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Show THE SEVENTH HOYT LECTURE Evaluation of the Retinal Nerve Fiber Layer: Descriptive or Predictive? Peter J. Savino, MD Abstract: For nearly a century, ophthalmologists have recognized that thinning of the retinal nerve fiber layer ( rNFL) could be observed ophthalmo-scopically in diseases of the optic nerve. Using high-resolution red- free fundus photography, Hoyt found slit- like rNFL defects that corresponded to visual field defects in glaucoma. Frise ´ n extended these observations to multiple sclerosis, predicting the later discovery that axonal loss occurs in the retina without clinical bouts of optic neuritis. In measurement of the rNFL, red- free fundus photography has been super-seded by more widely available, robust, and quantita-tive retinal imaging techniques, including Heidelberg retinal tomography, scanning laser polarimetry, and optical coherence tomography ( OCT). Having emerged as the technique of choice in measuring the rNFL, OCT has shown that the degree of pre-operative rNFL thinning reliably predicts whether vision will recover after surgery for pituitary adenoma. Such quantitative studies of the rNFL have the potential, therefore, of providing descriptive and predictive information that will be valuable in clinical care. ( J Neuro- Ophthalmol 2009; 29: 245- 249) W illiam F. Hoyt, MD, for whom this lecture is named, has made innumerable important contri-butions to the ophthalmologic, neurologic, and neurosur-gical literature. One of his more important contributions was to call our attention to the appearance of the retinal nerve fiber layer ( rNFL) and its appearance in a variety of disorders. In 1972, he used high- resolution red- free fundus photography to demonstrate slit- like defects in the rNFL that corresponded to the visual field defects found on perimetry ( 1). He noted that a similar description of the appearance and characteristics of the rNFL could be found in a 1921 publication by Vogt ( 2). Although this publication preceded the technological advancement of fundus pho-tography, Vogt beautifully described, in a series of illustrations, the normal appearance of the rNFL and the abnormal patterns produced by a variety of diseases. Using red- free photography of the rNFL, Hoyt et al ( 3) expanded in 1973 on Vogt's observations by eval-uating patients with glaucoma. They noted that the slit-like defects coalesced, widened, and deepened as the glaucoma worsened and visual field defects became worse. Their publication had a major impact on the way patients with glaucoma were evaluated clinically. A series of publi-cations that identified defects in the nerve fiber layer on red-free and color fundus photographs followed and confirmed Hoyt's observations and conclusions. This method of eval-uating and detecting defects in the rNFL was eventually described as the ‘‘ gold standard'' to be applied in clinical follow- up of patients with glaucoma ( 4,5). William Fletcher Hoyt, MD, professor emeritus of Ophthalmology, Neurology, and Neurosurgery, University of California, San Francisco, was born and raised in Berkeley, California. He took his undergraduate education at the University of California, Berkeley and his medical education at the University of California, San Francisco ( UCSF). After a year's study at the Wilmer Institute, Johns Hopkins University, under the mentorship of Frank B. Walsh, MD, he returned to UCSF in 1958 to found the neuro- ophthalmology service. During a 36- year academic career- all of it at UCSF- he authored 266 journal articles, co- authored ( with Frank B. Walsh, MD) the biblical third edition of Clinical Neuro- Ophthalmology, and trained 71 neuro- ophthalmology fellows. In 1983, he received the title of Honorary Doctor of Medicine from the Karolinska Institute. He is widely acknowledged as one of the titans of twentieth century neuro- ophthalmology. In recognition of his contributions, the North American Neuro- Ophthalmology Society ( NANOS), in conjunction with the American Academy of Ophthalmology, in 2001 initiated the Hoyt Lecture to be delivered each year at the Annual