Myelinated retinal nerve fiber layer
|Myelinated Retinal Nerve Fiber Layer|
|Classification and external resources|
Fundus photo of a 7 yo girl with myelinated RNFL, 20/20 vision, and mild hyperopia
- 1 Myelinated Retinal Nerve Fiber Layer
- 2 Pathophysiology
- 3 Histopathology
- 4 Genetics
- 5 Diagnosis
- 6 Ocular conditions associated with myelination of the RNFL
- 7 Management
- 8 References
- 9 Acknowledgements
Myelinated Retinal Nerve Fiber Layer[edit | edit source]
Myelinated retinal nerve fiber layer (RNFL) is often an incidental finding on ophthalmoscopic exam. It can vary in size and location and presents as well-demarcated patch of myelinated retinal ganglion cell axons. While a benign finding, it can be associated with anisometropia, strabismus, and amblyopia. Ophthalmic imaging can help differentiate myelinated RNFL from other mimicking ocular conditions (Table 2).
International Classification of Disease[edit | edit source]
ICD-9 377.49 Other disorders of optic nerve
ICD-10 H35.89 Defect, defective retinal nerve bundle fibers
History[edit | edit source]
Virchow was the first to describe myelinated retinal nerve fibers as “chalk-white spots” around the optic disc 1856. However, his observation was predated by over a century of neuronal study. In 1717, Leeuwenhoek described seeing a subset of nerves covered with “fatty parts.” Ehrenberg described “cylindrical tubes” in the myelinated nerve fibers in 1833. German embryologist and neurologist Remak postulated that the cylinders originate from neuronal ganglion cells in 1838. Schwann stated that the white substance around the nerve fiber is a sheath in 1839. In 1858, Virchow described that the “medullary sheath is not an absolutely necessary constituent of the nerve, but that it confines electricity within the nerve itself and allows discharge to take place only at the non-medullated extremities of the fibers.” Cajal recognized that the axis cylinder is the axonal process and that the myelin sheath is external and secreted by the axon in 1909. In 1918, Gradle stated: “The cause of sporadic medullation of retinal nerve fibers falls among still unexplored phases of ophthalmology…”
Definition[edit | edit source]
Myelinated retinal nerve fiber layers (RNFLs), also known as medullated retinal nerve fibers, are white or grey-white well-demarcated patches on the outermost surface of the retina that obscure the underlying retinal vessels. The frayed feathered borders correspond to retinal ganglion cell axons.
Epidemiology[edit | edit source]
In a retrospective study reviewing the fundus photos of 5,789 patients, the prevalence of myelination of the RNFL was found to be 0.57%.The incidence of myelination of the RNFL in an autopsy series of 7,936 eyes was 0.98% of cases and 0.54% of eyes. Myelinated RNFLs are bilateral in 7.7% of cases.While myelinated RNFLs were found more often in females in one study, this finding was not replicated in another study.
Subtypes[edit | edit source]
Clinically, myelinated RNFL patches most often appear in the superior sector of the optic nerve head and appear to be continuous with the optic nerve. They are often described as distributed around or contiguous with the optic disc and vascular arcades. Pathologic studies, however, show that myelinated RNFL patches are continuous with the optic nerve in only 33% of cases and discontinuous with the optic nerve head in 66% of affected eyes. Multiple distinct lesions were found in 12% of specimens.
While generally sporadic, familial cases (see Genetics) of myelinated RNFL patches have been reported both in isolation and in combination with ocular (see Table 2) and systemic syndromes (see Table 3).
Myelinated RNFLs are most often asymptomatic and have a variable effect on visual function, influenced by location, extent of myelination, and coexisting visual pathology. The most common ocular associations of myelinated RNFLs are axial myopia, amblyopia, and strabismus., (see Table 2).
Myelinated RNFLs are most often congenital and non-progressive, but few cases of acquired progressive lesions in childhood and adulthood have been reported (see Table 4). They have also been reported to disappear after surgery and insults to the optic nerve (see Table 5).
Pathophysiology[edit | edit source]
Myelination of the human central nervous system (CNS) generally originates proximally at the cell soma and progresses distally along the axon. Myelination of retinal ganglion cells differs because it proceeds from the optic tract toward the globe. Glial ensheathment of axons in the optic tract commences at five months of gestation.
