Neurofibromatosis and the Eye

Neurofibromatosis type 1 is an autosomal dominant disorder caused by mutation of the NF1 gene (chromosome 17, neurofibromin, a negative regulator of the RAS pathway), affecting 1 in 3000 births, with half of cases arising from new mutations. Neurofibromatosis type 2 is caused by mutation of the NF2 gene (chromosome 22, merlin) and affects 1 in 25000 births.

• In type 1, the eye is involved in nearly all patients: iris Lisch nodules, optic pathway glioma, eyelid and orbital plexiform neurofibromas and sphenoid wing dysplasia.
• In type 2, the typical ocular lesions are juvenile cataract, retinal hamartomas, epiretinal membranes, optic nerve sheath meningioma and cranial nerve palsies from schwannomas and meningiomas.
• Many ocular findings are the earliest diagnostic clues, and regular eye screening in children detects visually significant optic pathway glioma.

• Type 1 diagnostic features (two or more): six or more café-au-lait macules (over 5 mm before puberty, over 15 mm after), axillary or inguinal freckling, two or more neurofibromas or one plexiform neurofibroma, two or more Lisch nodules, optic pathway glioma, distinctive bony lesion (sphenoid dysplasia, tibial pseudarthrosis), and a first degree relative with the disease.
• Lisch nodules: tan to brown elevated dome shaped iris hamartomas on the iris surface, bilateral, present in over 90 percent of adults, harmless. Choroidal freckling or nodules (bright patches on near infrared imaging) in over 80 percent, and retinal astrocytic hamartomas or vascular tumours rarely.
• Optic pathway glioma (pilocytic astrocytoma): 15 to 20 percent of children with type 1, most under 7 years. Reduced acuity, colour vision loss, relative afferent pupillary defect, optic disc pallor or swelling, proptosis, and precocious puberty when the hypothalamus is involved. About half of symptomatic or imaged tumours remain stable.
• Eyelid and orbit: plexiform neurofibroma of the upper lid with S-shaped ptosis, thickened lid and temporal flare, proptosis, and facial asymmetry. Sphenoid wing dysplasia with absent greater wing and pulsatile exophthalmos (transmitted from the cerebral pulse), sometimes with temporal bulge.
• Glaucoma: ipsilateral to plexiform neurofibroma of the lid (congenital or early onset, from angle anomalies or direct infiltration) in about 50 percent of those with lid involvement.
• Type 2: posterior subcapsular or cortical cataract (60 to 80 percent, often early), combined hamartoma of the retina and retinal pigment epithelium, epiretinal membrane, optic nerve sheath meningioma (progressive visual loss, optociliary shunt vessels), and papilloedema (from intracranial tumour load). Bilateral vestibular schwannomas cause hearing loss and tinnitus. Ocular motor nerve palsies, corneal anaesthesia (fifth nerve).

• Clinical diagnostic criteria for type 1 or type 2, with genetic testing (NF1 and NF2 mutation analysis) to confirm and counsel.
• Slit lamp examination for Lisch nodules and glaucoma, and gonioscopy and IOP in lid plexiform disease.
• Screening for optic pathway glioma: visual acuity (age appropriate tests) and colour vision, pupils, optic disc examination and optical coherence tomography of the retinal nerve fibre layer annually until 8 years of age, then every 2 years until 18, plus a visual field when cooperative.
• MRI brain and orbits with gadolinium and fat suppression when vision is reduced, there is proptosis, pallor or precocious puberty (routine MRI of asymptomatic children is not required). Tumour appearance: fusiform enlargement of optic nerve with kinking, or chiasmal and hypothalamic mass.
• Cranial and orbital CT for sphenoid wing dysplasia.
• Type 2: slit lamp for cataract, dilated fundus examination for hamartoma and epiretinal membrane, MRI of brain and spine with gadolinium for schwannomas and meningiomas, audiology.

• Optic pathway glioma: observe if vision is stable (most do not progress) with serial acuity, field and MRI every 3 to 6 months at first. Treatment is started only for documented loss of vision or progressive tumour enlargement. First line: carboplatin 175 mg/m2 intravenously weekly for 4 weeks, 2 weeks of rest, then weekly for 4 weeks (10 weeks of induction), with vincristine 1.5 mg/m2 (maximum 2 mg) weekly over the same 10 weeks, followed by maintenance in 6-week cycles for 8 cycles: carboplatin 175 mg/m2 on day 1 and vincristine 1.5 mg/m2 on days 1, 8 and 15. Alternative: vinblastine 6 mg/m2 weekly, or selumetinib (a MEK inhibitor) 25 mg/m2 orally twice daily for children aged 3 years and over, with monitoring of cardiac function, creatine kinase and eye examination (retinal pigment epithelial detachment). Radiotherapy is avoided in neurofibromatosis type 1 because of the risk of moyamoya vasculopathy, endocrinopathy and second malignancies. Surgery is reserved for large disfiguring unilateral proptotic blind eyes.
• Amblyopia: refraction, patching and atropine penalisation to the better eye in asymmetric vision loss.
• Glaucoma: topical therapy (timolol 0.25 to 0.5% twice daily, dorzolamide 2% three times daily) then surgery (trabeculotomy, trabeculectomy with mitomycin C 0.2 to 0.4 mg/mL for 2 to 3 minutes, or drainage device) as early as possible in children, because of rapid progression.
• Plexiform neurofibroma: selumetinib 25 mg/m2 twice daily for inoperable symptomatic plexiform tumours (reduces volume in about 70 percent), surgical debulking in staged procedures by an orbital and oculoplastic team with the aim of reducing visual obstruction, ptosis surgery (frontalis sling) after debulking, and amblyopia treatment for deprivation from ptosis.
• Sphenoid wing dysplasia with pulsatile exophthalmos: surgical reconstruction of the orbital wall with bone graft or titanium mesh when the globe is displaced or vision is at risk.
• Type 2: cataract extraction with intraocular lens when vision is affected, epiretinal membrane peel for symptomatic cases, observation of hamartomas, and bevacizumab 7.5 mg/kg intravenously every 3 weeks for 6 months in progressive vestibular schwannoma to improve hearing and reduce tumour volume under the guidance of a neurosurgical and oncology team. Optic nerve sheath meningioma: fractionated stereotactic radiotherapy (50.4 Gy in 28 fractions).
• Surveillance and education: annual eye examination, regular blood pressure measurement (renal artery stenosis and phaeochromocytoma), scoliosis review, learning disability assessment, genetic counselling with a 50 percent risk to each child, and psychological support.