Tuberous Sclerosis and the Eye

Tuberous sclerosis complex is an autosomal dominant neurocutaneous disorder caused by mutations of TSC1 (hamartin) or TSC2 (tuberin), producing constitutive activation of the mTOR pathway and hamartomas in the brain, skin, kidney, heart, lung and retina. About two thirds of cases arise de novo, and TSC2 mutations give more severe disease.

• Retinal astrocytic hamartomas are present in 30 to 50 percent. They are usually asymptomatic and nonprogressive, but occasionally cause visual loss through macular involvement, exudation, haemorrhage or neovascular glaucoma.
• The eye is important in diagnosis, because retinal hamartomas and retinal achromic patches are diagnostic clues, and the visual system is at risk from the treatments (vigabatrin) and from intracranial disease (hydrocephalus, cortical visual impairment).
• Features beyond the eye include epilepsy and infantile spasms, intellectual disability and autism, facial angiofibromas, hypomelanotic macules, shagreen patches, subependymal nodules and giant cell astrocytomas, cardiac rhabdomyomas, renal angiomyolipomas and lymphangioleiomyomatosis.

• Retinal astrocytic hamartomas: three types. Type 1 flat, smooth, translucent grey lesions near the disc, easily missed. Type 2 elevated nodular multinodular mulberry like tumours with calcification (white or yellow), often adjacent to the disc, and may cause vitreous seeding. Type 3 transitional lesions with a flat translucent edge and a calcified centre. Usually bilateral and multiple.
• Retinal achromic patches (depigmented peripheral retina, similar to hypomelanotic skin macules) and iris depigmentation.
• Complications of hamartomas: macular oedema, exudative retinal detachment, vitreous haemorrhage and neovascular glaucoma, and optic nerve head involvement.
• Eyelid angiofibromas (Pringle adenoma like facial lesions) and periungual fibromas.
• Papilloedema from obstructive hydrocephalus caused by a subependymal giant cell astrocytoma at the foramen of Monro.
• Visual loss from cortical tubers and epilepsy (cortical visual impairment), homonymous field defects, and nystagmus. Cranial nerve palsies are uncommon.
• Vigabatrin toxicity: bilateral concentric (nasal more than temporal) constriction of the visual fields, which is usually asymptomatic until late and irreversible, and is related to the dose and duration of therapy.

• Clinical criteria: major features (hypomelanotic macules 3 or more, angiofibromas 3 or more or fibrous cephalic plaque, ungual fibromas 2 or more, shagreen patch, multiple retinal hamartomas, cortical dysplasias including tubers, subependymal nodules, subependymal giant cell astrocytoma, cardiac rhabdomyoma, lymphangioleiomyomatosis, angiomyolipomas 2 or more) and minor features (confetti skin lesions, dental enamel pits 3 or more, intraoral fibromas 2 or more, retinal achromic patch, multiple renal cysts, nonrenal hamartomas). Two major features or one major with two minor features confirm the diagnosis. A pathogenic TSC1 or TSC2 variant is diagnostic by itself.
• Dilated fundus examination with widefield imaging, optical coherence tomography (mulberry lesions are elevated and dense, flat lesions are hyperreflective in the inner retina), fluorescein angiography (hyperfluorescence of the hamartoma, feeder vessels and leakage), and B-scan ultrasonography (calcification with high reflectivity and shadowing).
• Genetic testing for TSC1 and TSC2.
• MRI brain (cortical tubers, subependymal nodules, giant cell astrocytoma), EEG, renal ultrasound or MRI, echocardiogram, chest CT in adult women, and skin and dental examination.
• Visual field testing (perimetry) when the child can cooperate, electroretinogram in younger infants, and acuity monitoring, every 3 to 6 months while on vigabatrin.

• Retinal hamartomas that are asymptomatic and stable: observation with an annual dilated examination, because most never need treatment, and more frequent review in infants and when there is calcification near the macula.
• Exudative or enlarging hamartoma threatening the macula: laser photocoagulation to the surface and feeding vessels, photodynamic therapy with verteporfin 6 mg/m2 (82 seconds light application at 50 J/cm2), intravitreal bevacizumab 1.25 mg/0.05 mL or ranibizumab 0.5 mg, with repeat injections as required for exudation, and plaque brachytherapy rarely. Vitrectomy for persistent vitreous haemorrhage or traction, and enucleation only for a painful blind eye with neovascular glaucoma.
• Systemic mTOR inhibition: everolimus 4.5 mg/m2 orally once daily for subependymal giant cell astrocytoma (target trough level 5 to 15 ng/mL, adjust after 2 weeks), or 10 mg daily for renal angiomyolipoma, and adjunct for refractory seizures (5 to 15 ng/mL). It may shrink retinal hamartomas. Monitor for mouth ulcers, infections, hyperlipidaemia, proteinuria and impaired wound healing, and pause around surgery.
• Facial angiofibromas: topical sirolimus 0.2 percent gel or ointment twice daily, vascular laser, and surgical shave excision for large lesions.
• Infantile spasms: vigabatrin 50 mg/kg/day in 2 divided doses increasing to 100 to 150 mg/kg/day over a week (maximum 150 mg/kg/day), first line in tuberous sclerosis because of high response. Because of retinal toxicity, the lowest effective dose is used and it is stopped if there is no clear response within 2 to 4 weeks, and withdrawn after 6 to 12 months of seizure control where possible. Visual field testing (kinetic or static perimetry) every 6 months as soon as the child can cooperate, with electroretinogram and optical coherence tomography in younger children, every 3 to 6 months while on treatment and after stopping. Other antiseizure drugs (levetiracetam, topiramate, cannabidiol 5 to 25 mg/kg/day) are used for other seizure types.
• Hydrocephalus from giant cell astrocytoma: neurosurgical resection or ventriculoperitoneal shunt, with urgent eye assessment for papilloedema and visual field loss.
• Cortical visual impairment: educational support, high contrast materials, and visual rehabilitation.
• Genetic counselling: 50 percent transmission risk from an affected parent, and the possibility of germline mosaicism when parents are unaffected (recurrence about 1 to 2 percent). Lifelong multidisciplinary surveillance (neurology, nephrology, cardiology, dermatology, ophthalmology).