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 layers (MRNF) occur in 0.57- 1% of the population and can occur bilaterally in 7.7% of affected patients. MRNF are grey-white well-demarcated patches with frayed borders along the retinal nerve fiber layer, obscuring underlying retinal vessels.1,2 Clinically, MRNF appear continuous with the optic nerve, but they are often discontinuous with the optic nerve head as well.1,2 Most patients with MRNF are asymptomatic; however, visual function can become affected, resulting in axial myopia, amblyopia, and strabismus in the affected eye.3,4 Though rare, familial cases of MRNF have been reported both in isolation and in combination with ocular and systemic syndromes (Table 2).5 MRNF are typically present at birth and are static lesions, but a few cases of acquired and progressive lesions in both childhood and adulthood have been described. Disappearance of MRNF have also been reported after surgery and insults to the optic nerve.
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 1856.2 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…”1
Pathophysiology[edit | edit source]
Axonal myelination in the human central nervous system (CNS) is a complex, orderly process carried out by oligodendrocyte progenitor cells (OPC) which migrate under the influence of neuro-hormonal signals to generate oligodendrocytes, which produce myelin. Myelination generally occurs from the neuron along the direction of the impulse conduction down the axon. Retinal ganglion cell myelination, however, proceeds in the opposite direction from the optic tract toward the globe.6
Histopathology[edit | edit source]
Myelinated fibers are not confined to a patch or fascicle, and single myelinated fibers can be found in between fascicles of unmyelinated fibers.10 Analysis of tissue within the MRNF shows no microscopic evidence of inflammation with few cell nuclei and reduced retinal ganglion cell population compared to retina outside of the patch, which is normal. MRNF have less condensed myelin along with larger axonal diameter causing the myelinated fiber to be greater than the respective optic nerve or retinal fibers in the same eye and can show degenerative signs of myelinolysis.10 The abnormal myelination results in increased thickness of the nerve fiber layer compressing the underlying retinal layers, reducing the width and altering the conformation of the inner and outer plexiform layers. This also causes an indistinct border between the inner nuclear layer and outer nuclear layer.4,10 Although MRNF appear macroscopically contiguous with the optic disk and vascular arcades, they are more likely to be discontinuous with the optic disk and rarely associated with the vascular supply.4,10 No abnormalities of the cribriform plate have been described in eyes with MRNF.
Genetics[edit | edit source]
Genetic control of myelination of mature retinal ganglion cells is largely unknown and an active area of research.12,13
Familial cases of isolated MRNF have been reported with a family with two generations of 10 cases and in an otherwise unremarkable mother and daughter with bilateral MRNF.5,14
Familial cases associated with other disorders have also been described. GAPO syndrome is an autosomal recessive syndrome of growth retardation, alopecia, pseudoanodontia, optic atrophy, and MRNF associated with hypertelorism, severe end-stage glaucoma and myelinated retinal nerve fiber layer.15
A syndrome of vitreoretinal degeneration, posterior subcapsular cataract, and skeletal abnormalities (missing digits) was also described.16 Goltz-Gorlin (multiple basal cell nevus) syndrome has also been reported to be associated with acquired myelination of the RNFL.17 A patient with Albright hereditary osteodystrophy was also found to have a focal area of myelination of the RNFL (unreported, seen at UCSD). Other systemic syndromes that have been associated include Turner syndrome18, epilepsy19, Downs Syndrome, and craniosynostosis4.
Diagnosis[edit | edit source]
[edit | edit source]
The majority of MRNF cases are incidentally diagnosed in asymptomatic, healthy children by ophthalmoscopy. The distinct peripapillary white striated patches with feathered borders involving from one disc diameter in size to larger areas of the retina, often found located in the superior sector of the optic nerve head, is observed on examination (see Figure below).
Figure 1. Multicolor image of myelination of the RNFL.
Ophthalmic Imaging Characteristics[edit | edit source]
Imaging characteristics of MRNF have been reviewed recently,23 and the results are summarized here. The myelin in MRNF has a high lipid content affecting imaging modalities. Infrared and red-free imaging are sensitive to, lipids resulting in the white appearance of MRNF. Myelin blocks detection of fluorescent material appearing dark on fundus autofluorescence. On optical coherence tomography (OCT), thickened MRNF (red arrow in Figure 2) causes hyper-reflectivity with back-scattering resulting in decrease visibility of retinal layers behind MRNF (see Figure 2).
