Ocular Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1) has many potential ocular manifestations, requiring a vigilant management approach, according to Robert A Avery DO, MSCE. NF1 is an autosomal dominant condition affecting about 1 in 3,500 live births that causes tumours, or neurofibromas, to grow in nerves throughout the body. About half of NF1 cases are inherited, and the rest arise spontaneously. NF1 is usually evident in children before the age of two years.

Optic pathway gliomas (OPGs) will develop along the anterior visual pathway that includes the optic nerve(s), optic chiasm, and optic tracts in about 20% of NF1 patients, and about a third to a

half of these will become sight-threatening. Growths involving multiple nerves known as orbital/periorbital plexiform neurofibromas (OPPNs) may also develop—sometimes leading to significant vision loss and disfigurement.

To detect new symptomatic OPGs, all patients diagnosed with NF1 should have annual ophthalmic exams, including visual acuity and visual field tests, until at least eight years old. Patients diagnosed with OPGs should have more frequent exams soon after diagnosis, including magnetic resonance imaging (MRI). When ocular plexiform neurofibromas are discovered, the child should have a minimum of annual eye exams, although sometimes more frequent depending on the severity and impact on vision, Dr Avery said.

It is not currently possible to predict which neurofibromas will progress to sight-threatening or which OPGs require chemotherapy or other treatment, so ongoing vigilance is essential to preserve sight, he added.

RECOGNISING OCULAR NF1

A common ocular manifestation of NF1 is Lisch nodules, which appear as brownish or coffee-coloured peduncular growths mostly on the lower half of the iris, often appearing between ages three to five years. However, they are primarily useful in diagnosing NF1 and do not affect vision, nor does their presence predict OPGs, OPPNs, or other NF1 conditions, Dr Avery said.

OPGs are the most common NF1 ocular manifestation. They are usually slow-growing, low-grade tumours that form along the optic nerve, chiasm, and optic tracts. OPGs occur in about 15% to 20% of children with NF1 and are usually apparent and fastest growing between ages one and eight years—and seldom require treatment after age eight, Dr Avery said. They may present with early vision loss or optic nerve head atrophy.

Immediately after diagnosis, OPG progress should be monitored every three months with eye exams, including quantitative visual acuity tests and visual fields and MRIs to visualise the optic pathway.

“It’s really hard to tell when vision gets worse with simple assessments like ‘fix and follow the object.’ That’s why we are really pushing for quantitative visual acuity assessments,” Dr Avery said.

For stable cases, monitoring intervals can be extended to every six months for two to three years, he added.

In general, OPG treatment with chemotherapy or other medications aims to preserve vision and is limited to those patients who need it. Carboplatin and vincristine, or vinblastine, are the most common first-line treatments. Bevacizumab and selumetinib, a recently approved MEK inhibitor, may also shrink OPGs, sometimes dramatically. Surgery is not an option because the tumour is part of the nerve and would result in blindness if removed.

Worsening vision, either central or peripheral, indicates treatment need. Tumour growth may sometimes, but not always, indicate a treatment need. Dr Avery is currently researching MRI volumetrics to get a better idea of when tumour growth predicts vision loss. OCT analysis of changes in retinal nerve fibre layer thickness may also help guide treatment decisions, but its utility and accuracy are still under investigation. Treatment usually begins before the patient is five years old.

OPPNS

Signs of OPPNs include ptosis, proptosis, strabismus, and nystagmus. These occur in about 5% of children with NF1 and usually appear in the first one to three years of life. OPPNs can interfere directly with vision or contribute to amblyopia or glaucoma. Patients with OPPNs should be examined every 3 to 12 months, with more severe cases and children still in the visual maturation process seen more often.

Treatment is indicated to preserve vision, reverse or prevent amblyopia, and improve appearance, Dr Avery said. Surgery is an option in certain cases, though often complicated by the fact plexiform tumours tend to grow back. Selumetinib can decrease tumour size in some cases.

Bulging eyes in NF1 patients may also indicate sphenoid wing dysplasia, in which the bone separating the brain from the orbit is underdeveloped, and the brain pushes the eyes forward. Eye exams should be conducted every 3 to 12 months depending on severity, with surgery to insert a mesh to hold the brain back indicated in some severe cases, Dr Avery said.

Current research includes a phase 3 clinical trial comparing selumetinib with chemotherapy for OPGs. Bevacizumab and other MEK inhibitors may also help, but impact on quality of life and vision is as important as tumour shrinkage. “We are not treating an MRI scan, we are treating a child’s vision,” Dr Avery stressed.

He is also conducting a large-scale study of OPGs for a better understanding of the ones likely to lead to vision loss.

“We hope our new research tools will improve the care of all children with NF1,” Dr Avery said.

Dr Avery presented at the 2022 NF Summit of the Children’s Tumor Foundation in Chicago, Illinois, US.

Robert A Avery DO, MSCE is a paediatric neuro-ophthalmologist at Children’s Hospital of Philadelphia and an associate professor of ophthalmology and neurology at the University of Pennsylvania, Philadelphia, US. averyr@chop.edu