Pediatric Neuro-ophthalmology Review - Optic Pathway Gliomas in Neurofibromatosis Type 1

Pediatric Neuro-ophthalmology Review - Optic Pathway Gliomas in Neurofibromatosis Type 1

Grant T Liu, Gregory T Armstrong, Lubaina M Rangwala
Published: US Neurological Disease 2006
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Patients with Neurofibromatosis type 1 (NF-1) have an increased incidence of many types of tumor, both benign and malignant. Optic pathway gliomas (OPGs) are the most common intracranial tumor in NF-1, and are prevalent in 15% of patients by the age of five. Development and progression of OPGs can result in vision loss, endocrine abnormalities, and death from mass effect and obstruction of normal cerebrospinal fluid (CSF) flow. The role of serial ophthalmologic evaluation and magnetic resonance imaging (MRI) in following patients with OPGs is well established.

NF-1
NF-1, also known as von Recklinghausen’s neurofibromatosis, is a common neurocutaneous disorder with an incidence of one in 3,000. Although genetic testing is available, NF-1 remains a clinical diagnosis. Two of seven diagnostic criteria, as developed by the National Institutes of Health (NIH) consensus conference, must be met to make the diagnosis (see Table 1).1,2 Café-au-lait macules are flat, uniformly hyperpigmented lesions, generally with smooth borders, which may be present at birth and typically increase in size and number with age. Other clinical findings develop over the course of childhood and early adolescence, so that 95% of patients with NF-1 have met diagnostic criteria by eight years of age.

NF-1 is an autosomal dominant genetic disorder with complete penetrance; however, as many as 50% of cases are a result of sporadic mutations.3 The NF-1 gene, identified in 1990, is large and has been mapped to chromosome 17q11.2. The types of mutations are diverse, ranging from total deletion of the NF-1 gene to a subtle change of a single base, in 300,000, in the gene. Direct genetic testing now exists and allows confirmation of the diagnosis of NF-1 in patients with only a single clinical manifestation, such as caféau- lait macules.4

One of the hallmarks of NF-1 is that affected individuals develop both benign and malignant tumors at increased frequency. Neurofibromin, the protein product of the gene, is expressed in many tissues.5 Most mutations of the NF-1 gene produce a truncated form of neurofibromin. This has serious implications for tumor formation based on the hypothesis that the NF-1 gene is a tumor suppressor gene. In this role, neurofibromin may downregulate cellular proto-oncogenes that direct cell growth and regulation.6 It is well established that patients with NF-1 have an increased lifetime risk of many other tumor types in addition to malignant peripheral nerve sheath tumors, such as OPGs and brainstem gliomas, pheochromocytomas, and certain sarcomas and leukemias.

OPGs
OPGs are the most common central nervous system (CNS) neoplasm in patients with NF-1. These lesions occur in young children, generally before the age of six, and rarely occur beyond adolescence.7,8 Computed tomography (CT) of asymptomatic patients with NF-1 has shown the prevalence of OPG in NF-1 to be 15% by five years of age, and prospective studies have suggested that the incidence may be even higher. Approximately 47% of patients with NF-1 and a known OPG will develop vision loss.9

OPGs may occur anywhere along the anterior visual pathway including the optic nerves, chiasm, and tracts. Rarely, they may affect the optic radiations.10 However, patients with NF-1 are more likely to experience involvement of the optic nerves and are less likely to develop a chiasmatic tumor compared with OPGs, which occur in non-NF-1 patients.7 Additionally, bilateral optic nerve gliomas (ONGs) without chiasmal involvement are more common in NF-1, comprising 30% of all OPGs in this patient population.11

Most OPGs are benign, low-grade astrocytomas. In the setting of NF-1, and when the neuroradiologic features are typical (see Figure 1 and 2), biopsies of CNS lesions located along the optic pathway are not commonly obtained.11,12 Though often indolent, some OPGs will progress with time; however, progression is less common in patients with known NF-1. One study reported that 87% of children without NF-1 have evidence of tumor progression at a median follow-up of 72 months compared with only 14% of patients with NF-1.13 Unfortunately, the natural history cannot be predicted from pathology and there are no established MRI criteria for the prediction of tumor progression.7 There is a continuous spectrum of growth from a small number of tumors that grow rapidly to a larger majority of tumors, which progress slowly or not at all, to the infrequent, but documented, occurrence of spontaneous regression.12,14,15 Since OPG in the setting of NF-1 is less likely to exhibit rapid progression than in patients who do not have NF-1, treatment is usually reserved for those with evidence of progression of disease or progressive vision loss.16

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