Oligodendocyte progenitor cells (OPC) originate from neuroepithelial cells in the ventral ventricular zone of the embryonic spinal cord and possibly the forebrain. Neurosignaling influences the migration of OPCs laterally and dorsally to all parts of the developing CNS. Progenitor cell fate is determined by master regulatory genes (including Olig1 and Yy1), chemoattractants and repellants, and specific regional transcription factors. OPC migration patterns can be influenced by extracellular signals (including netrin-1  and CXCL1 ). A specific combination of transcription factors program the OPC to terminally differentiate into a myelinating oligodendrocyte which ensheaths its terminal axons.
By eight months of gestation, myelination has generally advanced beyond the chiasm to the optic nerve. Myelination continues distally until it reaches the lamina cribrosa, where it usually ceases. The lamina cribrosa is thought to be a physical barrier to myelination by blocking the migration of OPCs. This theory is supported by the facts that rabbits, which lack a lamina cribrosa, have naturally myelinated retinal nerve fibers, and retinas transplanted outside of the lamina cribrosa become myelinated. It has been shown that myelination continues in the human optic nerve during postnatal visual development after full-term gestation.
The current theory is that ectopic OPCs lead to myelinated retinal nerve fibers. Rather than being a random process, axons may influence and even recruit nearby oligodendocytes in the myelination process.
Histopathology[edit | edit source]
Several cases of human myelinated RNFLs have been extensively analyzed.  Retina adjacent to a myelinated retinal nerve fiber layer patch is normal. The histopathology of the retina involving the myelinated retinal nerve fiber layer is abnormal. The tissue within the myelinated retinal patch has no microscopic signs of inflammation and few cell nuclei. There is a reduced retinal ganglion cell population in the patch compared to adjacent areas. The myelinated RNFLs compresses the underlying retinal layers, reducing the width and altering the conformation of the inner and outer plexiform layers. The border between the inner nuclear layer and outer nuclear layer in this area is also indistinct.  
Despite proximity to the retinal vessels, association with the vascular supply is rarely seen. Myelinated fibers are not confined to a patch or fascicle, and single myelinated fibers could be found in between fascicles of unmyelinated fibers.
The axonal diameters of myelinated and unmyelinated fibers within the myelinated patch are larger than the axons outside the myelinated patch. Additionally, myelinated fibers in the patch are larger than any optic nerve and retinal fibers in the same eye. Myelin is less condensed in these large fibers and can show degenerative signs of myelinolysis. Myelination is more frequently discontinuous with the optic nerve than continuous.  No abnormalities of the cribriform plate have been reported in eyes with myelinated RNFL.
Genetics[edit | edit source]
Associated with other disorders
Recently, an autosomal recessive syndrome of growth retardation, alopecia, pseudoanodontia, optic atrophy (GAPO syndrome) was associated with hypertelorism, severe end-stage glaucoma and myelinated retinal nerve fiber layer. A syndrome of vitreoretinal degeneration, posterior subcapsular cataract, and skeletal abnormalities (missing digits) was also described. Goltz-Gorlin (multiple basal cell nevus) syndrome has also been reported to be associated with acquired myelination of the RNFL.  A patient with Albright hereditary osteodystrophy was also found to have a focal area of myelination of the RNFL (unreported, seen at UCSD) (see Table 1).
Table 1. Systemic syndromes associated with myelination of the RNFL
[edit | edit source]
| GAPO Syndrome with congenital glaucoma |
|Vitreoretinopathy and skeletal malformations|
| Goltz-Gorlin syndrome (multiple basal cell nevus syndrome) |
| Turner syndrome  |
| Epilepsy |
| Dolichocephaly  |
| Craniosynostosis |
| Downs Syndrome|
| Albright hereditary osteodystrophy|
| Von Recklinhausen’s disease  |
| Arnold-Chiari malformation and hydrocephalus|
Diagnosis[edit | edit source]
[edit | edit source]
Most cases of myelination of the RNFL are diagnosed incidentally in asymptomatic healthy children or adults by ophthalmoscopy. The clinical appearance of fan-shaped peri-papillary white striated patches in the distribution of the retinal nerve fiber layer is distinct (see Figure 1). The size of the lesions can vary from small (approximately one disc diameter in size) to involving large areas of the retina.
Figure 1. Myelination of the RNFL in a 7 year old boy associated with anisomyopia and amblyopia.
