Neurosurgical Implications of Neurofibromatosis Type I in Children

Neurosurg Focus 19 (6):E2, 2006

Neurosurgical implications of neurofibromatosis Type I in children

MERDAS AL-OTIBI, M.D., AND JAMES T. RUTKA, M.D., PH.D., F.R.C.S.(C) Division of Neurosurgery, University of Toronto, Ontario, Canada

Neurofibromatosis Type 1 (NF1) is one of the most common inherited diseases in humans. It is caused by a mutation in the NF1 gene on chromosome 17, and is associated with numerous central and peripheral nervous system manifestations. Children with NF1 are at high risk of harboring numerous lesions that may require the attention of a neurosurgeon. Some of these include optic nerve gliomas, hydrocephalus, intraspinal tumors, and peripheral nerve tumors. Although most of the neoplasms that affect the brain, spine, and peripheral nerves of children are low-grade lesions, there is a small but real risk that some of these lesions may become high grade over time, requiring other forms of therapy than surgery alone. Other associated disorders that may result from NF1 in childhood include Chiari malformation Type I, scoliosis, and pulsating exophthalmos from the absence of the sphenoid wing. In this review, the major lesions that are found in children with NF1 are reviewed as well as the types of treatment that are offered by neurosurgeons and other members of the treating team. Today, optimum care of the child with NF1 is provided by a multidisciplinary team comprising neurosurgeons, neurologists, ophthalmologists, radiologists, orthopedic surgeons, and plastic surgeons.

KEY WORDS • neurofibromatosis • neurofibroma • optic glioma • hamartoma • peripheral nerve tumor • spinal tumor • children

Neurofibromatosis Type 1, also known as von Reck- velopment Conference on Neurofibromatosis33 (Table 1). linghausen disease, was first described by Frederick von Many of these signs may not appear until late childhood or Recklinghausen, who proposed that the characteristic der- adolescence. Café-au-lait spots and plexiform neurofibromas mal tumors that he observed in patients with NF1 arose are usually recognized within the 1st year of life, whereas from the fibrous tissue surrounding peripheral nerves optic pathway gliomas and axillary freckling may not appear (hence the term neurofibroma). This disease is a common until 3 to 5 years of age. Dermal neurofibromas usually genetic disorder, with an incidence of one per 3500 live are first observed during adolescence, and often increase births and without a preference for sex or race.14,40 An auto- throughout puberty.19 The clinical manifestations of NF1 in- somal-dominant disorder, NF1 results from mutation of the clude cutaneous, ophthalmological, musculoskeletal, and NF1 gene, which has been mapped to chromosome 17. neurological lesions. Among these, ocular and cutaneous This gene spans more than 350 kb of genomic DNA, en- lesions are the most common. coding an RNA of 11 to 13 kb with at least 59 exons. Its protein product, called neurofibromin, contains 2818 ami- Cutaneous Manifestations no acids with an estimated molecular mass of 220 kD andЈ Some of the most common and earliest manifestations of shows close homology to the proteins of the guanosine 5 - NF1 are café-au-lait macules, axillary freckling, and Lisch triphosphatase–activating family, which act as tumor sup- nodules. Café-au-lait macules are apparent in most affected pressors. Neurofibromatosis Type 1 has virtually 100% children. These macules are characterized by homogeneous penetrance by the age of 5 years. Approximately 50% of pigmentation with a smooth regular border, varying in size cases represent new mutations, and the mutation rate is one from a few millimeters to a few centimeters. These “spots” of the highest recorded in humans. do not evolve into tumors and often fade during adulthood. They may be found anywhere on the body except on the Clinical Diagnosis of NF1 scalp, eyebrows, palms, or soles. Histologically, café-au- The diagnosis of NF1 is based on clinical criteria estab- lait spots represent increased numbers of melanocytes as lished by the National Institutes of Health Consensus De- well as giant pigmented granules (macromelanosomes). Freckling in regions that are not exposed to the sun, such as axillary and inguinal regions, is also a common mani- Abbreviations used in this paper: CNS = central nervous system; festation of NF1, occurring in 80% of children by 6 years MR = magnetic resonance; NF1 = neurofibromatosis Type 1; of age. In addition, freckling can be observed under the OPT = optic pathway tumor; PNST = peripheral nerve sheath neck and breast in areas where skin folds exist. tumor. Lisch nodules are iris hamartomas that do not have any