Meeting of the American Academy of Ophthalmology. William F. Hoyt, MD Shiley Eye Center, University of California- San Diego, 9415 Camp Point Drive, La Jolla, CA 92093- 0946; E- mail: pjsavino@ aol. com J Neuro- Ophthalmol, Vol. 29, No. 3, 2009 245 Application of the red- free photographic technique to neuro- ophthalmologic disorders was described soon there-after. Working with Hoyt, Frise ´ n ( 6) applied this photo-graphic technique to patients with multiple sclerosis ( MS) and visual loss. He elegantly documented rNFL defects that exactly corresponded to scotomas. In addition to extending the horizon of the original observations beyond glaucoma, Frise ´ n speculated that these rNFL defects ‘‘ attest to the insidious attrition of axons'' in MS ( 6). It would take almost a quarter of a century before his suggestion of loss of axons as a primary result of demyelinating disease was confirmed in 1998 in the seminal publication of Trapp et al ( 7). However, visualization of the defects described by Hoyt and Frise ´ n proved to be a challenge. Many physicians and institutions did not have the technology to produce high- quality red- free fundus images. Attempts to detect these rNFL defects using ophthalmoscopy or standard fundus photography could be thwarted by opacities in the anterior segment or the vitreous. As a result, their technique to evaluate patients with optic nerve disease was employed by only a handful of neuro- ophthalmologists and glaucoma specialists. The subsequent development of several technologies to image the optic nerve and retina caused renewed interest in the evaluation of the characteristics of the rNFL in a variety of diseases. Initially, Heidelberg retinal tomography ( HRT) and scanning laser polarimetry ( SLP) were used largely to define and follow the changes in optic disc topography in patients with glaucoma. Although these instruments did provide a measurement of rNFL thickness, initially this measurement was considered only a secondary and less important criterion by most physicians. Several investigators have attempted to apply these two technologies to a variety of optic nerve disorders in an attempt to determine their utility. ANTERIOR ISCHEMIC OPTIC NEUROPATHY ( AION) After glaucoma, AION is the most frequent optic neuropathy affecting individuals aged older than 50 years. The causes, risk factors, and precipitating causes of this disorder remain an enigma. HRT and SLP have been used to study patients with nonarteritic and arteritic AION in the acute phase, when optic disc edema is present and after resolution of the edema. It was determined that no useful information could be gleaned from imaging the acutely swollen optic disc. The extent of the visual deficit or the possibility of visual recovery could not be determined from any information collected in the acute phase. It was found, however, that after resolution of the edema, the appearance of the optic disc and, more particularly, of the optic cup, was different in patients who had the arteritic form of AION and those who had nonarteritic form. Those with the arteritic form developed optic disc excavation that was not present before the ischemic event occurred. Optic disc excavation was not a consistent finding in patients who had the nonarteritic form of AION ( 8). Because the excavation of the optic disc after arteritic AION was similar although not identical to the excavation seen in glaucoma, the authors ( 8) speculated that ischemia ( the known mechanism of arteritic AION) might be involved in the production of the excavation characteristic of glaucoma. These investigators also confirmed that there was excellent correlation between measurement of the rNFL by SLP and the visual field defects plotted perimetrically in these patients when the optic disc swelling had resolved completely ( 9). More recently, Bellusci et al ( 10) confirmed that optical coherence tomography ( OCT) imaging in the acute phase of AION is of no help in predicting the ultimate visual outcome. Therefore, as of today, there appears to be no role for optic disc scanning with SLP or OCT in patients with acute AION. On the