Chapter 11

Introduction

Advances in genetics and neuroimaging have revolutionized the diagnosis of intracranial disease in children. An integrated approach to these diseases has also emerged from the proliferation of multidisciplinary clinics and programs combining expertise in pediatric neurology, neurosurgery, neuropathology, neuroradiology, neuro-oncology, and neuro-ophthalmology. The role of genetic defects is increasingly recognized in many intracranial disorders, and basic research elucidates their pathogenesis at the molecular level. Refinement in neurosurgical management continues to advance the treatment of these disorders, while preventative and therapeutic measures will arise from molecular genetic research.

Recent documentation of increased cancer risk in children exposed to multiple computed tomographic (CT) scans has emphasized the need to order diagnostic magnetic resonance (MR) imaging if possible.112

This chapter provides dedicated discussion on the intracranial disorders of neuro-ophthalmologic consequence in children.

The Phakomatoses

van der Hoeve,901 a Dutch ophthalmologist, first used the term “phakoma” to describe retinal astrocytic hamartomas in tuberous sclerosis and myelinated retinal nerve fibers in neurofibromatosis. Noting that the retinal astrocytic hamartomas resembled dried lentils (“phaki”), he assumed that tuberous sclerosis and neurofibromatosis were related conditions and coined the term “phakomatosis” as an umbrella term to describe congenital disorders that produce benign growths in the central nervous system (CNS).828 He later expanded this concept to include other conditions characterized by CNS, cutaneous, and often ocular involvement,828 but never specified that the skin or central nervous system had to be involved.99

In its present usage, phakomatosis is a loosely defined and somewhat arbitrary term that has evolved to include a heterogeneous group of multisystem disorders that share a predisposition to develop hamartomas within the CNS, often in association with cutaneous, ocular, or visceral lesions.73 Approximately 20–30 disorders have been classified as phakomatoses, and some patients display features found in more than one phakomatosis. All of these diseases are congenital in origin, but their inheritance patterns vary, and some do not appear to be genetically transmitted.99 Borchert99 and Parsa671 have argued that application of the term phakomatosis should ideally be limited to tuberous sclerosis, NF1, NF2, von Hippel Lindau disease, and ataxia telangectasia because these conditions share mutations in tumor suppressor genes, and patients with these diseases have a higher frequency of malignancies. Consistent with Knudson’s “two-hit hypothesis,” germline mutations in responsible genes result in increased susceptibility to tumor formation following the development of a secondary somatic mutation and loss of heterozygosity. In contrast, neither hamartomas nor heredity is clearly involved in Wyburn–Mason syndrome or Sturge–Weber syndrome, and neither Wyburn–Mason syndrome nor von Hippel–Lindau syndrome produces cutaneous findings. The phakomatoses (both definite and arguable) of neuro-ophthalmologic significance are discussed below.

Neurofibromatosis (NF1)

von Recklinghausen neurofibromatosis (NF1) is an autosomal dominant disorder that affects numerous organ systems, including the eye.520,734,871 It is one of several autosomal diseases that are associated with advanced paternal age. NF1 has no clear predilection for race or sex. It has an incidence of approximately one in 3,000, making it the most common phakomatosis.317,412,871 NF1 is essentially fully penetrant, but there is considerable variation in the intrafamilial and inter-

familial features of the disease. Only 50% of patients have affected relatives,805 and NF1 is said to have one of the highest mutation rates in humans.871

