both eyes and are often multiple (212). They may not be present at birth, developing over the first few months to years of life (224,225); the affected globe may be small (224) and leukocoria may be present, leading to presumptive diagnoses of persistent hyperplastic primary vitreous (see Chapter 5) or retinoblastoma (see Chapter 7). They originate as fairly flat, semitransparent, whitish lesions. Eventually, when they turn whitish gray or yellow and become nodular, they are said to resemble a clump of mulberries (226). Retinal hamartomas are seen on CT as nodular masses originating from the retina (Fig. 6-33); when hamartomas calcify, they can be seen as small, calcified retinal masses that may be difficult to differentiate from a retinoblastoma (224,227). The presence of calcified SENs in the brain will help to make the differentiation. On MR, retinal hamartomas appear as solid retinal nodules that show moderate uniform enhancement after administration of paramagnetic contrast (Figs. 6-33 and 6-34). A subretinal exudate may be present, leading the ophthalmologist toward a presumptive diagnosis of Coats disease (see Chapter 5) (228); again, the observation of SENs in the brain will lead to the proper diagnosis. The reader should be aware that, although they are most common in tuberous sclerosis (they are seen in over half of the cases), retinal hamartomas are seen occasionally in the other phakomatoses as well (227).
Figure 6-33 Retinal hamartoma. A. Axial noncontrast CT image shows a subretinal exudate with a focal nodule (arrow). B. Axial T1-weighted image shows a nodule (arrow) in the right globe that is isointense to the subretinal exudate. C. Postcontrast axial T1-weighted image shows that the nodule enhances moderately.
Intracranial Manifestations
Subependymal Nodules
SENs are benign collections of swollen glia and unusual multinucleated cells that are mainly located along the ventricular surface of the caudate nucleus, most often on the lamina of the thalamostriate sulcus immediately posterior to the foramen of Monro (202,229). Less commonly, the nodules may be detected along the frontal and temporal horns, the lateral ventricular bodies, the third ventricle, or the fourth ventricle. SEN are hamartomas that differ histologically from the cortical hamartomas (tubers) and therefore behave differently on imaging studies.
In neonates, subependymal hamartomas can be detected by transfontanelle sonography, on which they appear as echogenic subependymal masses (Fig. 6-35A). They cannot be differentiated from germinal matrix hemorrhages or gray matter heterotopia by cranial sonography alone. The imaging appearance of subependymal hamartomas on CT and MR changes with the age of the patient. They are rarely calcified in the first year of life; the number of calcifications typically increases with the age of the patient (217). Thus, they may be difficult to detect on CT scans of infants (Fig. 6-36C) but become progressively easier to identify as they calcify (Fig. 6-37, also Fig. 6-40B). On MR scans, subependymal hamartomas appear as irregular SENs that protrude into the adjacent ventricle. Their appearance changes as the signal of the surrounding white matter changes (209,230). In fetuses and infants, who have unmyelinated white matter, the hamartomas are relatively hyperintense on T1-weighted images and hypointense on T2-weighted images (Figs. 6-35 and 6-36) (231); in fetuses and newborn (especially premature) infants, these may be mistaken for subependymal hemorrhages unless other lesions of tuberous sclerosis are identified. As the brain myelinates, the SENs gradually become isointense with the white matter. They are most easily visualized on T1-weighted images where they contrast with low signal intensity of the CSF. Small nodules may not be apparent on T2-weighted images. Larger SENs manifest variably low signal intensity on the T2-weighted images, depending upon the extent of calcification (209,232,233). T2*-weighted gradient echo or susceptibility-weighted images are optimal for showing the calcification because of the magnetic susceptibility differences of calcium and brain (see Fig. 6-41). After intravenous administration of paramagnetic contrast, SENs show variable enhancement; some will enhance markedly, some mildly, and some not at all (209,234,235). The presence or absence of enhancement has no clinical significance. SENs have increased diffusivity and reduced FA compared to surrounding white matter (236).

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Nov 11, 2018 | Posted by in NEUROLOGICAL IMAGING | Comments Off on Neurocutaneous Disorders

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