Figure 2. OCT of myelination of the RNFL
Ocular conditions associated with myelination of the RNFL[edit | edit source]
MRNF are often isolated but may be associated with ipsilateral myopia, amblyopia, strabismus and other ocular conditions (Table 1). Strabismus was found in 66% with MRNF in one review.24 Visual acuity is usually not affected; however, if a sufficient number of myelinated fibers are present a relative scotomas may develop depending on the location of the MRNF. If the myelination involves the optic disk, macula or peripheral retina an enlarged blind spot, ringed scotomas, or isolated peripheral scotomas may develop respectively. These scotomas are smaller than the size of the MRNF patch would suggest.4,25 Visual acuity and prognosis depends on the severity of ocular complications or associated syndromes (Table 1).
Ocular associations with myelination of the RNFL[edit | edit source]
|Refractive and Sensorimotor:|
|Optic nerve associated:|
|Uveal and Retinal:|
Conditions associated with acquired and progressive myelination of the RNFL
[edit | edit source]
There are a few case reports of acquired and progressive myelination in childhood, adolescence, and adulthood.35 These cases are associated with 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.18,35,21,22,35,46,47
Conditions associated with loss of myelination of the RNFL[edit | edit source]
The disappearance of MRNFL has also been reported and associated with multiple neurologic, inflammatory and retinal diseases. The neurological disease associations include pituitary adenoma, optic neuritis, acute optic neuropathy, and primary open angle glaucoma. 48,49,50,51,52 The inflammatory disease associations are Bechet’s disease after recurrent papillitis and vitritis and plaque radiotherapy for choroidal melanoma. 53,54 Retinal disease such as BRAO, CRAO, diabetic retinopathy, pars palna vitrectomy for epiretinal membrane have been associated with disappearance of MRNFL.55,56,57,58
Management[edit | edit source]
MRNF are typically benign but can be mistaken for other potentially serious conditions. A complete blood count may be helpful in differentiating from a neoplastic infiltrate. Ophthalmoscopy and fluorescein angiography can help determine if an embolic phenomenon is in the differential. If gross visual defects are present, formal visual field testing to rule out a concomitant neuro-ophthalmologic issue, as visual defects in MRNF are usually mild. Management of MRNF is focused on serial eye examinations assessing for and treating associated complications such as retinal vascular complications, including neovascularization and recurrent vitreous hemorrhage, with possible argon photocoagulation. Myopia should be treated with corrective lenses. If significant anisometropia is present, correction with glasses may not be tolerated secondary to aniseikonia, and contact lenses should be prescribed. Amblyopia must be treated aggressively to optimize visual outcomes.3,56 Strabismus should be managed with the usual protocols, and patients often respond well to surgical realignment.59 It is important to recognize the generally benign nature of MRNF to avoid additional diagnostic evaluations increasing healthcare costs and causing undo patient anxiety.
References[edit | edit source]
1. Virchow VR. Zur pathologischen anatomic der netzaut und des scherven. Virchows Arch Pathol Anat. 1856;10:170–193.
2. Gradle HS. The Blind Spot: III. The Relation of the Blind Spot to Medullated Nerve Fibers in the Retina. Journal of the American Medical Association. 1921;77(19):1483–7.
3. Kodama T, Hayasaka S, Setogawa T. Myelinated retinal nerve fibers: prevalence, location and effect on visual acuity. Ophthalmologica. Journal international d’ophtalmologie. International journal of ophthalmology. Zeitschrift für Augenheilkunde. 1990;200(2):77–83. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2338989. Accessed July 20, 2013.
4. Straatsma BR, Foos RY, Heckenlively JR, Taylor GN. Myelinated retinal nerve fibers. American journal of ophthalmology. 1981;91(1):25–38. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7234927. Accessed July 20, 2013.
5. Funnell CL, George NDL, Pai V. Familial myelinated retinal nerve fibres. Eye (London, England). 2003;17(1):96–7. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12579180. Accessed July 20, 2013.
6. Magoon EH, Robb RM. Development of Myelin in Human Optic Nerve and Tract: A Light and Electron Microscopic Study. Archives of Ophthalmology. 1981;99(4):655–659. Available at: http://archopht.jamanetwork.com/article.aspx?articleid=633760. Accessed July 22, 2013.
