Ophthalmology – Neurofibromatosis

Basics

Description

Neurofibromatosis refers to inherited tumor-predisposition syndromes affecting the:

• Nervous system
• Skin
• Eyes
• Bones
• Soft tissues

The two historically recognized major forms are:

• Neurofibromatosis type 1 (NF1) – formerly von Recklinghausen disease
• NF2-related schwannomatosis – historically called neurofibromatosis type 2 or central neurofibromatosis

NF1 and NF2 are genetically and clinically distinct disorders.

Neurofibromatosis Type 1

NF1 is the much more common form.

Important ophthalmic manifestations include:

• Lisch nodules
• Optic pathway glioma
• Choroidal abnormalities
• Plexiform neurofibroma involving the eyelid/orbit
• Proptosis
• Strabismus
• Sphenoid wing dysplasia

NF2-Related Schwannomatosis

NF2-related schwannomatosis is characterized predominantly by tumors of the central and peripheral nervous systems.

The hallmark is:

Bilateral vestibular schwannomas

Important ocular manifestations include:

• Early-onset cataract
• Epiretinal membrane
• Retinal hamartoma
• Optic nerve sheath meningioma
• Strabismus or cranial nerve palsies from intracranial tumors

Epidemiology

NF1

Occurs in approximately:

1 in 3,000–3,500 individuals

NF2-Related Schwannomatosis

Much rarer, traditionally estimated at approximately:

1 in 25,000–60,000

Both sexes are affected approximately equally.

Genetics

Both NF1 and NF2-related schwannomatosis are inherited in an:

Autosomal dominant pattern

However, many patients have a new pathogenic variant without an affected parent.

NF1 Gene

The NF1 gene is located on:

Chromosome 17q11.2

It encodes:

Neurofibromin

Neurofibromin acts as a tumor suppressor and negatively regulates RAS signaling.

NF2 Gene

The NF2 gene is located on:

Chromosome 22q12

It encodes:

Merlin, also called schwannomin.

Merlin functions as a tumor-suppressor protein involved in cellular growth regulation.

Penetrance and Expression

NF1 has:

• Very high penetrance
• Markedly variable expression

Thus, members of the same family may have very different disease severity.

Mosaic forms can also occur.

Genetic Counseling

Because inheritance is autosomal dominant, an affected individual generally has a:

50% chance of transmitting the pathogenic variant to each child.

Genetic counseling is appropriate for:

• Affected patients
• Parents
• Families planning pregnancy

Prenatal and preimplantation genetic testing may be possible when the familial pathogenic variant is known.

Pathophysiology

Both neurofibromin and merlin act as tumor suppressors.

Loss of normal tumor-suppressor function predisposes to development of:

• Schwannomas
• Neurofibromas
• Gliomas
• Meningiomas
• Other benign and malignant tumors

Neurofibromatosis Type 1 – Diagnostic Features

Modern diagnostic criteria for NF1 incorporate clinical findings and molecular testing.

In a patient without an affected parent, the diagnosis generally requires at least 2 characteristic features.

Important features include:

• Six or more café-au-lait macules
• Axillary or inguinal freckling
• Two or more neurofibromas or one plexiform neurofibroma
• Optic pathway glioma
• Two or more Lisch nodules
• Characteristic choroidal abnormalities
• Characteristic osseous lesion
• Pathogenic heterozygous NF1 variant

Café-au-Lait Macules

Typical café-au-lait macules are:

• Flat
• Hyperpigmented
• Well-defined

Diagnostic size thresholds are approximately:

• >5 mm before puberty
• >15 mm after puberty

Six or more are characteristic of NF1.

Axillary and Inguinal Freckling

Freckling in skin-fold areas is highly characteristic.

Common sites include:

• Axilla
• Groin
• Inframammary folds

Neurofibromas

Patients may develop:

• Cutaneous neurofibromas
• Subcutaneous neurofibromas
• Plexiform neurofibromas

A plexiform neurofibroma is particularly characteristic of NF1.

Ophthalmic Manifestations of NF1

Lisch Nodules

Lisch nodules are benign melanocytic hamartomas of the iris.

They appear as:

• Small
• Dome-shaped
• Pigmented iris nodules

They are best detected by:

Slit-lamp examination

Lisch nodules:

• Usually do not affect vision
• Become increasingly common with age
• Are highly characteristic of NF1

Choroidal Abnormalities

Near-infrared fundus imaging may reveal multiple bright choroidal nodules.

These abnormalities are now included among recognized diagnostic features of NF1.