The responsible gene for NF1 is located in the pericentromeric region of the long arm of chromosome 17 and encodes a 2818 amino acid.44,871 It functions as a tumor suppressor gene,708 and expression of the gene product, neurofibromin, is predominantly restricted to neuronal tissue in adults.414 Pathological mutations range from single nucleotide substitutions dispersed throughout the gene to large-scale genomic deletions, sometimes including the entire gene. Part of the protein encoded by neurofibromin shows high sequence homology with the GTPase activator protein (GAP) family of proteins that interact with ras proteins to regulate cell growth and differentiation and act as negative regulators of neurotrophin-mediated signaling. The mammalian target of rapamycin (mTOR) pathway is aberrantly activated in NF1deficient primary cells and in human tumors.222,439 This activation is mediated by the phosphorylation and inactivation of the TSC2-encoded protein tuberin. Tumor cell lines derived from NF1 patients are highly sensitive to rapamycin; an increased level of mTOR pathways activation is reported in human NF1-associated pilocytic astrocytomas.293 Deletions of the entire gene are associated with a more severe phenotype, including a high frequency of mental retardation and severe learning difficulties.485

The numerous dysgenetic, hamartomatous, and neoplastic lesions that arise in NF1 have been attributed to a disturbance in neural crest migration brought about by the NF1 mutation, causing abnormal aggregations of Schwann cells or melanoblast precursors occur during the migratory phase of neural crest development.96 Because many of the disparate findings in NF1 relate to a common neural crest origin, Bolande96 once termed NF1 “the quintessential neurocristopathy” to encapsulate the fact that malignancies of neural crest-derived cells, such as malignant schwannoma, occur more commonly in NF1 patients.96,871 However, many features of NF1, such as short stature, intellectual impairment, macrocephaly, speech impediment, pseudoarthrosis, and malignancies of non-neural crest origin (e.g., myelogenous leukemia, rhabdomyosarcoma) cannot be reconciled with a neural crest origin.871

NF1 is a progressive condition with variable complications occurring over the time course of the disease. Café au lait spots, pseudoarthrosis, and externally visible plexiform neurofibromas can generally be identified during infancy. Freckling, optic gliomas, and severe scoliosis occur in the first decade of life. Pseudarthrosis occurs in 5% of patients and usually involves the distal one-third of the tibia and fibula.848

The cardinal pathologic features of NF1 are the café au lait spots of the skin and a variety of neural hamartomas, known collectively as neurofibromas, that develop in the peripheral, autonomic, and central nervous system.96,731,732,735

Café au lait spots are pigmented macules of the skin that result from aggregation of heavily pigmented melanoblasts in the basal layers of the epidermis.96 They are present in the majority of children with NF1 at birth and become prominent by the end of the first decade of life. Children with NF1 may also have diffuse skin hyperpigmentation or innumerable freckles. Axillary freckling in NF1 tends to be congenital, whereas diffuse freckling or freckling at points of friction (e.g., inguinal or other intertriginous zones) is often acquired.708

Peripheral neurofibromas are a hallmark of NF1.588 They arise from cells in the peripheral nerve sheath and contain a mixture of cell types such as Schwann cells, fibroblasts, mast cells, and vascular elements.96,548,588 The proportion and growth pattern of these constituents account for the morphologic differences so that plexiform neurofibromas, pure schwannomas, and neuromas are described.96 Neurofibromas occurring as subcutaneous nodules near the terminations of peripheral nerves in the dermis comprise the most conspicuous feature of neurofibromatosis, but neurofibromas may also arise within the central and autonomic nervous systems.96 Cutaneous neurofibromas develop toward the end of the first decade, just before puberty. They are initially sessile but often become pedunculated.708 Enlarging neurofibromas may produce intense pruritis that may respond to mast cell stabilizers.

The histology of neurofibromas is typically hypocellular, and the cytology is indolent.96 However, if a skin neurofibroma is being constantly traumatized by friction with clothing, it is generally recommended that it be removed, because of the potential risk of malignant transformation.708 NF1 patients have a 10% lifetime risk of developing malignant peripheral nerve sheath tumor or neurofibrosarcoma, which usually arises within a neurofibroma as an aggressive and often fatal malignancy.281,890

Malignant peripheral nerve sheath tumors usually arise with preexisting plexiform or a focal subcutaneous neurofibromas, whereas cutaneous neurofibromas do not become malignant.281 However, large patches of cutaneous hyperpigmentation in patients with neurofibromatosis tend to overlie these large plexiform neuromas, which have an unusually high incidence of degeneration to neurofibrosarcomas. When the hyperpigmentation overlying a plexiform neurofibroma extends to midline, it may signify underlying spinal cord involvement.708