other hand, rNFL imaging does Peter Savino, MD was born and raised in Brooklyn, New York, attended college at Manhattan College in Riverdale, NY, and medical school at the University of Bologna in Bologna, Italy. After an ophthalmology res-idency at Georgetown University in Washing-ton, DC, he completed a fellowship in neuro-ophthalmology from 1973 to 1974 at the Bascom Palmer Eye Institute, University of Miami, under the mentorship of Joel S. Glaser, MD. From 1974 to 1976, he served as an ophthalmologist in the United States Navy in Philadelphia, PA, rising to the rank of Lieutenant Commander. Then he moved uptown to join the neuro- ophthalmology faculty of the Wills Eye Institute, Jefferson Medical College, where he served for 34 years, establishing himself as a consummate clinician, prolific contributor to the medical literature, trainer of dozens of neuro- ophthalmology fellows, and most- wanted speaker on the international lecture circuit. He is currently clinical professor of ophthal-mology at the University of California- San Diego. Peter J. Savino, MD 246 q 2009 Lippincott Williams & Wilkins J Neuro- Ophthalmol, Vol. 29, No. 3, 2009 Savino correlate with the visual field deficits produced in AION when the optic disc edema has subsided ( 11). PAPILLEDEMA/ PSEUDOPAPILLEDEMA Papilledema is defined as elevation of the optic discs due to increased intracranial pressure. The characteristic ophthalmoscopic appearance of papilledema is usually obvious, so that the only other studies required are those to determine the cause of the increased intracranial pressure. At times, however, the optic disc elevation may be so subtle that diagnosis is difficult. At other times, optic discs that are normal may simulate the appearance of papilledema ( pseudopapilledema). Therefore, it would be useful if analysis of the rNFL could distinguish between these two entities. Unfortunately, analysis of the rNFL is effective in distinguishing normal subjects from patients with either papilledema or pseudopapilledema but cannot distinguish unequivocally between papilledema and pseudopapilledema ( 12). MS MS is a disorder of the central nervous system that results in the destruction of the myelin sheath that envelopes axons. Initially it was believed that the under-lying axons were unaffected by MS, but Trapp et al ( 7) convincingly demonstrated that transected axons are fre-quently observed in MS lesions and concluded that axonal transection may be the pathologic correlate of irreversible neurologic impairment in MS ( 7). Several investigators have applied the technology of rNFL imaging to investigate the effect of MS on the rNFL in patients with and without a history or evidence of past optic neuritis. Trip et al ( 13) used Heidelberg retinal tomography- II ( HRT- II) to detect the optic disc changes produced in patients by a single episode of optic neuritis and compared them with optic discs in a group of control subjects. These investigators concluded that HRT is capable of detecting differences in rNFL thickness and neuroretinal rim volume between the two groups. OCT has become the technology of choice in eval-uating the rNFL in MS studies. Several studies have shown that OCT may be used to predict visual outcome in patients with optic neuritis. A study ( 14) selected patients who experienced incomplete recovery of vision after a single episode of optic neuritis and found that a reduction in the rNFL thickness corresponded to defects in visual acuity, visual field, color vision, and visual evoked potential ampli-tude. A subsequent investigation ( 15) compared patients with incomplete and full recovery of visual function after optic neuritis. rNFL thinning, detected in 74% of patients, occurred within 3- 6 months of the onset of optic neuritis. Those with incomplete visual recovery demonstrated greater rNFL loss than those with complete visual recovery. It has now been well demonstrated that after a bout of optic neuritis, there is a decrease in rNFL thickness. How-ever, there appears to be a measurable attrition in rNFL thickness even in patients with MS who have not had documented acute optic neuritis ( 16,17). It is possible that OCT will become an important biomarker in the inves-tigation of the efficacy of therapeutic regimens in MS. CHIASMAL COMPRESSIVE SYNDROMES Compression of the optic chiasm is usually produced by slowly growing benign lesions. This process results in progressive visual loss in one or both eyes manifested by decreased visual acuity, visual field, or both. The most frequent mass encountered is the pituitary adenoma which, when endocrinologically active, may produce a variety of syndromes, including acromegaly, infertility, and amenor-rhea- galactorrhea in women and impotence in men. Most often, however, these tumors are endocrinologically in-active and the only manifestation is visual loss. Meningi-omas, craniopharyngiomas, gliomas, and aneurysms are other slowly growing mass lesions that can produce chiasmal compression with visual loss. Although the mechanism by which compression of the optic chiasm by pituitary tumors produces visual loss is not known, surgical removal of the compressive lesion is the treatment of choice in most patients. When patients have asked about restoration of vision, the appropriate response has been that recovery of vision cannot be expected and that the primary goal of treatment is to prevent further visual loss. It has not been possible to identify any factors ( size of the tumor, extent the visual field loss, or time of compression) that could be used to calculate the probability of visual restoration. Danesh- Meyer et al ( 18) have shown that OCT can be a predictor of visual recovery after successful surgical decompression of the optic chiasm. These investigators compared the structure- function correlation of rNFL thick-ness, as measured by OCT, to standard automated perimetry ( SAP) in patients with chiasmal compression and demon-strated that the rNFL is topically related both globally and sectorally to decreased SAP with the temporal sectors showing the strongest correlations. In a study ( 19) in which patients with chiasmal compression due to tumors were prospectively evaluated with OCTand SAP before and after successful surgery, a thinner preoperative rNFL thickness measurement ( 75- 80 m) was associated with worse visual acuity and visual field after surgery. Eyes with normal preoperative rNFL thickness had significant postopera-tively improvement in visual acuity and visual field. 247 Seventh Hoyt Lecture J Neuro- Ophthalmol, Vol. 29, No. 3, 2009 I offer two clinical examples: Case 1 A 59- year- old woman complained of progressive visual loss over 1 year and was found to have a pituitary tumor ( Fig. 1A). Preoperatively, visual acuity was finger counting in the right eye and 20/ 100 in the left eye. The visual fields showed a central scotoma in the right eye combined with a temporal hemianopic optic defect in the left eye ( junction scotoma). OCT showed marked thinning of the rNFL ( Fig. 1BC). Postoperatively, visual acuity recovered to 20/ 400 in the right eye and 20/ 30 in the left eye. Visual fields showed persistent dense deficits. ( Fig. 1D). Case 2 A 64- year- old woman complained of decreased vision in the right eye for 4 months. MRI showed a mass lesion consistent with a craniopharyngioma ( Fig. 2A). Preoperatively, visual acuity was finger counting in the right eye and 20/ 25 in the left eye. Visual fields, as in Case 1, showed a junction scotoma ( Fig. 2B). OCT showed normal rNFL thickness ( Fig. 2C). Postoperatively, visual acuity improved to 20/ 25 in the right eye and 20/ 20 in the left eye with marked resolution of visual field defects ( Fig. 2C). It appears, therefore, that although imaging of the rNFL is at the present time merely descriptive of visual dysfunction in most optic neuropathies, in the case of optic chiasmal compression, the preoperative rNFL thickness as determined by OCT can be predictive of the degree of visual rehabilitation. Further improvements and refine-ments of these technologies offer the exciting prospect of being able to anticipate which patients are at risk of experi-encing visual loss in a variety of neuro- ophthalmologic disorders and of being able to tailor specific treatments to those patients. FIG. 1. Case 1. A. Postcontrast coronal brain MRI shows a sellar/ suprasellar mass ( pituitary adenoma) elevating and compressing the optic chiasm. B. Preoperative visual fields show dense junction scotoma. C. Preoperative optical coherence tomography shows marked thinning of the retinal nerve fiber layer in both eyes. D. Postoperative visual fields show moderate improvement relative to preoperative visual fields. 