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The effects of neurofibromatosis on the visual pathway: Course Code C-16641 O/D.

Fabrizio Bonci, Dip. Optom (ITA), MCOptom

Neurofibromatosis (NF) is an inherited genetic disorder in which the nerve tissue grows tumours known as neurofibromas. The growth of these tumours in different locations damages the nerves and other tissues. NF occurs in the nervous system, including the central nervous system (CNS) and spinal cord, affecting Schwann cells, melanocytes and endoneurial fibroblasts. According to the Office of Rare Diseases (ORD) of the National Institutes of Health, NF is considered as a rare disease with an incidence of less than 200,000 people in USA. This article discusses the effects of this condition of the visual system and pathway.

NF is classified as Type 1 (NF-1), known also as Von Recklinghausen disease, and Type 2 (NF-2) or central neurofibromatosis. (1) These two forms have different genetic conditions with different genetic bases.

Type 1 Neurofibromatosis (NF-1)

Type 1 NF (NF-1) is an autosomal dominant disorder characterised by skin pigment changes and tumours that grow along the nerves, in the skin, brain, and otheT parts of the body. The worldwide incidence of NF-1 is estimated to be approximately 1 per 2500 to 3000 individuals. It is caused by a germ-line-inactivating mutation in the NF-1 gene on chromosome 17, (2) which encodes a protein known as ncurofibromin type 1 (also known as neurofibromatosis- related protein NF-1). Abnormal pigments can be found on the skin of the trunk, under the arms, and in the groin area. They appear as pale, tanned or light brown, discolorations (cafe au lait spots].

The severity of disease is variable, from mild to severe. (3) However, the pigments increase in number and in size with age. Around 97% of affected people have six or more cafe au lait spots by age 20 years, whilst the neurofibromas on the skin occur in the second decade of life. (4) Neurofibromas can also occur both on the peripheral and in the central nervous system and arise from the supportive tissue within the nerve itself, infiltrating and disrupting the sheaths of fibres.

Sub-types of neurofibromas include:

* Cutaneous, which are superficial with no malignancy

* Subcutaneous, where tumours are localized in the dermis and may cause pain or tenderness


* Nodular plexiforms, which arc largo and often linked to other nodules involving the dorsal nerve roots

* Diffuse plexiforms, which are invasive tumours that involve the skin, muscle, bone and blood vessels

Orthopaedic disorders such as sphenoid dysplasia, thinning of the cortex on the long bones, demineralization, scoliosis, hypotonia and poor coordination are very common in patients with NF-1. People affected by NF-1 also have cognitive delay, learning disabilities and attention deficits.

Type 2 Neurofibromatosis (NF-2)

NF-2 is an inherited disorder with an autosomal dominant mode of transmission due to mutation of Merlin gene, in which it is coded by the gene NF-2 in chromosome 22. (5) The incidence of this disease is rare and it affects around 1 person in fi0,0f)0 people. (6)

The main neurological manifestation of NF-2 is the development of non-malignant brain tumours in the region of the VIlTth cranial nerve (auditory-vestibular nerve), which functions to transmit sensory information from the inner ear to the brain. Acoustic neuroma (Figure 1) may occur in 90% of cases of patients with NF-2. It is a benign tumour of the my el in-forming cells of the vcstibulo-cochlear nerve. Unfortunately the patient with acoustic neuroma tends to lose hearing functionality and reports disturbance of balance, vertigo and nausea, and tinnitus. Symptoms are generally worse in bilateral cases whilst large neuromas can also involve other cranial nerves, leading to meningiomas and ependymomas.

Meningioma [Figure 2] arises from the arachnoid cells of the arachnoid villi in the meninges, whilst ependymoma arises from opendyma. In young children, it is located in the CNS, in the forth ventricle, whilst in adults it is located in the spinal cord.78

Treatment of neurofibromatosis

Unfortunately there are no treatments to eradicate the NF diseases. (9) Different therapeutic approaches are currently available to reduce the complications of the disease and surgery for removing a neurofibroma is often only advised if it can compress important structures, if it is thought to be malignant, or to correct any bone malformations.

Neurosurgery combined with neurotology (n euro-otology) surgery is the first choice of treatment for removing an acoustic neuroma, to prevent the permanent loss of hearing. Chemotherapy and radiotherapy are used as adjuvant therapies to the surgery, to reduce the size of the neurofibroma.