Although multiple cell types (i.e., Schwann cells, mast cells, perineural cells, fibroblasts, and endothelial cells) are found in neurofibromas,733 Schwann cells are proposed to be the true tumorigenic cell population.476,750,764 Diffuse plexiform neurofibromas are usually congenital or appear in early childhood, whereas nodular lesions develop later in life.484,916

Cutaneous involvement of the face is relatively uncommon in NF1, but plexiform neurofibroma of the upper lid tends to be associated with ipsilateral dysgenesis of the globe and orbit. Plexiform neurofibroma of the upper lid classically produces

the “swan neck” or “lazy S” deformity (Fig. 11.1). Approximately 50% of children with plexiform lid neurofibromas have congenital glaucoma which occurs only in association with orbitofacial involvement.615a In addition to congenital glaucoma and buphthalmos, children with plexiform neurofibroma of the upper eyelid may have ipsilateral orbital enlargement, ipsilateral sphenoid dysplasia (absence of the sphenoid wing and anterior clinoid, with or without pulsating exophthalmos), and progressive facial hemihypertrophy (Francois syndrome) (Fig. 11.2).43,408 These changes may be associated with prolapse of the temporal lobe into the orbit or lateral expansion of the middle cranial fossa (termed orbitotemporal neurofibromatosis).425 The plexiform neurofibroma is congen-

ital in origin but may not be evident at birth until it grows to a size that causes cosmetic disfigurement.658 Although surgical debulking has historically been the treatment for plexiform neurofibomas, targeted biologically based treatments are now under investigation.658

Some children with NF1 have buphthalmos in the absence of congenital glaucoma.431 Weiner931 and Hoyt and Billson408 have suggested that buphthalmos in neurofibromatosis sometimes represents a generalized hyperplasia of the orbit and its contents (i.e., an expression of regional gigantism) rather than a consequence of uncontrolled intraocular pressure. Some children also display congenital iris ectropion secondary to endothelialization of iris, with the iris adherent to Schwalbe’s line. Choroidal ganglioneuroma has also been reported in this setting.819 Prior to neuroimaging, the combination of unilateral proptosis and poor vision in such cases was often incorrectly attributed to orbital optic glioma. When correctly diagnosed, this constellation of findings signifies a unilateral process.

The most common ocular feature of neurofibromatosis is Lisch nodules of the iris.551,552,708,871 Lisch nodules are tan to brown, avascular, dome-shaped lumps in the anterior iris (Fig. 11.3). Pathologically, they have been considered to be

melanocytic hamartomas with a compact plaque of spindle cells overlying a loose stromal accumulation of melanocytes.439 More recently, Richetta et al738 found that Lisch nodules are composed of pigmented cells, fibroblast-like cells, and mast cells similar to neurofibromas. In blue and green irides, they appear pale to medium brown with feathery margins; in dark brown irides, they are cream colored, domeshaped, and extremely well defined (Fig. 11.1).708 When present in young children, they tend to be glassy and translucent in appearance.944 Ragge et al710 combined data from six large studies of Lisch nodules in different age groups, and found that the prevalence of Lisch nodules in neurofibromatosis gradually increases to about 50% at age 5 years, 75% at age 15 years, and 95–100% of adults over age 30.710 Despite the absence of Lisch nodules in many young children, the diagnosis of neurofibromatosis can usually be established on the basis of other criteria.641 Unlike neurofibromas, there is no acceleration in the rate of appearance of Lisch nodules associated with puberty.534 Lisch nodules are highly suggestive, but not pathognomonic, of NF1, as they have been rarely reported to occur in patients with segmental neurofibromatosis,934 NF2,174 and Cushing disease.106