7. Berliner ML. Cytologic studies on the retina. Normal coexistence of oligodendroglia and myelinated nerve fibres. Arch. Ophthalmol. 1931;(6):740.
8. Perry VH, Lund RD. Evidence that the lamina cribrosa prevents intraretinal myelination of retinal ganglion cell axons. Journal of neurocytology. 1990;19(2):265–72. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2358833. Accessed July 22, 2013.
9. Vaney DI. A quantitative comparison between the ganglion cell populations and axonal outflows of the visual streak and periphery of the rabbit retina. The Journal of comparative neurology. 1980;189(2):215–33. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7364963. Accessed July 22, 2013.
10. FitzGibbon T, Nestorovski Z. Morphological consequences of myelination in the human retina. Experimental eye research. 1997;65(6):809–19. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9441705. Accessed July 20, 2013.
11. Butt AM, Ransom BR. Morphology of astrocytes and oligodendrocytes during development in the intact rat optic nerve. The Journal of comparative neurology. 1993;338(1):141–58. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8300897. Accessed July 22, 2013.
12. Wegner M. A matter of identity: transcriptional control in oligodendrocytes. Journal of molecular neuroscience : MN. 2008;35(1):3–12. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18401762. Accessed May 28, 2013.
13. Howng SYB, Avila RL, Emery B, et al. ZFP191 is required by oligodendrocytes for CNS myelination. Genes & development. 2010;24(3):301–11. Available at: http://genesdev.cshlp.org/content/24/3/301.long. Accessed May 22, 2013.
14. Francois J. Myelinated nerve fibres. In: Heredity in Ophthalmology. St Louis, MO: Mosby; 1961:494–496.
15. Bozkurt B, Yildirim MS, Okka M, Bitirgen G. GAPO syndrome: four new patients with congenital glaucoma and myelinated retinal nerve fiber layer. American journal of medical genetics. Part A. 2013;161(4):829–34. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23494824. Accessed July 20, 2013.
16. Traboulsi EI, Lim JI, Pyeritz R, Goldberg HK, Haller JA. A new syndrome of myelinated nerve fibers, vitreoretinopathy, and skeletal malformations. Archives of ophthalmology. 1993;111(11):1543–5. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8240111. Accessed July 20, 2013.
17. De Jong PT, Bistervels B, Cosgrove J, de Grip G, Leys A, Goffin M. Medullated nerve fibers. A sign of multiple basal cell nevi (Gorlin’s) syndrome. Archives of ophthalmology. 1985;103(12):1833–6. Available at: http://www.ncbi.nlm.nih.gov/pubmed/4074174. Accessed July 21, 2013.
18. Aaby AA, Kushner BJ. Acquired and progressive myelinated nerve fibers. Archives of ophthalmology. 1985;103:542–544.
19. Kiso K. Beitrage zur Kenntis von der Vererbung der markhaltigen Sehnervenfasern der netzhaut. Graefes Arch Clin Exp Ophthalmol. 1928;120:154–174.
20. Schaffer D. Congenital abnormalities of retina. In: Tasman W, ed. Duane’s Ophthalmology. Philadelphia: Lippincott Raven; 1995:5–6.
21. Ali BH, Logani S, Kozlov KL, Arnold AC, Bateman B. Progression of retinal nerve fiber myelination in childhood. American Journal of Ophthalmology. 1994;118:515–517.
22. Parulekar M V, Elston JS. Acquired retinal myelination in neurofibromatosis 1. Archives of ophthalmology. 2002;120(5):659–5. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12003622. Accessed July 21, 2013.
23. Shelton JB, Digre KB, Gilman J, Warner JEA, Katz BJ. Characteristics of myelinated retinal nerve fiber layer in ophthalmic imaging: findings on autofluorescence, fluorescein angiographic, infrared, optical coherence tomographic, and red-free images. JAMA ophthalmology. 2013;131(1):107–9. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23307221. Accessed June 30, 2013.
24. Tarabishy AB, Alexandrou TJ, Traboulsi EI. Syndrome of myelinated retinal nerve fibers, myopia, and amblyopia: a review. Survey of ophthalmology. 52(6):588–96. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18029268. Accessed June 18, 2013.
