Myelinated Retinal Nerve Fiber Layer

Key points at a glance

Highlights of this condition

• Myelinated retinal nerve fiber layer (MRNF) is a congenital anomaly in which myelin sheaths form on retinal nerve fibers that are normally unmyelinated.
• The prevalence is approximately 0.3–1%, and it is mostly unilateral.
• It is often discovered incidentally on fundus examination as a brush-like white opacity along the course of the nerve fibers.
• Most cases are asymptomatic and do not require treatment.
• Rarely, it may be associated with high myopia, amblyopia, strabismus, or retinal vascular abnormalities.
• Note that it can cause overestimation of RNFL thickness (segmentation error) in OCT evaluation for glaucoma and other conditions.

1. What is Myelinated Retinal Nerve Fiber Layer?

Myelinated retinal nerve fiber layer (MRNF) is a congenital anomaly in which myelin sheaths form on the optic nerve fibers within the retina, which are normally unmyelinated. It was first reported by von Jäger in 1855. The following year, in 1856, the German pathologist Rudolf Virchow provided a histological description.

Normally, optic nerve fibers are covered by myelin sheaths from oligodendrocytes posterior to the lamina cribrosa, but anterior to the lamina cribrosa, within the optic disc and retina, they are unmyelinated. In MRNF, oligodendrocytes cross the lamina cribrosa and invade the retina, forming localized myelinated nerve fibers.

The incidence is reported to be 0.3–1% [1,3,4]. Most cases are sporadic and unilateral, with bilateral involvement seen in about 7% [1]. The cause is unknown. In a 10-year follow-up study from the Beijing Eye Study, the prevalence was 0.4%, no new cases developed during follow-up, but enlargement of existing lesions was observed [4].

Q Is myelinated retinal nerve fiber layer inherited?

A

Most cases are sporadic, but familial cases have been reported. A family with 10 affected individuals over two generations and a mother-daughter pair with bilateral MRNF have been described. It can also be associated with hereditary syndromes such as GAPO syndrome and Albright hereditary osteodystrophy.

2. Main symptoms and clinical findings

Subjective symptoms

Most cases are asymptomatic and discovered incidentally during fundus examination. When the area of myelination is extensive, the following symptoms may occur.

• Decreased visual acuity: Visual acuity is negatively correlated with the area of MRNF [3]. Extensive MRNF covering the macula causes severe visual impairment.
• Visual field defect: A relative scotoma may occur corresponding to the MRNF area. The scotoma is often smaller than expected from the size of the MRNF patch.

Clinical Findings (Findings Confirmed by Physician Examination)

On fundus examination, it is observed as a brush-like (feathery) white opacity along the course of the retinal nerve fibers. The border margins have a characteristic fluffy appearance.

• Distribution: Most often spreads in a fan shape continuously from the optic disc. Isolated lesions away from the disc also exist.
• Appearance: The myelin sheath has strong reflection, is flat without edema. It is characteristic that relatively thick retinal vessels are covered by the lesion.
• Fluorescein angiography (FA): Blocks background fluorescence, and no fluorescein leakage is observed in the lesion.
• Fundus autofluorescence (FAF): Normal autofluorescence is blocked by the myelin sheath, showing hypofluorescence.
• Infrared and red-free photography: Appears white due to high lipid content in the myelin sheath.
• OCT: Observed as a thickened, highly reflective retinal nerve fiber layer.

The following ophthalmic findings associated with MRNF have been reported.

• Refractive error: High myopia (axial myopia) is most common. It may be accompanied by anisometropia [2,5]. The triad of MRNF, myopia, and amblyopia is known as “Straatsma syndrome” [2].
• Amblyopia/Strabismus: In one review, strabismus was observed in 66% of MRNF cases [2].
• Anterior segment abnormalities: Keratoconus, congenital cataract, polycoria, etc.
• Optic nerve abnormalities: Optic nerve hypoplasia/dysplasia, optic disc drusen, etc.
• Retinal vascular complications: Telangiectasia, neovascularization, recurrent vitreous hemorrhage, retinal detachment, etc.

Q Does it affect vision?

A

In most cases, vision is not affected. However, in extensive MRNF, visual acuity shows a negative correlation with MRNF area. Visual impairment may occur when high myopia or amblyopia is present.

3. Causes and Risk Factors

The mechanism of MRNF is understood as follows.

Myelination of the optic nerve begins around the fifth month of gestation from the lateral geniculate body. It progresses toward the eye and stops at the lamina cribrosa. In MRNF, oligodendrocyte precursor cells cross the lamina cribrosa and invade the retina, forming ectopic myelin sheaths.