The major neuro-ophthalmologic manifestations in children with NF1 are proptosis, optic disc swelling, optic atrophy, ptosis, strabismus, and amblyopia. Pulsatile proptosis may occur when the sphenoid wing is absent, and only the dura separates the brain and orbit. Enophthalmos may also be seen occasionally in this setting. Nonpulsatile proptosis occurs most commonly with ipsilateral orbital optic glioma but may also result from a localized or plexiform orbital neurofibroma.602 When optic disc swelling is accompanied by ipsilateral proptosis, the causative lesion is usually an orbital optic glioma. Optic disc swelling without proptosis may herald hydrocephalus secondary to hypothalamic/chiasmal glioma extending into the third ventricle, hydrocephalus associated with aqueductal stenosis, an intracranial arachnoid cyst, a spinal ependymoma, or some other NF1associated spinal tumor. Optic atrophy may occur primarily with optic glioma or pursuant to prolonged optic disc swelling from any of the above-mentioned causes. Ptosis in NF1 is usually S-shaped and associated with an upper lid plexiform neurofibroma. Strabismus and amblyopia may result from nonaxial proptosis because of orbital optic glioma, or from visual deprivation when a plexiform neurofibroma of the lids or buphthalmos are present.

Caucasians with neurofibromatosis frequently have choroidal pigment hamartomas in the posterior pole, which tend to be flat and hyperpigmented or silvery gray. These easily overlooked lesions are probably the next most common ocular finding in neurofibromatosis following Lisch nodules. Choroidal and ciliary body neurofibromas are well recognized but uncommon manifestations of NF1.240 Although myelinated nerve fibers are said to be more

common in children with neurofibromatosis, this association may be fortuitous. The reported association between enlargement of the corneal nerves and neurofibromatosis is equally dubious, with previously described cases possibly occurring in patients with a multiple endocrine neoplasia syndrome.602 Yasunari et al960 found bright, patchy choroidal lesions in 100% of NF1 patients, a frequency that exceeded that of Lisch nodules (76%) and plexiform neurofibroma (29%).

Primary retinal involvement is more common in NF2, but may occasionally occur in NF1. Several reports of retinal dialysis and detachment adjacent to a peripheral astrocytic hamartoma in children with NF1 suggest that unlike the visually benign astrocytic hamartomas of tuberous sclerosis, NF1-associated astrocytic hamartomas are more likely to produce retinal traction, dialysis, and ultimately detachment.240,575 Retinal vascular disease is another occasional finding.240,611 Children with NF1 have been described with bilateral capillary hemangiomatosis240 as well as retinal vascular occlusive disease,611 which may be similar in etiology to the vascular ischemic manifestations that have been described in the aortic, cerebral, and renal vasculature.784

Retinal vascular abnormalities have now been recognized in NF1. Muci-Mendoza et al451,621 described a distinctive microvascular abnormality in 12 of 37% of patients with NF1. In ten cases, the abnormality was subtle, consisting of tortuosity and a corkscrew appearance of a secondor thirdorder venule or a tributary of a major retinal vein. Two cases had more striking vascular abnormalities, with a venovenous anastomosis and an extensive arteriovenous malformation (AVM) coexisting with an epiretinal membrane.

Certain features on magnetic resonance (MR) imaging are highly suggestive of NF1 (Figs. 11.4 and 11.5).708 These include (1) bilateral optic gliomas; (2) tubular expansion with lengthening and kinking of one or both optic nerves;

(3) a double-intensity signal to the orbital optic nerve, with a bright outer signal on T2-weighted images corresponding to the perineural tumor and the dark central core corresponding to the optic nerve194,418,798; (4) chiasmal glioma extending into both optic tracts; and (5) high-signal intensity foci in the brain parenchyma on T2-weighted images, especially in the globus pallidus, basal ganglia, and cerebellar white matter.250