25. Miller NR. Clinical neuro-ophthalmology. 4th ed. (Wilkins W and, ed.). Baltimore; 1982:367–9.
26. Williams TD. Medullated retinal nerve fibers: speculations on their cause and presentation of cases. American journal of optometry and physiological optics. 1986;63(2):142–51. Available at: http://www.ncbi.nlm.nih.gov/pubmed/3953757. Accessed July 22, 2013.
27. Duke-Elder S. Congenital deformities. In: Duke-Elder S, ed. St. Louis: Mosby, CV; 1963:646–651.
29. Hittner HM, Kretzer FL, Antoszyk JH, Ferrell RE, Mehta RS. Variable expressivity of autosomal dominant anterior segment mesenchymal dysgenesis in six generations. American journal of ophthalmology. 1982;93(1):57–70. Available at: http://www.ncbi.nlm.nih.gov/pubmed/6801987. Accessed August 6, 2013.
30. Straatsma BR, Heckenlively JR, Foos RY, Shahinian JK. Myelinated retinal nerve fibers associated with ipsilateral myopia, amblyopia, and strabismus. American journal of ophthalmology. 1979;88(3 Pt 1):506–10. Available at: http://www.ncbi.nlm.nih.gov/pubmed/484678. Accessed July 21, 2013.
31. Schmidt D, Meyer JH, Brandi-Dohrn J. Wide-spread myelinated nerve fibers of the optic disc: do they influence the development of myopia? International ophthalmology. 20(5):263–8. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9112197. Accessed July 21, 2013.
32. Cockburn DM. Tilted disc and medullated nerve fibres. American journal of optometry and physiological optics. 1982;59(9):760–1. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7137318. Accessed August 7, 2013.
33. Merritt JC. Myelinated nerve fibers associated with afferent pupillary defect and amblyopia. Journal of pediatric ophthalmology. 14(3):139– 40. Available at: http://www.ncbi.nlm.nih.gov/pubmed/915641. Accessed July 27, 2013.
34. Gharai S, Prakash G, Kumar D, Jacob S, Agarwal A, Arora V. Spectral domain optical coherence tomographic characteristics of unilateral peripapillary myelinated retinal nerve fibers involving the macula. Journal of AAPOS. 2010;14(5):432–434.
35. Jean-Louis G, Katz BJ, Digre KB, Warner JE, Creger DD. Acquired and progressive retinal nerve fiber layer myelination in an adolescent. American journal of ophthalmology. 2000;130(3):361–2. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11020421. Accessed July 20, 2013.
36. Eide N. Retinal break in an area with medullated nerve fibres. Acta ophthalmologica. 1986;64(3):271–3. Available at: http://www.ncbi.nlm.nih.gov/pubmed/3751515. Accessed July 21, 2013.
37. Hubbard GB, Thomas MA, Grossniklaus HE. Vitreomacular traction syndrome with extensively myelinated nerve fibers. Archives of ophthalmology. 2002;120(5):670–1. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12003629. Accessed July 21, 2013.
38. Karadimas P, Kapetanios A, Panayotidhou E, Bouzas EA. Epiretinal membrane occurring with myelinated retinal nerve fibers and vascular abnormalities. Retina (Philadelphia, Pa.). 2003;23(6):880–1. Available at: http://www.ncbi.nlm.nih.gov/pubmed/14707848. Accessed July 21, 2013.
39. Kreidl KO, Lin DY, Egbert JE. Myelination of the macula associated with disabling photophobia. Archives of ophthalmology. 2003;121(8):1204–5. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12912705. Accessed June 18, 2013.
40. Berliner ML. Medullated nerve fibers associated with choroiditis: report of a case with preliminary studies on the cause of the apparance of medullated nerve fibers in the retina. Archives of Ophthalmology. 1931;6(3):404–413. Available at: http://archopht.jamanetwork.com/article.aspx?articleid=609280. Accessed July 23, 2013.
41. Jackson E. Uveitis with opaque optic nerve fibers. Am. J. Ophthal. 1918;1(448).
42. Rosen B, Barry C, Constable IJ. Progression of myelinated retinal nerve fibers. American Journal of Ophthalmology. 1999;127(4):471–473. Available at: http://dx.doi.org/10.1016/S0002-9394(98)00377-8. Accessed July 24, 2013.