Neurofibromatosis and visual associations

As healthcare professionals providing primary eye care for a large population, optometrists may encounter patients with NF and therefore should recognize the first signs of this disease, and also should be aware of the ocular implications of the neurofibromatosis diseases, so that appropriate remedial action can be sought through referral to a specialist. Neurofibromatosis diseases can have several manifestations on both ocular and non-ocular structures. The following examples are reported as the main manifestations of NF.


Orbital abnormalities

The main craniofacial bono dysplasia for patients affected by NF-1 involves the sphenoid wing, which makes the nearby bone structures asymmetric, including the orbital cave. Proptosis occurs in severe cases due to progressive re-sorption of the sphenoid wing. (10) Congenital bilateral or unilateral ptosis can also be seen in children with NF-1 and an urgent referral to ophthalmology and early management might prevent, or at least reduce, the degree of amblyopia; ptosis can occut secondary to a neurofibroma of the upper eyelid too.

Lisch nodules

Lisch nodules [Figure 3) can be easily seen by slit lamp examination, by focusing on the anterioT surface of the iris. Their appearance depends on the colour of the iris: in people with a light (blue or green) iris, the Lisch nodules appear as reddish brown round spots and are elevated from the anterior surface of the iris, whilst in people with a dark (brown) iris, the nodules are less pigmented.

Lisch nodules are pigmented hamartomatous naevus, (11) which occur from proliferation of melanocytes and fibroblasts. They are visible in people over 20 years of age affected by NF-1 and aTe generally asymptomatic. (12)

Retinal abnormalities

Microvascular retinal abnormalities, such as corkscrew configuration, have been found in patients with NF-1. (12) Retinal tumours such as astrocytic hamartoma, combined hamartoma of the retinal pigment epithelium (RPE) and retina, and retinal capillary haemangioma can rarely affect people with NF-1. (13) Retinal astrocytic hamartomas are less common in people with NF, and tend to occur on the retina of people affected by tuberous sclerosis.

It appears initially as a greyish, flat lesion and can be seen close to the optic nerve; retinal glial tumours show as chalky white-cheesy central areas surrounded by a greyish margin, with a typical glistening, yellow, mulberry-like appearance. The patient's symptoms depend on the tumour site on the fundus.

Combined hamartoma of the RPE and retina generally occurs in one eye and tends to involve the juxtapapillary retina, macula, or both, and impair the visual acuity (VA). Leukocoria, floaters, strabismus, and amblyopia can be found in those patients. The tumour appears whitish due to epi-retinal and intra- retinal gliosis, and can be associated with marked retinal blood vessel tortuosity.


Retinal capillary hacmangioma occurs more frequently in Von Hippel-Lindau disease as opposed to NF. It is a benign vascular tumour of the retina or the optic disc. Hacmangioma appears as a red- orange, round shaped lesion and in some cases it may enlarge and produce visual loss due to Tetinal complications such as exudative retinal detachment, opi-rotinal membrane and vitreous haemorrhages. (14,5)


Glaucoma, as an ocular complication in patients affected by NF, is uncommon. However, a recent study, (16) which evaluated the presence of glaucoma associated with ocular globe enlargement in children with NF-1, reported an increased prevalence. It is possible that this relates to developmental anomalies in the iridocorneal angle, which affects aqueous outflow. Indeed, it has been reported that based on the known neurohistopathic aetiology of NF-1 and the neuro-ectodermal embryologic derivation of the iridocorneal angle, there is under-development of the angular region, in patients affected by NF-1, as confirmed by gonioscopic examination.


The association between cataract and NF has been reported in those patients affected by NF-2. (18) Early studies reported different types of lens opacities in patients with NF-2. The prevalence of posterior sub-capsular cataracts seems to be highest (27-72%),1922 but cortical wedge cataracts and mixed cataracts have also been found (14-33%). (19-22) The main crystalline lens abnormalities were found at an early age. (23)

Optic nerve glioma

Optic nerve glioma is the most common primary neoplasm of the optic nerve, which occurs more in children and young adults affected by NF-1. Optic nerve gliomas occur with an incidence of 4% of all OTbital tumours, 2% of all intracranial tumours and 4% of all gliomas. According to the World Health Organization (WHO), the optic nerve glioma is a grade I astrocytoma (pilocytic astrocytoma) because it is slow-growing and it does not develop metastases. The peak incidence is from 2 to 8 years nf age with 75% manifesting in the first decade of life and 90% in the first two decades of life. Spontaneous regression of glioma in patients with NF-1 has been reported.