By far the most common abnormality detected on MR imaging in patients with NF1 is foci of increased signal on T2-weighted images (Fig. 11.6). These lesions are seen most commonly in the basal ganglia, internal capsule, brainstem, and cerebellum.694 They are typically small and may be solitary, multiple, or confluent. They tend to increase in number in early childhood and then regress later in childhood, which suggests that they may represent age-related abnormalities in myelination.808 They tend to disappear with age and have no known clinical significance.252,423,707,828

Fig. 11.4  Distinctive MR imaging characteristics of orbital optic glioma in NF1. (a) T1-weighted axial MR image of left orbital glioma. Fusiform area of low intensity (closed arrow) surrounds central core of high signal intensity. An arachnoid cyst (open arrow) occupies left anterior temporal fossa. Note that peripheral (outer) tumor signal is isointense to CSF contained within arachnoid cyst. Tumor is kinked posteriorly. (b) T1-weighted MR image of right orbital glioma showing linear enlargement of right optic nerve with circumferential zone of low signal intensity (closed arrow) surrounding central core of higher signal intensity. Open arrow denotes CSF within arachnoid cyst that is hypointense to brain on T1-weighted images. (c) T1-weighted coronal MR image of left orbital glioma. There is marked enlargement of optic

nerve with ring of low signal intensity (dark arrow) surrounding core of higher signal intensity. Large area of low signal intensity inferior and lateral to optic nerve (white arrow) corresponds to anterior extent of arachnoid cyst. (d) T2-weighted axial MR image through superior aspect of both optic gliomas. In left orbit, there is donut-shaped area of high signal intensity (dark arrow) surrounding inner circle of low signal intensity. Image represents tangential cut through superior aspect of upwardly kinked tumor. In right orbit, linear area of high signal intensity surrounds central core of low signal intensity. Note that outer signal within both tumors remains isointense to CSF (Open arrow denotes CSF in arachnoid cyst that is hyperintense to brain on T2-weighted images.)116

The most common intracranial tumor in NF1 is optic pathway glioma.536 The prevalence of optic pathway glioma on CT scanning in neurofibromatosis has been estimated to be 15%.532 Optic gliomas are typically WHO grade I pilocytic astrocytomas arising within the optic pathway and hypothalamus.527,672 In a child with NF1, the finding of hypertelorism heralds the presence of optic glioma.938 Visual evoked potential screening provides correlative information415,463,952 but offers no clear advantage to routine clinical screening.824

Parsa et al showed that optic gliomas can undergo spontaneous regression.674 According to Parsa and Givrad,672 tumor suppressor genes encode proteins that serve to control cell proliferation. These proteins induce cells that multiply in an abnormal way to either slip into senescence or undergo apoptosis. When heterozygous mutations occur in genes, the resulting haploinsufficiency of expressed proteins can allow the occasional replicating cell in normal tissues to undergo proliferation for an otherwise longer period before being brought under control. Thus, hamartomas such as gliomas

can occasionally grow in infancy and during the first decade of life, but their growth potential decreases dramatically thereafter. Decreased proliferative activity is a feature of older glial tumors, and, over time, the apoptotic processes may lead to eventual spontaneous regression of these juvenile pilocytic tumors.141,674

Once diagnosed, optic pathway tumor progression is uncommon in children with NF1.792 Although the prognosis is better in patients with NF1, even in isolated cases, this tumor is characterized by early rapid enlargement in the prediagnostic phase, followed by stagnation or diminution.792 In one study, no child found to have a tumor confined to the optic

nerve by neuroimaging screening developed decreased vision or other evidence of progression.537 Because orbital optic gliomas without chiasmal involvement do not “grow backward” and extend into the chiasm, surgical removal of an optic nerve glioma, particularly the intracranial portion, to prevent “spread” to the chiasm is unnecessary.540 However, all patients with chiasmal involvement need clinical and endocrinologic evaluation at initial presentation and on subsequent followup to monitor for the onset of precocious puberty. As optic nerve gliomas in childhood are rare, if ever, malignant, biopsy or surgical resection is rarely necessary.970 Surgical excision or debulking carries a significant risk of iatrogenic visual loss.