43. Mehta JS, Raman J, Gupta N, Sinha A. Retinal vascular anomalies in acquired myelinated nerve fibres. Acta ophthalmologica Scandinavica. 2003;81(3):311–2. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12780415. Accessed July 21, 2013.
44. Leys AM, Leys MJ, Hooymans JM, et al. Myelinated nerve fibers and retinal vascular abnormalities. Retina (Philadelphia, Pa.). 1996;16(2):89–96. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8724950. Accessed July 20, 2013.
45. Silvestri G, Sehmi K, Hamilton P. Retinal vascular abnormalities. A rare complication of myelinated nerve fibers? Retina (Philadelphia, Pa.). 1996;16(3):214–8. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8789859. Accessed July 21, 2013.
46. Baarsma GS. Acquired medullated nerve fibres. The British journal of ophthalmology. 1980;64(9):651. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1043786&tool=pmcentrez&rendertype=abstract. Accessed July 21, 2013.
47. Kushner BJ. Optic nerve decompression. Arch Ophthalmol. 1979;97:1459–1461.
48. A. S. Schwund Markhaltiger Nervenfasern in der Netzhaut bei intzundlicher Atrophie des Sehnervern in Folges eines Tumor oerebri. Z. Augenheilkd. 1905;13:739–50.
49. Gupta A, Khandalavala B, Bansal RK, Jain IS, Grewal SP. Atrophy of myelinated nerve fibers in pituitary adenoma. Journal of clinical neuro-ophthalmology. 1990;10(2):100–2. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2141848. Accessed July 21, 2013.
50. Sharpe JA, Sanders MD. Atrophy of myelinated nerve fibres in the retina in optic neuritis. The British journal of ophthalmology. 1975;59(4):229–32. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1042599&tool=pmcentrez&rendertype=abstract. Accessed July 20, 2013.
51. Schachat AP, Miller NR. Atrophy of myelinated retinal nerve fibers after acute optic neuropathy. American journal of ophthalmology. 1981;92(6):854–6. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7315937. Accessed July 20, 2013.
52. Katz SE, Weber PA. Photographic documentation of the loss of medullated nerve fibers of the retina in uncontrolled primary open angle glaucoma. Journal of glaucoma. 1996;5(6):406–9. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8946297. Accessed July 22, 2013.
53. Chavis PS, Tabbara KF. Demyelination of retinal myelinated nerve fibers in Behcet’s disease. Documenta ophthalmologica. Advances in ophthalmology. 1998;95(2):157–64. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10431799. Accessed July 21, 2013.
54. Mashayekhi A, Shields CL, Shields JA. Disappearance of retinal myelinated nerve fibers after plaque radiotherapy for choroidal melanoma. Retina (Philadelphia, Pa.). 2003;23(4):572–3. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12972781. Accessed July 20, 2013.
55. Teich SA. Disappearance of myelinated retinal nerve fibers after a branch retinal artery occlusion. American journal of ophthalmology. 1987;103(6):835–7. Available at: http://www.ncbi.nlm.nih.gov/pubmed/3591888. Accessed July 20, 2013.
56. R. B. Schwund markhaltiger Nervenfasern in der Netzhaut nach Embolie der Art. Centralies retinae. Albrecht von Graefes Arch. Ophthalmol. 1922;107(10).
57. Gentile RC, Torqueti-Costa L, Bertolucci A. Loss of myelinated retinal nerve fibres in diabetic retinopathy. The British journal of ophthalmology. 2002;86(12):1447. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1771408&tool=pmcentrez&rendertype=abstract. Accessed July 20, 2013.
58. Williams AJ, Fekrat S. Disappearance of myelinated retinal nerve fibers after pars plana vitrectomy. American journal of ophthalmology. 2006;142(3):521–3. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16935613. Accessed July 20, 2013.
59. Rootman DB, Gonzalez E, Mallipatna A, et al. Hand-held high-resolution spectral domain optical coherence tomography in retinoblastoma: clinical and morphologic considerations. The British journal of ophthalmology. 2013;97(1):59–65. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23104902. Accessed July 24, 2013.
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. We thank Christopher Rugaber, OD, Faculty of Optometry, Rangsit University, Pathum Thani,Thailand for his valuable suggestions to improve this wiki page.