They usually:

• Do not reduce vision
• Are difficult to see on ordinary ophthalmoscopy
• Are readily visible with near-infrared imaging

Optic Pathway Glioma

Optic pathway glioma (OPG) is one of the most important ophthalmic complications of NF1.

It is usually a:

Low-grade pilocytic astrocytoma

and may involve:

• Optic nerve
• Optic chiasm
• Optic tract
• Hypothalamic region

Epidemiology of Optic Pathway Glioma

Radiographic optic pathway gliomas occur in approximately:

15–20% of children with NF1

However, many remain asymptomatic and never require treatment.

Most clinically significant tumors present during childhood.

Clinical Features of Optic Pathway Glioma

Possible manifestations include:

• Reduced visual acuity
• Color vision loss
• Relative afferent pupillary defect
• Optic disc pallor
• Optic disc swelling
• Proptosis
• Strabismus
• Visual field loss
• Nystagmus

Chiasmal or hypothalamic tumors may be associated with:

• Precocious puberty
• Endocrine abnormalities

Plexiform Neurofibroma of the Eyelid

Plexiform neurofibromas commonly involve the:

• Upper eyelid
• Orbit
• Temporal region

Possible findings include:

• Thickened eyelid
• S-shaped upper lid
• Ptosis
• Facial asymmetry
• Proptosis
• Strabismus

These lesions can become extensive and difficult to excise completely.

Sphenoid Wing Dysplasia

Sphenoid wing dysplasia may lead to:

• Enlargement of the orbit
• Pulsatile proptosis
• Facial asymmetry

The temporal lobe may herniate toward the orbit when the sphenoid wing is markedly deficient.

Glaucoma in NF1

Glaucoma may occur, particularly in eyes with:

• Ipsilateral eyelid plexiform neurofibroma
• Orbital involvement
• Anterior segment developmental abnormalities

Congenital or early-onset glaucoma should therefore be considered in affected children.

Other Manifestations of NF1

Neurologic manifestations may include:

• Seizures
• Learning difficulties
• Attention problems
• Gliomas
• Spinal tumors
• Chiari malformation
• Vascular abnormalities

Skeletal Manifestations

Possible findings include:

• Scoliosis
• Long-bone dysplasia
• Tibial bowing
• Pseudarthrosis
• Sphenoid wing dysplasia
• Reduced bone mineral density

Vascular Disease

NF1 can cause vascular abnormalities such as:

• Renal artery stenosis
• Cerebral vasculopathy
• Aneurysms
• Moyamoya arteriopathy

Moyamoya Disease

NF1 is associated with moyamoya arteriopathy, a progressive stenotic disorder affecting intracranial arteries around the Circle of Willis.

Children may present with:

• Transient ischemic attacks
• Stroke
• Seizures
• Weakness

Adults may also develop intracranial hemorrhage.

Hypertension

Hypertension in NF1 may result from:

• Essential hypertension
• Renal artery stenosis
• Pheochromocytoma

Blood pressure should therefore be monitored regularly.

Pheochromocytoma

Symptoms may include:

• Episodic headache
• Palpitations
• Sweating
• Hypertension

Evaluation may include plasma or urinary metanephrines when clinically indicated.

Malignant Peripheral Nerve Sheath Tumor

Patients with NF1 have an increased risk of malignant peripheral nerve sheath tumor (MPNST).

Warning symptoms include:

• Rapid tumor enlargement
• Persistent or increasing pain
• Hardening of a previously soft neurofibroma
• Neurologic deficit

These require urgent evaluation.

NF2-Related Schwannomatosis

The defining tumor predisposition differs substantially from NF1.

Typical tumors include:

• Vestibular schwannomas
• Other cranial nerve schwannomas
• Spinal schwannomas
• Meningiomas
• Ependymomas

Vestibular Schwannomas

The classic hallmark is:

Bilateral vestibular schwannomas

Symptoms include:

• Progressive hearing loss
• Tinnitus
• Imbalance
• Vertigo

Presentation often occurs in adolescence or early adulthood.

Other Cranial Nerve Tumors

Schwannomas may involve other cranial nerves, including:

• CN III
• CN V
• CN VII

These can produce:

• Diplopia
• Ptosis
• Facial sensory abnormalities
• Facial weakness

Ophthalmic Manifestations of NF2

Important ocular abnormalities include:

• Early-onset cataract
• Epiretinal membrane
• Combined hamartoma of retina and RPE
• Retinal abnormalities
• Optic nerve sheath meningioma
• Strabismus
• Cranial nerve palsies

Cataract in NF2

A characteristic finding is a:

Juvenile posterior subcapsular or cortical cataract

Cataract may precede neurologic symptoms and can therefore provide an early clue to the diagnosis.