Fig. 11.6  Multiple focal hyperintense lesions in the midbrain of a child with NF1

Surgical excision of tumors that have led to proptotic eyes without functional vision should be reserved for cosmetic purposes or to treat complications of exposed globes.

Optic pathway gliomas occasionally appear to behave aggressively in young patients, with local expansion resulting in progressive clinical findings. This enlargement may correspond to a brief period of transient neoplasia before the control of cellular proliferation is reasserted or to accumulation of extracellular mucosubstance.672,673 No reports have documented spontaneous malignant transformation of a WHO grade I pilocytic astrocytomain in this location.672,673

Chiasmal/hypothalamic gliomas are associated with a higher probability of visual loss.38 These children also develop more complications such as hydrocephalus and precocious puberty.542 Involvement of the optic radiations signals a more aggressive optic pathway glioma in patients with NF1.543 Aggressive chiasmal/hypothalamic NF1-associated tumors have been found on biopsy to represent high-grade astrocytomas or difficult-to-classify gliomas or have other worrisome indices, such as high proliferative indices.542 Chemotherapy or en bloc resection are occasionally used in this setting.459

Despite significant advances in pediatric neurooncology,539,657 no highly effective treatment exists for anterior visual pathway gliomas, whether associated with NF or not.

No correlation with long-term outcomes in terms of improvement of clinical symptomatology or progression-free period or survival has been demonstrated. Several authors have

reported similar visual outcomes in observed and treated patients with anterior visual pathway gliomas.337,879 Even when tumor reduction occurs with chemotherapy, visual function is often unchanged.657 Moreover, mutagenic chemotherapy carries a risk of toxicity, infection, and secondary tumor development.

Vincristine and carboplatin have been the most frequently employed agents.824 Vincristine has potential neurotoxicity and can cause an optic neuropathy.823 The addition of etoposide to the chemotherapy regimen has been suggested to increase progression-free rates, but results for isolated visual gliomas are not reported, and acoustic toxicity remains a concern.576 Any purported treatment effect must also take into account the natural propensity of these tumors for spon-

taneous regression.149,360,666,674,785

Radiotherapy is no longer generally employed in younger children because of the vulnerability of the immature nervous system to therapeutic doses, as well as the potential risk for inducing secondary malignancies many years later. There is evidence that NF patients are unusually sensitive to the potential mutagenic effects of radiotherapy, making it even less desirable in this group.658 Radiotherapy can lead to secondary malignancies or cerebrovascular disease with moyamoya in patients with NF1.430 In the future, stereotactic radiotherapy may be more promising, but secondary tumors remain a concern.568,824

Children with NF1 also display a variety of disparate CNS manifestations unrelated to tumor formation. Headaches are particularly common in patients with NF1. Intellectual impairment, learning disability, or hyperactivity is seen in approximately 40% of children with NF1. Macrocephaly is common and does not seem to correlate with intellectual performance, seizures, or electroencephalographic abnormalities.602,731 Although the presence of unidentified bright objects (UBOs) that appear hyperintense on T2-weighted MR imaging multiple hyperintense T2-weighted lesions have been suggested to correlate with learning disabilities,273,905 recent studies have failed to confirm a convincing relationship.266,300,695,845 Macrocephaly in NF1 is associated with abnormal development of both gray and white matter in the brain.845 Aqueductal stenosis can result from tumor compression or, more commonly, from a structural alteration of the aqueduct rather than tumor compression.602 Hydrocephalus due to aqueductal stenosis is an uncommon complication of NF1 that results from periaqueductal proliferation of subependymal glial cells or from a Chiari 1 malformation.2,374

Brainstem and cerebellar gliomas are independently associated with neurofibromatosis and deemed to have a more favorable overall prognosis than their sporadic counterparts.90,149,291,538,614,697,910 Brainstem gliomas can be distinguished from (UBOs) because they exhibit focal or diffuse brainstem enhancement, demonstrate mass effect, and may enhance with gadolinium.86