The main hypotheses regarding the mechanism are as follows:

• Ectopic oligodendrocyte precursor cell hypothesis: Precursor cells invade the retina before the lamina cribrosa is formed or through incomplete closure of the lamina cribrosa.
• Structural abnormality of the lamina cribrosa: Y-shaped fissures in the lamina cribrosa have been observed in cases of progressive MRNF, suggesting embryological incomplete closure.
• Other hypotheses: Induction of oligodendrocyte differentiation due to plasma protein leakage from choroidal circulation, and migration inhibitory factor by type 1 astrocytes have been proposed.

Systemic diseases reported to be associated with MRNF include the following:

• Genetic syndromes: GAPO syndrome (growth retardation, alopecia, pseudoanodontia, optic atrophy), Albright hereditary osteodystrophy, nevoid basal cell carcinoma syndrome
• Others: Turner syndrome, trisomy 21, epilepsy, craniosynostosis

Acquired and progressive MRNF

MRNF is usually a congenital and stationary condition, but rarely acquired and progressive MRNF has been reported in childhood or adulthood. It is known to be associated with blunt trauma, optic nerve sheath fenestration, optic disc drusen, neurofibromatosis type 1 (NF1), and Leber hereditary optic neuropathy (LHON).

4. Diagnosis and Examination Methods

Most MRNFs are discovered incidentally during health checkups or fundus examinations for other purposes.

Fundus Examination

A characteristic finding is a fluffy, brush-like white opacity at the border of the optic disc. The shape along the nerve fibers and the covering of large retinal vessels are diagnostic clues.

Differential Diagnosis

Small MRNFs need to be differentiated from soft exudates. The key points for differentiation are as follows:

Finding	MRNF	Soft exudate
Reflection	Strong myelin reflection	Slightly weak
Edema	None (flat)	Often present
Relationship with blood vessels	Large vessels are covered	Unrelated to blood vessels

Extensive MRNF in infants can cause leukocoria. It is important to differentiate it from major diseases that cause leukocoria.

• Retinoblastoma: Retinal tumor. Calcification is seen on ultrasound.
• Persistent fetal vasculature (PFV): Fibrous membrane behind the lens. Associated with microphthalmia.
• Coats disease: Dilated retinal vessels and exudative changes.

In MRNF, the key points for differentiation are a shape along the nerve fibers and the absence of elevation or depression.

Imaging Tests

• FA: Confirms blockage of background fluorescence and absence of leakage, useful for differentiating from embolic diseases.
• Fundus autofluorescence: Shows hypofluorescence due to blockage of autofluorescence by myelin.
• OCT: Depicted as an increase in RNFL thickness. However, note that segmentation errors may overestimate RNFL thickness.
• Orbital ultrasound: Useful in differentiating from retinoblastoma (with calcification) in the evaluation of leukocoria.

If there is a large visual field defect, formal visual field testing is necessary to rule out concurrent neuro-ophthalmic problems.

Q Does it affect glaucoma test results?

A

MRNF can cause segmentation errors on OCT that overestimate RNFL thickness. This may mask true RNFL thinning due to glaucoma. In eyes with MRNF, special caution is needed when interpreting OCT results [1,7]. In glaucomatous eyes, OCT segmentation correction is often required, and the risk of relying solely on automated analysis has been noted [7].

5. Management and Follow-up

MRNF is usually benign and does not require treatment if localized and asymptomatic. However, management should be based on associated ocular findings.

Observation

Regular fundus examination: Document changes in MRNF over time.

Storage of imaging records: Since loss of myelin can be a sign of retinal nerve damage, baseline imaging is recommended for preservation.

Caution in OCT evaluation: Consider segmentation errors when evaluating RNFL in conditions such as glaucoma.

Management of Complications

Refractive correction: Prescribe glasses or contact lenses for myopia. Contact lenses are preferable for strong anisometropia.

Amblyopia treatment: Treatment may be performed for childhood amblyopia, but the effect is considered limited [2]. However, recent long-term observations have reported that partial occlusion therapy (part-time patching) correlates with visual acuity improvement in the affected eye [5].

Strabismus treatment: Manage according to standard protocols. Often responds well to surgical correction.

Retinal vascular complications: Argon laser photocoagulation may be performed for neovascularization or vitreous hemorrhage.

Disappearance of MRNF is a red flag

If MRNF has disappeared compared to previous records, it may indicate retinal nerve damage due to optic neuritis, retinal artery occlusion, glaucoma, or other conditions. Prompt investigation of the cause should be performed. Cases of long-term atrophy and regression of myelination in primary open-angle glaucoma have also been reported [6].

Q Is treatment necessary?

A

For localized and asymptomatic cases, observation alone is sufficient. If complications such as amblyopia, strabismus, or myopia are present, treatment should be given accordingly. Retinal vascular complications may require laser treatment.