Neurosurg. Focus / Volume 20 / January, 2006 1 Unauthenticated | Downloaded 09/29/21 11:55 PM UTC M. Al-Otibi and J. T. Rutka effect on visual function. They are uncommon in young TABLE 1 children, and are found in approximately 30% of individu- Diagnostic criteria of NF1* als with NF1 by the age of 6 years. They are highly charac- Ն Ͼ teristic of NF1 and are best detected by slit lamp examina- 6 café-au-lait maculesϾ 5 mm in greatest diameter in prepubertal Ն individuals or 15 mm in greatestՆ diameter postpuberty tion. Less common ocular findings in NF1 include 2 neurofibromas of any type or 1 plexiform neurofibroma congenital glaucoma, conjunctival and orbital neurofibro- Նfreckling in axillary or inguinal regions mas, retinal astrocytomas, and sectorial retinitis pigmentosa. 2 Lisch nodules distinct osseous lesion, such as sphenoid wing dysplasia or thinning of Musculoskeletal Abnormalities cortex of long bones (w/ or w/o pseudarthrosis) 1st-degree relative (parent, sibling, offspring) w/ NF1 according to these Distinctive bone abnormalities, including skeletal dys- criteria plasia (particularly sphenoid wing dysplasia), scoliosis, and * Diagnosis is NF1 if two or more of these signs are present. Modified tibial pseudarthrosis are observed in patients with NF1. from “Neurofibromatosis. Conference statement” released by the National Scoliosis affects 10 to 20% of children with NF1 and may Institutes of Health Consensus Development Conference. occur at an earlier age than in the general population (Fig. 1).5,28 When associated with paravertebral neurofibromas, scoliosis may present with an abrupt angle curvature (dys- puberty, and symptoms and signs of raised intracranial trophic scoliosis). This type of scoliosis is difficult to cor- pressure (often from obstructive hydrocephalus). Optic ra- rect surgically. Short stature is estimated to affect between diation tumors are relatively rare in the context of NF1 and 25 and 35% of patients. A repeated pathological fracture may signal a more aggressive OPT.27 with incomplete healing secondary to cortical thinning of The period of greatest risk for the development of symp- the long bones is also seen in patients with NF1. Rarely, tomatic OPTs in NF1 is during the first 6 years of life.18 The musculoskeletal malignancies such as rhabdomyosarcoma OPTs found in the chiasm of children younger than 3 years may arise in patients with NF1, hence the need to recognize of age often have a very aggressive course (Fig. 3). After quickly and diagnose fast-growing soft tissue lesions in the the age of 6 years, the appearance of symptomatic OPTs, as context of this disorder. well as the progression of known OPTs requiring therapy, is extremely unusual. Some studies suggest, however, that Neurological Manifestations symptomatic OPTs can appear as late as the third decade of 35 The neurological manifestations of NF1 include a wide life. Most OPTs are low-grade pilocytic astrocytomas. variety of lesions in both the peripheral nervous system and The natural history of OPTs reveals that they are clinically indolent tumors and may regress spontaneously or the CNS, including macrocephaly, epilepsy, spinal menin- 3,17 goceles, neurofibromatosis, and peripheral neuropathy. Hy- remain static. Interestingly, as a general rule, the growth of optic gliomas in patients with NF1 is less aggressive drocephalus can result from aqueductal stenosis associated 25,47 with nonprogressive proliferation of subependymal glial than in patients without this disorder. The National cells around the aqueduct and may require surgical diver- Institutes of Health guidelines for patients with newly diag- sion when symptomatic. Abnormalities of the intracranial nosed NF1, who have no known OPT, recommend a com- vasculature, although rare, have been reported in patients plete ophthalmological examination at diagnosis, followed with NF1. by annual examinations until the age of 6 years. For chil- Optic pathway tumors are the most frequently identified dren older than 6 years, periodic eye screening is recom- CNS neoplasm in young patients with NF1. They were ini- mended at longer intervals. These guidelines also recom- tially reported in less than 5% of NF1 cases, but this was mend neuroimaging only when clinically indicated rather before the advent of computerized tomography and MR than as a routine screening procedure. For children with newly diagnosed OPTs, regular ophthalmic examinations imaging. More recent estimates made using modern neu- 26 roimaging techniques have stated that the prevalence of accompanied by neuroimaging are suggested. OPTs is between 11 and 19% of NF1 cases, which approx- The principal aim of treatment for children with OPTs imates the lifetime risk of suffering an optic glioma.22,25 and NF1 is to prevent visual loss. This can be accomplished by judicious use of surgery, radiation therapy in children Approximately one half of all optic pathway gliomas are 45–47 asymptomatic at diagnosis. When symptomatic, the mani- older than 3 years of age, and chemotherapy. In general, festations will be related to the tumor’s location along the children younger than 3 years of age who have progressive, optic pathway. The OPTs can be divided into intraorbital symptomatic lesions involving the chiasm will undergo a and chiasmatic/hypothalamic tumors. trial of chemotherapy. In this age group, surgery is reserved Intraorbital tumors are relatively rare and cause progres- for large tumors causing a mass effect or in children in sive proptosis of the globe, strabismus, optic nerve papille- whom chemotherapy has failed. Caution is now used in rec- dema, and atrophy (Fig. 2). Occlusion of the central retinal ommending radiation therapy for patients with NF1. Che- artery may occur, resulting in unilateral or bilateral blind- motherapy cycles, generally well tolerated by most patients, are conducted in sequence for time periods longer than 1 ness. Good long-term results can be achieved with total ex- 5,13,15 cision of the intraorbital part of the optic nerve in progres- year. sive cases, even if the margin of the proximal cut end is not Plexiform Neurofibroma tumor free. Radiation therapy and chemotherapy are typi- cally not used for intraorbital tumors. Plexiform neurofibromas are a common manifestation of Chiasmatic tumors pose special problems for the treating NF1.40 They can be classified as benign PNSTs that involve physician and neurosurgeon. They may cause visual distur- multiple nerve fascicles or branches of major nerves. They bance, developmental delay, endocrinopathy, precocious may arise from cranial or upper cervical nerves. Plexiform