Visual pathway gliomas can involve anywhere from the optic nerve to the visual cortex. The main abnormalities that an optometrist may detect are: painless proptosis, papilloedema and optic atrophy. Large size lesions may compress the optic chiasm area, causing nystagmus, cranial nerve palsy and visual field defects. Lesions that compress the third ventricle, due to obstructive hydrocephalus, increase the intracranial pressure. Such lesions are accompanied by papilloedema, headache, nausea, vomiting and Vlth nerve palsy.

Vllth cranial nerve palsy

The VHIth cranial nerve, which is affected by acoustic neuroma in NF-2, is close to other cranial nerves. As such, acoustic neuromas can come into intimate contact with the facial nerve (Vllth nerve), causing palsy of this nerve. More commonly, surgical intervention to remove such an acoustic neuroma can load to a temporary palsy of the Vllth nervo, (24) causing the anterior ocular surface to be constantly exposed (reduced innervation of the orbicularis oculi muscle reduces blinking), resulting in corneal oedema end subsequent loss of corneal transparency.

This ocular complication can be well-managed by an optometrist fitting a scleral contact lens, (25,26) since this allows good protection from the atmosphere and retention of the tears between the lens and the anterior ocular surface.


Neurofibromatosis is a rare group of diseases and most of the people affected by this disease are asymptomatic and have a normal life. Some people, unfortunately, might develop important and severe systemic and ocular abnormalities. NF-2 occurs mainly in the CNS, developing benign tumours such as acoustic neuroma, meningioma and ependymoma. Both NF-1 and NF-2 can affect the ocular and non-ocular structures, including associations with increased prevalence of cataracts and, less frequently, glaucoma.

The optometrist should recognize the first signs of the ocular effects of NF so that prompt referral of the patient to a specialist can be performed and urgent medical management obtained, in order to reduce the severity of ocular complications.

About the author

Fabrizio Bond is an optometrist and clinical research fellow at the division of clinical neuToscience and mental health, Imperial College, London, and the Faculty of Medicine, Charing Cross Hospital, London.


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Module questions

Course code: C-16641 O/D

PLEASE NOTE There is only one correct answer. All CET is now FREE. Enter online. Please complete online by midnight on September 30 2011 -Youwillbeunableto submit exams after this date--answers to the module will be published on CET points for these exams will be uploaded to Vantage on October 10 2011.

1. Which of the following statements regarding type 1 neurofibromatosis (NF-1) is TRUE?

a) It occurs in people after the age of 30 years

b) Both types of NF have the same genetic bases

c) NF-1 is caused by a germ-line-inactivating mutation on chromosome 22

d) NF-1 is caused by a germ-line-inactivating mutation on chromosome 17

2. The main neurological 1CNS) manifestations of NF occur:

a) Only in NF-1

b) Only in NF-2

c) In both NF-1 and NF-2

d) More in NF-2 than in NF-1

3. Which of the following statements about Lisch nodules is TRUE?

a) They are benign iris nodules, seen in patients over the age of 10 years with NF-2

b] They are benign nodules in the iridocorneal angle, causing secondary glaucoma

c] They are benign iris nodules, seen in patients over the age of 20 years with NF-1

d) They are malignant nodules, requiring prompt referral to HES

4. What is the MOST common clinical finding inthe crystalline lens of people affected by NF-2?

a) Posterior sub-capsular cataract

b) Nuclear cataract

c) Cortical cataract

d) None of the above

5. Which of the following is the MOST appropriate management option for a patient with Vllth nerve palsy, following surgery to remove an acoustic neuroma?

a) Prescribe artificial tears and topical antibiotics for use twice a day

b) Fit a silicone hydrogel extended wear contact lens

c) Fit a RGP contact lens with a total diameter of 10mm

d) Fit a scleral contact lens

6. Which of the following statements about optic nerve glioma and NF is TRUE?

a) It always occurs in all people with NF

b) 75% of cases manifest in the first decade of life, and 90% in the first two decades

c) It can occur in children and young adults with NF-1 and may regress

d) All of the above
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Author:Bonci, Fabrizio
Publication:Optometry Today
Geographic Code:4EUUK
Date:Sep 2, 2011
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