Ophthalmic Imaging Characteristics[edit | edit source]
The imaging characteristics of myelination of the RNFL have been reviewed recently, and the results are summarized here. In addition to fundus photography, MultiColor imaging may be useful in determining fine anatomic details with excellent contrast (Figure 2a) On optical coherence tomography (OCT), myelinated RNFL is easily identified (red arrow). With dense myelination, there can be focal compression of the inner retina (Figure 2b). On infrared (Figure 2b) and red-free (Figure 2c) imaging, the RNFL appears white because of the high lipid content. Myelination of the RNFL appears dark on fundus autofluorescence (Figure 2d) also causes blockage on fluorescein angiography (FA) (Figure 2e).
a. MultiColor imaging of the posterior pole in a patient with myelinated retinal nerve fiber layer.
b. Infrared image and Spectralis® OCT of myelinated RNFL
c. Red free image of myelinated RNFL
d. Fundus autofluorescence of myelinated RNFL
e. Fluorescein angiography appearance of myelinated RNFL
Current clinically used ophthalmic imaging techniques can help differentiate myelination of the RNFL from other potentially serious conditions, including a cotton wool spot, BRAO, and retinal infiltration (Table 2).
Table 2. Features differentiating myelination of the RNFL from other potentially mimicking retinal processes
[edit | edit source]
| Differential Diagnosis
|| Differentiating features using ophthalmic imaging|
| Cotton wool spot (CWS):
local infarction of the RNFL with a localized backup of axoplasmic flow
| OCT: focally elevated RNFL area with compression of the underlying retinal levels down to the photoreceptor layer; acutely, thickness map will show retinal thickening; follow-up OCT will show an area of retinal thinning; The vitreous may appear elevated over the CWS ; lesion will fade in 2 months|
| Branch retinal artery occlusion (BRAO)
|| FA: a branch of the central retinal artery will have an acute drop off in arterial flow into one of its branches ± an intra-arterial embolus |
OCT: hyperreflectivity and thickness (edema) of the nerve fiber and inner retinal layers in the ischemic retina compared to normal retina in the acute phase; if present, a cholesterol embolus may result in shadowing
| Peripapillary epiretinal membrane (ERM)
|| OCT: The epiretinal membrane will be visible as a hyperreflective layer above the inner limiting membrane with or without vitreoretinal traction, increased retinal thickness, disruption of the foveal contour, intraretinal fluid, and disruption of the IS/OS.|
| Serous retinal pigment epithelium detachment (SPED)
|| OCT: subretinal fluid, highly reflective substances beneath the retinal pigment epithelium with detachment of the sensory retina|
FA: focal areas of pooling or a smokestack pattern of leakage in the area of the retinal pigment epithelial detachment
ICG: focal hyperfluorescence in areas of choroidal neovascularization
| Retinal infiltrates
(infectious, inflammatory, or neoplastic)
| Imaging varies based on the etiology|
OCT: vitritis (if infectious or inflammatory), subretinal or intraretinal hyperreflective deposits and serous macular detachments (neoplastic)
FA: retinal vascular leakage or late staining, leakage from the disc, macular edema, capillary dropout, and neovascularization in Behcet’s disease; ± CRVO and retinal hemorrhages in leukemia
|| OCT: larger isodense intraretinal lesions confined to the inner retinal layers with preservation of the overlying inner retina in early tumors|
| Retinal necrosis
|| FA: blockage of background choroidal fluorescence by the opacified necrotic retina in a wedge shape, cystoid macular edema in late recirculation; occlusive arteritis with periarteritic infiltrates, venous distention & tortuosity |
OCT: vitritis, inner retinal hyperreflectivity with outer retinal edema acutely, progressing to outer retinal disorganization with persistent inner retinal hyperreflectivity; with resolution of the retinal opacity: atrophic changes will be present, including a schisis cavity, RPE irregularity, and retinal atrophy 
Ocular conditions associated with myelination of the RNFL
[edit | edit source]
Myelination of the RNFL is often associated with anisometropia, strabismus, amblyopia and many other ocular conditions. In one review, strabismus (exotropia and esotropia) was found in 66% of patients with myelination of the RNFL.  If a sufficient number of myelinated nerve fibers are present, a visual field deficit smaller than the size of the myelination can be present.   If the myelination of the RNFL involves the optic nerve, blind spot enlargement may result. Similarly, myelinated RNFL patches surrounding the macula may result in ring scotomas. Isolated peripheral scotomas corresponding to the location of the myelinated nerve fiber patch may also be seen. Visual acuity and prognosis is variable and depends on the severity of the ocular complications (see Table 2). Treatment is geared toward the complications or associated syndromes (see Management).