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sion exists. It is hoped that future therapy with drugs such as 13-cis retinoic acid or interferon-alpha may have a role to play in treating these problematic tumors.21 Individuals affected with NF1 have a 2 to 5% risk of malignant transformation of their plexiform neurofibroma.1,11,28,48 Malignant PNSTs or neurofibrosarcomas are the main lesions that result from malignant transformation. These lesions often occur during adolescence and young adulthood. Malignant PNSTs present as a marked neurological deficit, persistent pain, or rapid growth of a plexiform neurofibroma. Individuals with internal plexiform neurofibromas are 18 times more likely to suffer malignant PNSTs than patients without internal plexiform neurofibroma. The 5-year survival of patients with malignant PNSTs is approximately 40%.28,48 The general treatment of malignant PNSTs includes diagnostic biopsy sampling followed by extensive excision to achieve wide margin resection, radiation, and chemotherapy. Spinal and Paraspinal Tumors Intraspinal tumors occur in approximately 2% of patients with NF1. These lesions can occur in all spinal segments (Fig. 5). On the other hand, paraspinal neurofibromas are the most common tumors to affect patients with NF1. The tumors arise generally from the dorsal roots in the cervical and lumbar regions of the spine, and can cause radicular symptoms, the most common of which is pain. Most of those lesions are intracanalicular and intraforaminal and demonstrate extension into the spinal canal with growth. Over time, enlargement of the spinal canal and widening of the interpeduncular distance can occur, resulting in insta- bility and scoliosis.36 These lesions appear on MR images as dumbbell-shaped tumors in the foramina. If they extend into the spinal canal toward the spinal cord, they can dis- place or compress the cord. The histopathological findings are usually neurofibroma, rarely astrocytoma, and some- times ependymoma.23,44 Resection is indicated for lesions causing mass effect. The goal is to achieve complete removal of the tumor whenever it is safe to do so, because the recurrence rate is high in partially resected tumors. Fig. 1. Scoliosis seen on 3-f standing x-ray film, anteroposteri- Tumors of the CNS or view, in a teenager with lumbar plexiform neurofibroma. Tumors of the CNS occur in 5 to 11% of patients with NF1,12,16 and 30% of these will be optic pathway lesions.26 neurofibromas can vary from a few millimeters in diameter Several studies suggest that individuals with NF1 are at in- to massive overgrowths several centimeters in size (Fig. 4). creased risk for the development of brain tumors during They can cause hyperpigmentation or hypertrophy of the their lifetimes.1,20,29 The tumors appear in the cerebral cor- overlying skin. These neurofibromas can be cosmetically tex, basal ganglia, cerebellum, brainstem, and pineal re- disfiguring, not to mention the psychological discomfort that gion.40,42,48 Although many of these lesions will be sympto- arises when the lesions are found in and around the facial matic, some of them will be discovered during the MR area. Plexiform neurofibromas can grow quickly either in imaging screening in the context of NF1. These lesions ap- early childhood or during times of hormonal change such as 2 9 pear as areas of high signal intensity on T -weighted im- those occurring during puberty or pregnancy. ages. They can also show focal contrast enhancement. In On MR images, plexiform neurofibromas display a high some studies MR spectroscopy has been used to investigate signal intensity on T2-weighted images with central areas of CNS lesions in patients with NF1 to distinguish between low signal. The treatment of these lesions remains a surgi- hamartomas and neoplasms, with modest success.4 The cal challenge because of the potential for extensive growth most common CNS tumor in NF1 is a pilocytic astrocy- and invasion of surrounding normal structures. According- toma; however, there are reported cases of high-grade glio- ly, conservative management is recommended for asymp- mas in older children.20 Other rare types of tumor include tomatic lesions, whereas symptomatic lesions may require ependymomas, ganglioglioma, medulloblastoma,41 and excision to minimize morbidity. For all lesions, the specter dysplastic neuroepithelial tumors.24 Because the frequency of recurring neurofibromas that will require repeated exci- of malignant change in these tumors was found to be high-