Epiretinal Membrane

Epiretinal membranes may occur at an unusually young age.

They may cause:

• Metamorphopsia
• Reduced visual acuity
• Macular distortion

Combined Hamartoma of Retina and RPE

This lesion may appear as:

• Elevated gray retinal lesion
• Retinal distortion
• Vascular tortuosity
• Epiretinal fibrosis

It can reduce vision if the macula is involved.

Optic Nerve Sheath Meningioma

NF2 predisposes to meningiomas, including those around the optic nerve.

Possible manifestations include:

• Progressive visual loss
• Optic atrophy
• Optociliary shunt vessels
• Proptosis

Diagnosis

History in NF1

Ask about:

• Café-au-lait lesions
• Skin tumors
• Family history
• Bone abnormalities
• Learning difficulties
• Visual decline
• Proptosis
• Precocious puberty
• Headaches
• Hypertension

History in NF2

Ask about:

• Hearing loss
• Tinnitus
• Balance problems
• Family history
• Diplopia
• Progressive visual loss
• Early cataract
• Neurologic deficits

Ophthalmic Examination

For NF1, examine:

• Visual acuity
• Pupils
• Color vision
• Ocular motility
• Optic discs
• Iris by slit lamp
• Eyelids and orbit
• Fundus

Near-infrared imaging may identify choroidal abnormalities.

Ophthalmic Examination in NF2

Evaluate for:

• Cataract
• Epiretinal membrane
• Retinal hamartoma
• Optic nerve abnormalities
• Strabismus
• Cranial nerve palsies

Genetic Testing

Molecular testing may include:

• NF1 gene sequencing and deletion/duplication analysis
• NF2 gene testing
• Mosaicism assessment when appropriate

Genetic testing is especially useful when:

• Clinical findings are incomplete
• Atypical phenotype is present
• Family planning is being considered

Imaging in NF1

MRI may be indicated when there are:

• Visual abnormalities suggesting optic pathway glioma
• Proptosis
• Neurologic symptoms
• Precocious puberty
• Suspected intracranial or spinal tumor

Routine screening MRI solely to look for an asymptomatic optic pathway glioma is generally not required when reliable ophthalmic surveillance is possible.

MRI Findings in NF1

Possible findings include:

• Optic pathway glioma
• Other low-grade gliomas
• T2-hyperintense focal areas historically called unidentified bright objects

These focal signal abnormalities are particularly common in children.

Imaging in NF2

MRI is central to surveillance because of the high tumor burden.

Serial MRI may assess:

• Vestibular schwannomas
• Meningiomas
• Spinal tumors
• Other cranial nerve schwannomas

Volumetric MRI can be useful for monitoring tumor growth.

Hearing Evaluation in NF2

Assessment may include:

• Pure-tone audiometry
• Speech discrimination testing
• Auditory brainstem response testing

Hearing surveillance is an essential part of management.

Differential Diagnosis of NF1

Important alternatives include:

• Legius syndrome
• McCune-Albright syndrome
• Constitutional café-au-lait pigmentation
• Other RASopathies
• Segmental/mosaic NF1

Legius Syndrome

Legius syndrome is caused by pathogenic variants in:

SPRED1

It can produce:

• Café-au-lait spots
• Axillary or inguinal freckling

but typically lacks:

• Neurofibromas
• Lisch nodules
• Optic pathway gliomas

This is an important differential in young children with pigmentary findings alone.

Differential Diagnosis of NF2

Consider:

• Other forms of schwannomatosis
• Sporadic vestibular schwannoma
• Multiple meningioma syndromes
• Other hereditary tumor-predisposition syndromes

Treatment of NF1

Treatment is individualized according to the complication.

There is no single therapy for NF1 itself.

Optic Pathway Glioma – Observation

Many NF1-associated optic pathway gliomas:

• Grow slowly
• Remain asymptomatic
• Do not require treatment

Treatment is generally based more on:

Documented visual deterioration

than on MRI appearance alone.

Optic Pathway Glioma – Treatment

Treatment is considered when there is:

• Progressive visual loss
• Significant tumor progression with functional impact
• Other clinically important progression

Systemic chemotherapy has traditionally included regimens such as:

• Carboplatin
• Vincristine

Modern targeted treatment, including MEK inhibition, may be considered in selected progressive NF1-associated tumors under specialist care.