6. Pathophysiology and detailed mechanism

Myelination of optic nerve fibers is an orderly process carried out by oligodendrocyte precursor cells. Myelination begins around the eighth month of pregnancy at the lateral geniculate body and reaches the posterior part of the eye around birth. By seven months after birth, almost all fibers have completed myelination. Normally, this process stops at the level of the lamina cribrosa.

MRNF occurs when oligodendrocyte precursor cells cross the lamina cribrosa and invade the retina. A leading hypothesis suggests incomplete closure of the lamina cribrosa or precursor cell invasion before lamina cribrosa formation.

Histopathological Features

Histologically, the following findings have been observed.

• Within the MRNF area, myelinated and unmyelinated fibers coexist. They are not limited to specific patchy areas or nerve bundles, and single myelinated fibers are scattered among unmyelinated fiber bundles.
• Both myelinated and unmyelinated fibers in the MRNF area have a larger diameter than fibers in the normal retina.
• In the MRNF area, the population of retinal ganglion cells is reduced, and the thickness of the inner and outer plexiform layers beneath them is also decreased.
• Cell nuclei are relatively sparse, and no microscopic inflammatory findings are observed.
• Even MRNF that appears macroscopically continuous with the optic disc may not be histologically continuous with the myelinated region of the optic nerve.

Disappearance of MRNF

Disappearance of MRNF has been reported in the following diseases. This disappearance is thought to reflect pathological degeneration of retinal nerve axons.

• Neurological diseases: Pituitary adenoma, optic neuritis, acute optic neuropathy, primary open-angle glaucoma
• Inflammatory diseases: Papillitis and vitritis due to Behçet’s disease
• Retinal diseases: Branch retinal artery occlusion (BRAO), central retinal artery occlusion (CRAO), diabetic retinopathy
• Iatrogenic: Brachytherapy for choroidal melanoma, vitrectomy for epiretinal membrane

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7. Latest Research and Future Perspectives (Research-stage Reports)

For patients: Please read this

The following content is currently at the research stage or under clinical trial and is not standard treatment available at general hospitals. This is reference information for professionals regarding future medical developments.

Whole Genome Sequencing

Whole genome sequencing has been performed in patients with MRNF, identifying disease-associated gene mutations and novel variants of uncertain significance. This disease is suggested to arise from the cumulative effects of many genetic mutations. The study also showed that while these patients have a high risk of optic disc anomalies and retinal detachment, their genetic predisposition to age-related macular degeneration is below average.

New Imaging Technologies

A transscleral optical phase imaging method using adaptive optics has been developed. This technique allows non-invasive observation of myelinated nerve fibers at a resolution of 2–3 micrometers.

Pathophysiology of Acquired and Progressive MRNF

There have been case reports of bilateral acquired progressive MRNF without obvious underlying disease, suggesting that the myelination process may be spontaneously activated in some cases. Elucidation of the exact mechanism remains a future challenge.

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References

1. Ramkumar HL, Verma R, Ferreyra HA, Robbins SL. Myelinated Retinal Nerve Fiber Layer (RNFL): A Comprehensive Review. Int Ophthalmol Clin. 2018;58(4):147-156. doi:10.1097/IIO.0000000000000239. PMID: 30239369

2. Tarabishy AB, Alexandrou TJ, Traboulsi EI. Syndrome of myelinated retinal nerve fibers, myopia, and amblyopia: a review. Surv Ophthalmol. 2007;52(6):588-596. doi:10.1016/j.survophthal.2007.08.016. PMID: 18029268

3. Kodama T, Hayasaka S, Setogawa T. Myelinated retinal nerve fibers: prevalence, location and effect on visual acuity. Ophthalmologica. 1990;200(2):77-83. doi:10.1159/000310082. PMID: 2338989

4. Pan Z, Wei CC, Peng X, et al. Myelinated Retinal Nerve Fiber Progression in a 10-Year Follow-Up. The Beijing Eye Study 2001/2011. Am J Ophthalmol. 2021;230:68-74. doi:10.1016/j.ajo.2021.04.018. PMID: 33951445

5. Shen Y, Zhao J, Sun L, et al. The long-term observation in Chinese children with monocular myelinated retinal nerve fibers, myopia and amblyopia. Transl Pediatr. 2021;10(4):860-869. doi:10.21037/tp-20-452. PMID: 34012835

6. Sowka JW, Nadeau MJ. Regression of myelinated retinal nerve fibers in a glaucomatous eye. Optom Vis Sci. 2013;90(7):e218-e220. doi:10.1097/OPX.0b013e3182968b1a. PMID: 23708924

7. Mansberger SL, Menda SA, Fortune BA, Gardiner SK, Demirel S. Automated Segmentation Errors When Using Optical Coherence Tomography to Measure Retinal Nerve Fiber Layer Thickness in Glaucoma. Am J Ophthalmol. 2017;174:1-8. doi:10.1016/j.ajo.2016.10.020. PMID: 27818206