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Fig. 2. A: Axial MR image with contrast added, demonstrating a right-sided intraorbital optic glioma. B: Coronal MR image demonstrating a large mass lesion occupying the orbital apex. er than for tumors at comparable sites in patients without ity of choice for visualizing these lesions. They appear as 42 NF1, surgical removal should be proposed whenever pos- low-signal-intensity lesions on T1-weighted images and as sible, especially for symptomatic, enhancing lesions. Sur- high-signal-intensity areas on T2-weighted images in as gery should be combined with radiation therapy or chemo- many as 60% of children with NF1.2,10 The histopathologi- therapy where indicated. cal finding in most instances is a low-grade glioma.6,31 Because the clinical course is usually indolent as far as the Tectal Glioma mass lesion is concerned, treatment of hydrocephalus as it 30,37,39 Tectal glioma in patients with NFI is a benign subgroup develops is the cardinal rule. Endoscopic third ven- of brainstem lesions that most often cause symptoms as a triculostomy is the best form of therapy for the hydro- result of increased intracranial pressure due to obstructive cephalus that develops in these patients. Direct surgery can hydrocephalus. Magnetic resonance imaging is the modal- be performed on radiologically and clinically progressive lesions. Radiation therapy and chemotherapy can also be

Fig. 3. Sagittal MR image obtained in a 2.5-year-old girl with Fig. 4. Coronal MR image of the abdomen obtained in a patient visual failure and macrocephaly. A large midline optic chiasmat- with NF1, demonstrating bilateral plexiform neurofibromas ema- ic/hypothalamic glioma is seen, with accompanying obstructive nating from the spinal nerve roots and extending peripherally along hydrocephalus. the course of the nerves.

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used for residual, clinically aggressive lesions.13,15 Spon- taneous regression or involution of these lesions has been reported.32,43 Other Manifestations of NF1 Cognitive impairments are prevalent in children with NF1 and can result in specific learning disabilities in 30 to 65% of patients.34 Defects in learning affect visual spatial and visual motor integration skills. Some studies have dem- onstrated a correlation between focal areas of signal hyper- intensity on MR images, so-called unidentified bright objects, and cognitive dysfunction.10,34 Unidentified bright objects are found mostly in the brainstem, basal ganglia, thalamus, and cerebellum, and have been observed in 60 to 70% of children with NF1 (Fig. 6). Currently, the relation- ship between these objects and cognitive dysfunction in NF1 remains controversial.

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