Radiation in NF1

Radiotherapy is generally avoided when possible, particularly in children with NF1, because of increased risks of:

• Secondary tumors
• Radiation-induced vasculopathy
• Moyamoya-type vascular disease

Plexiform Neurofibroma

Management may include:

• Observation
• Surgical resection
• Targeted systemic treatment for symptomatic, inoperable lesions

The MEK inhibitor selumetinib is used for selected children with symptomatic, unresectable NF1-associated plexiform neurofibromas.

Treatment of NF2-Related Schwannomatosis

Management may include:

• Observation with serial MRI
• Microsurgery
• Stereotactic radiation in selected patients
• Systemic targeted therapy

Treatment aims to preserve:

• Hearing
• Facial nerve function
• Neurologic function
• Vision

Bevacizumab in NF2

Bevacizumab can be useful in selected patients with progressive vestibular schwannomas, particularly when hearing is deteriorating.

Potential benefits include:

• Tumor shrinkage
• Hearing improvement or stabilization

Treatment requires specialist systemic monitoring.

Cataract Treatment

Visually significant cataract is treated with:

• Cataract extraction
• Intraocular lens implantation when appropriate

Epiretinal Membrane

Observation is appropriate when mild.

Vitrectomy with membrane peeling may be considered when there is significant:

• Visual loss
• Metamorphopsia
• Macular distortion

Multidisciplinary Care

Patients may require involvement of:

• Ophthalmology
• Neuro-ophthalmology
• Neurology
• Neurosurgery
• Neuro-oncology
• Genetics
• ENT/audiology
• Orthopedics
• Dermatology
• Endocrinology
• Cardiology or vascular specialists

Ongoing Ophthalmic Surveillance in NF1

Children require regular ophthalmic examinations, particularly during the years when optic pathway glioma is most likely to become symptomatic.

Monitoring should include:

• Age-appropriate visual acuity
• Pupils
• Color vision when possible
• Ocular alignment
• Optic nerve examination
• Eyelid/orbital assessment

Blood Pressure Monitoring

Patients with NF1 should undergo regular blood pressure assessment because hypertension may indicate:

• Renal artery stenosis
• Pheochromocytoma
• Other vascular disease

Pregnancy Considerations

During pregnancy, women with NF1 may experience:

• Enlargement of existing neurofibromas
• Development of additional neurofibromas

Pregnancy planning should include:

• Genetic counseling
• Assessment of significant tumor burden
• Blood pressure monitoring

Patient Education

Patients and families should seek evaluation for:

• New visual loss
• New strabismus
• Proptosis
• Persistent headache
• New neurologic deficit
• Rapidly enlarging painful neurofibroma
• Hearing loss
• Tinnitus
• Balance problems

Prognosis

NF1

Many patients have relatively mild disease and normal or near-normal life expectancy.

Morbidity depends on complications such as:

• Malignant peripheral nerve sheath tumor
• Severe vascular disease
• CNS tumors
• Large plexiform neurofibromas

NF2-Related Schwannomatosis

NF2 generally causes greater neurologic morbidity because patients frequently develop multiple:

• Schwannomas
• Meningiomas
• Spinal tumors

Modern surveillance, surgery, hearing rehabilitation, and targeted therapy have substantially improved management.

Complications

NF1

Important complications include:

• Visual loss from optic pathway glioma
• Amblyopia
• Glaucoma
• Proptosis
• Skeletal deformity
• Seizures
• Moyamoya disease
• Hypertension
• Malignant peripheral nerve sheath tumor

NF2

Important complications include:

• Hearing loss
• Tinnitus
• Balance dysfunction
• Cranial nerve palsies
• Spinal cord compression
• Visual loss
• Cataract
• Retinal or epiretinal abnormalities

Ophthalmology Pearls

• NF1 = café-au-lait spots + axillary/inguinal freckling + neurofibromas + Lisch nodules + optic pathway glioma.
• Lisch nodules are benign iris hamartomas and usually do not affect vision.
• Choroidal abnormalities detectable by near-infrared imaging are now recognized diagnostic features of NF1.
• The most important vision-threatening lesion in children with NF1 is the optic pathway glioma.
• Most NF1-associated optic pathway gliomas do not require treatment unless visual function deteriorates.
• Plexiform neurofibroma involving the upper eyelid can cause the characteristic S-shaped eyelid deformity.
• NF1 is associated with moyamoya disease, renal artery stenosis, and pheochromocytoma.
• NF2-related schwannomatosis = bilateral vestibular schwannomas until proven otherwise.
• Early cataract, epiretinal membrane, or retinal hamartoma in a young patient may provide an ophthalmic clue to NF2.
• Radiation is generally used cautiously in NF1 because of increased risks of secondary tumors and vasculopathy.
• Both NF1 and NF2 require lifelong multidisciplinary surveillance.