Table 3. Ocular associations with myelination of the RNFL
[edit | edit source]
| Anterior segment:|
Prominent Schwalbe’s line
Congenital cataracts 
Anterior segment mesenchymal dysgenesis
Tilt of the crystalline lens 
| Refractive and Sensorimotor: |
Decreased visual acuity
| Optic nerve associated: |
Afferent pupillary deficit
Visual field deficits 
Optic nerve hypoplasia and dysplasia 
Optic nerve head drusen 
| Uveal and Retinal: |
Persistence of the hyaloid artery 
Uveal coloboma 
Retinal break in an area of the myelinated RNFL 
Vitreomacular traction syndrome 
Epiretinal membrane 
Extreme photophobia with macular myelination 
Chroiditis  and uveitis
Retinal detachment 
Macular pigment dispersion
Macular thickening 
Retinal vascular complications 
a. Telangectasias 
b. Branched retinal artery occlusion 
c. Branch vein occlusion
d. Neovascularization 
e. Recurrent vitreous hemorrhage
There are a few case reports of acquired and progressive myelination in childhood, adolescence, and adulthood. In a young girl with an inoperable arterial venous malformation complicated by chronic papilledema, bilateral optic nerve sheath fenestrations were performed, and the child acquired myelination of the RNFL in the right eye five months after the surgery and in the left eye six years later. In two children with NF1 and ipsilateral optic nerve gliomas, myelinated RNFLs developed without a decrease in visual acuity. One 23 year old male developed striated whitening of the retinal nerve fiber layer after blunt trauma to the eye. A nine year old boy with an Arnold-Chiari malformation and hydrocephalus was described to have progressive retinal nerve fiber layer myelination.One 46 year old woman had decreased vision from progression of a perifoveal MRNFL that was complicated by telangectasias, microaneurysms, and macular thickening that did not respond to argon laser photocoagulation. 
Table 4. Conditions associated with acquired and progressive myelination of the RNFL
[edit | edit source]
| Blunt trauma |
|Optic nerve sheath fenestration for chronic papilledema |
| Optic nerve drusen |
| Family history of optic nerve hypoplasia (unaffected child)|
| Arnold-Chiari malformation associated with hydrocephalus|
| Von Recklinhausen’s disease|
The disappearance of MRNFL has also been reported and associated with multiple neurologic and retinal diseases (see Table 5).
Table 5. Conditions associated with loss of myelination of the RNFL
[edit | edit source]
| Neurologic disease|
Optic neuritis 
Acute optic neuropathy 
Primary open angle glaucoma 
| Inflammatory disease|
Bechet’s disease after recurrent papillitis and vitritis
Plaque radiotherapy for choroidal melanoma 
| Retinal disease|
Diabetic retinopathy 
Pars plana vitrectomy for epiretinal membrane 
Management[edit | edit source]
When making the initial diagnosis, it is very important to differentiate this typically benign condition from a neoplastic infiltrate. A complete blood count is helpful in making this distinction. Differentiating myelination of the RNFL from an embolic phenomenon can be done with ophthalmoscopy and fluorescein angiography. The management of myelination of the RNFL is focused on following the patient over time and assessing for and treating associated complications. Myopia should be treated fully with glasses. Full correction with glasses will not cause aniseikonia, as dictated by the Knapp rule. If there is significant anisometropia, correction with contact lenses may not be tolerated secondary to aniseikonia. When diagnosed in children, amblyopia must be treated aggressively to optimize visual outcomes. Strabismus should be treated following the usual management protocols, and patients often respond well to surgical realignment. If gross visual defects are noted, formal visual field testing should be done to rule out a concomitant neuro-ophthalmologic issue, as visual field deficits are usually mild. If retinal vascular complications are noted, including neovascularization and vitreous hemorrhage, argon photocoagulation may be required. While typically benign condition, the above mentioned associated conditions and complications require ongoing ophthalmologic care to ensure the best visual and ocular outcomes for patients with myelination of the RNFL.
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Acknowledgements[edit | edit source]
The authors thank Penny Coppernoll-Blach and the UCSD Library staff for their help in facilitating the literature review necessary for this paper. Special thanks to Giulio Barteselli and Gabriel Balea for the ophthalmic photography presented here.