248 q 2009 Lippincott Williams & Wilkins J Neuro- Ophthalmol, Vol. 29, No. 3, 2009 Savino REFERENCES 1. Hoyt WF, Schlicke B, Eckelhoff RJ. Fundoscopic appearance of a nerve- fibre- bundle defect. Br J Ophthalmol 1972; 56: 577- 83. 2. Vogt A. Die Nervenfaserzeichnung der menschlichen Netzhaut im rotfreien Licht. Klin Monatsbl Augenheil 1921; 66: 718- 30. 3. Hoyt WF, Frise ´ n L, Newman NM. Fundoscopy of nerve fiber layer defects in glaucoma. Invest Ophthalmol 1973; 12: 814- 29. 4. Sommer A, Miller NR, Pollack I, et al. Arch Ophthalmol 1977; 95: 2149- 56. 5. Quigley HA, Miller NR, George T, et al. Arch Ophthalmol 1980; 98: 1564- 71. 6. Frise ´ n L, Hoyt WF. Insidious atrophy of retinal nerve fibers in multiple sclerosis. Fundoscopic identification in patients with and without visual complaints. Arch Ophthalmol 1974; 92: 91- 7. 7. Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transaction in the lesions of multiple sclerosis. N Engl J Med 1998; 338: 278- 85. 8. Danesh- Meyer H, Savino PJ, Spaeth GL, et al. Comparison of arteritis and nonarteritic anterior ischemic optic neuropathies with the Heidelberg retina tomography. Ophthalmology 2005; 112: 1104- 12. 9. Danesh- Meyer HV, Carroll SC, Ku JY, et al. Correlation of retinal nerve fiber layer measured by scanning laser polarimeter to visual field in ischemic optic neuropathy. Arch Ophthalmol 2006; 124: 1720- 26. 10. Bellusci C, Savini G, Carbonelli M, et al. Retinal nerve fiber layer thickness in non- arteritic anterior ischemic optic neuropathy: OCT characterization of the acute and resolving phases. Graefes Arch Clin Exp Ophthalmol 2008; 246: 641- 7. 11. DeLeon- Ortega J, Carroll KE, Arthur SN, et al. Correlations between retinal nerve fiber layer and visual field in eyes with nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol 2007; 143: 288- 94. 12. Karam EZ, Hedges TR. Optical coherence tomography of the retinal nerve fibre layer in mild papilloedema and pseudopapilloedema. Br J Ophthalmol 2005; 89: 294- 8. 13. Trip SA, Schlottmann PG, Jones SJ, et al. Quantification of optic nerve head topography in optic neuritis: a pilot study. Br J Ophthalmol 2006; 90; 1128- 31. 14. Trip SA, Schlottmann PG, Jones SJ, et al. Retinal nerve fiber layer axonal loss and visual dysfunction in optic neuritis. Ann Neurol 2005; 58; 383- 91. 15. Costello F, Coupland S, HodgeW, et al. Quantifying axonal loss after optic neuritis with optical coherence tomography. Ann Neurol 2006; 59: 963- 9. 16. Henderson AP, Trip SA, Schlottmann PG, et al. An investigation of the retinal nerve fibre layer in progressive multiple sclerosis using optical coherence tomography. Brain 2008; 131: 277- 87. 17. Sepulcre J, Murie- Fernandez M, Salinas- Alaman A, et al. Diagnostic accuracy of retinal abnormalities in predicting disease activity in MS. Neurology 2007; 68: 1488- 94. 18. Danesh- Meyer HV, Carroll SC, Foroozon R, et al. Relationship between retinal nerve fiber layer and visual field sensitivity as measured by optical coherence tomography in chiasmal compression. Invest Ophthalmol Vis Sci 2006; 47: 4827- 35. 19. Danesh- Meyer HV, Papchenko T, Savino PJ, et al. In vivo retinal nerve fiber layer thickness measured by optical coherence tomog-raphy predicts visual recovery after surgery for parachiasmal tumors. Invest Ophthalmol Vis Sci 2008; 49: 1879- 85. FIG. 2. Case 2. A. Postcontrast coronal brain MRI shows a large suprasellar mass ( arrow). B. Preoperative visual fields show a junction scotoma. C. Preoperative optical coherence tomography results are normal. D. Postoperative visual fields show marked improvement relative to preoperative visual fields. 249 Seventh Hoyt Lecture J Neuro- Ophthalmol, Vol. 29, No. 3, 2009 |
