The 14th Hoyt Lecture Ischemic Optic Neuropathy: The Evolving Profile, 1966-2015: Comment

Retinal and optic disc perfusion in nonarteritic anterior ischemic optic neuropathy (NAION) is incompletely understood. Our aim was to investigate the characteristics of the microvascular structures at the peripapillary area and optic disc, and their associations with retinal structure and function in patients with NAION. We conducted a prospective, observational case series study. Thirty-four eyes, consisting of 15 NAION eyes and 19 normal eyes, were included. Optical coherence tomography (OCT) angiography was used to measure the vessel densities in the peripapillary superficial retina and whole-depth mode inside the optic disc. Measurement of circumpapillary retinal nerve fiber layer (cpRNFL) thickness was performed using OCT. Sectorial division analysis of cpRNFL was performed by eliminating the influences of the difference in disc rotation between OCT images and OCT angiography images. The vessel densities of peripapillary retina and inside the optic disc were significantly reduced in the NAION compared to the normal (both P < 0.001). Both the severity of visual field defect and cpRNFL thinning were significantly associated with the peripapillary vessel density (P = 0.006, P = 0.046), but not with the optic disc vessel density (P = 0.981, P = 0.856). cpRNFL and peripapillary vessel density showed reduction predominantly in the superior sectors, corresponding to the visual field defect. However, the correlations showed discrepancy of the sectors. The microvascular structures in the peripapillary retina and optic disc were reduced, but the cpRNFL thinning was associated with vessel density only in the peripapillary retina, indicating that the vessel densities in the peripapillary retina and optic disc may be differently affected in the pathological process of NAION.

Letters to the Editor Neither our clinical examination nor neuroimaging suggested leukemic infiltration of the optic nerves. During our patient's clinical course, GCA was in the differential diagnosis and a temporal artery biopsy was performed. It was the finding of perivascular lymphocytes on the biopsy specimen that prompted us to pursue a hematologic evaluation, and arrive at the correct diagnosis of chronic lymphocytic leukemia. Tim Westland, MD Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands Renate R. van den Bos, MD, PhD Department of Dermatology, Erasmus Medical Center, Rotterdam, the Netherlands FIG. 1. Temporal artery biopsy shows no signs of giant cell arteritis. An aggregate of lymphocytes (arrow) is seen in the adventitia (hematoxylin and eosin, ·100). within the surrounding tissue, lymphocyte aggregates were seen (Fig. 1). Additional testing revealed a leukocytosis of 27 · 109 cells/L. Flow cytometry showed a monoclonal B-cell population of 44% which was kappa light chain positive and CD5, CD19, CD20, and CD23 positive. The immunoglobulin heavy chain gene mutation status was not mutated; 11q and 17p deletions were not found. Diagnosis of chronic lymphocytic leukemia (Rai stage II) was made. Treatment was not begun because the patient did not meet the criteria for active disease (2). However, because of recurrent episodes of decreased vision in each eye, he was prescribed prednisone 60 mg a day for 7 days, which lead to subjective improvement in vision. Because the possible association of eye symptoms with chronic lymphocytic leukemia was present, and no other underlying causes were found, the patient was placed on a regimen of rituximab, chlorambucil, and prednisone each 28 days. After 6 monthly cycles, the patient was in full remission, and after 8 cycles, his hematologist switched him to rituximab maintenance monotherapy. The patient's leukocyte count normalized to 4.4 · 109 cells/L, and his visual acuity stabilized at 20/40, right eye and 20/20, left eye. Visual function has remained stable during follow-up. Although the precise cause of our patient's bilateral optic neuropathy is uncertain, possibilities include vaso-occlusion or paraneoplastic syndrome due to chronic lymphocytic leukemia. The 14th Hoyt Lecture Ischemic Optic Neuropathy: The Evolving Profile, 1966-2015: Comment I read with interest the Hoyt Lecture by Arnold (1) dealing with nonarteritic anterior ischemic optic neuropathy 218 Claire Siemes, MD, MSc, PhD Department of Hematology, Erasmus Medical Center, Rotterdam, the Netherlands Robert M. Verdijk, MD, PhD Department of Pathology, Section Ophthalmic Pathology, Erasmus Medical Center Johannes R. Vingerling, MD, PhD Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands The authors report no conflicts of interest. REFERENCE 1. Ghinai RAM, Mahmood S, Mukonoweshuro P, Wechalekar AD, Moore SE. Diagnosing light chain amyloidosis on temporal artery biopsies for suspected giant cell arteritis. J Neuroophthalmol. 2017;37:34-39. 2. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111:5446-5456. (NAION). The observation of a small cup-to-disc ratio in these patients was made by William F. Hoyt, but Arnold erroneously attributed this to Sohan Singh Hayreh from an article discussing the development of disc cupping after an attack of arteritic AION instead (reference 17 in Arnold's article). Yet, Bill Hoyt was the first to recognize this disc morphology in patients with NAION-what was Letters to the Editor: J Neuro-Ophthalmol 2017; 37: 216-221 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Letters to the Editor subsequently aptly termed "the disc-at-risk" by Ron Burde (reference 18 of Arnold's article). Hoyt's seminal observations and statements were made public in February 1982 at the Rocky Mountain Neuro-Ophthalmologic Society Meeting, spurring others in attendance to obtain additional supportive evidence. He also later advised a young Roy Beck to make use of the extensive database at the University of Iowa to obtain confirmatory results, Hayreh's initial skepticism notwithstanding. Despite not having requested authorship on any of the ensuing manuscripts, recognition and attribution of credit was nonetheless made to Hoyt by both Beck and Hayreh within the text of several publications (citations no. 19 and 24 cited by Arnold) and by other colleagues in various corroborating investigations (2,3). Three decades later, it appears that some publications (1,3) which confuse the discovery of the optic disc risk factors reflect only a perusal of manuscript titles and author listings, without attention to the manuscript text. Arnold further indicates that such relatively cupless discs may lead to a compartment syndrome in the pathogenesis of NAION (1,3,4). However, no supportive data, whether through MRI or other means, has emerged to support such a mechanism. Indeed, this neuropathy may occasionally occur in discs with large cup-to-disc ratios as Hoyt and colleagues published in this journal 19 years ago (5). A more crucial oversight, however, has been to neglect any discussion of the potential effects of abrupt vitreous separation from or about the optic nerve head. It is precisely around such at-risk discs where vitreous is most strongly adherent to axons devoid of a protective internal limiting membrane and where vitreous attachments to the central disc vessels are located (6-8) in apposition to neural tissue. The possibility of vitreous separation inducing an optic neuropathy was first considered and publicly voiced by Hoyt in 1978 at the sixth Annual Aspen Retinal Detachment Society Meeting, Snowmass, Aspen, Colorado. However, this observation has been entirely elided from Arnold's latest publications dealing with NAION (1,9), despite an editorial in Ophthalmology by Hoyt and myself detailing a likely dynamic pathophysiologic mechanism (8). This evolution and refinement of the original 1978 proposal has engendered considerable debate in the neuroophthalmic community, including in public forums between Dr. Arnold and the author (12th European Neuro-Ophthalmology Society Meeting, Optic neuropathies I, June 22, 2015, Ljubljana, Slovenia), as well as numerous letters to the editor. The proposed mechanism is supported by data accumulated in the literature, pointing out that despite its common designation, ischemia that has been assumed is not actually evident in so-called NAION (8). Findings instead point to a papillary vitreous Letters to the Editor: J Neuro-Ophthalmol 2017; 37: 216-221 detachment neuropathy, or PVD-N, produced when elevated vitreous shear stress forces develop at the optic nerve head during abrupt vitreous separation. Such rapid stretch of viscoelastic axons (which become less elastic with age) causes cytoskeletal microtubular damage much like concussive brain damage that results from sudden blows to the cranium. Surface capillary tearing with hemorrhage also may occur, which does not correlate with loss of visual acuity (10), unlike the corresponding and distinctive disc pallor noted with arteritic ischemic optic neuropathy. Open-mindedness, skepticism of established dogma, scholarly inclusiveness, and rigorous use and citation of the literature have been the hallmarks of Hoyt's scientific teaching and career. The above comments should be included to accurately represent the evolving profile of NAION in the 14th annual Hoyt lecture. Cameron F. Parsa, MD Quinze-Vingts National Eye Hospital, UPMC-Sorbonne Universities, Paris, France The author reports no conflicts of interest. REFERENCES 1. Arnold AC. The 14th Hoyt Lecture: ischemic optic neuropathy: the evolving profile, 1966-2015. J Neuroophthalmol. 2016;36:208-215. 2. Beck RW, Savino PJ, Repka MX, Schatz NJ, Sergott RC. Letter to the Editor. Structural factors in the pathogenesis of ischemic optic neuropathy. Am J Ophthalmol. 1984;98:649-650. [Reply. Feit RH, Tomsak RL, Ellenberger C Jr. Am J Ophthalmol. 1984;98:650]. 3. Hayreh SS, Zimmerman MB. Nonarteritic anterior ischemic optic neuropathy: refractive error and its relationship to cup/ disc ratio. Ophthalmology. 2008;115:2275-2281. 4. Kupersmith MJ, Miller NR. A nonarteritic anterior ischemic optic neuropathy clinical trial: an industry and NORDIC collaboration. J Neuroophthalmol. 2016;36:235-237. 5. Parsa CF, Muci-Mendoza R, Hoyt WF. Anterior ischemic optic neuropathy in a disc with a cup: an exception to the rule. J Neuroophthalmol. 1998;18:169-170. 6. Foos RY, Roth AM. Surface structure of the optic nerve head. 2. Vitreopapillary attachments and posterior vitreous detachment. Am J Ophthalmol. 1973;76:662-671. 7. Rao NA, Spencer WH. Optic nerve. In: Spencer WH, ed. Ophthalmic Pathology: An Atlas and Textbook. Vol 1, 4th edition. Philadelphia, PA: Saunders, 1996:513-622. 8. Parsa CF, Hoyt WF. Nonarteritic anterior ischemic optic neuropathy (NAION): a misnomer. Rearranging pieces of a puzzle to reveal a nonischemic papillopathy caused by vitreous separation. Ophthalmology. 2015;122:439-442. 9. Miller NR, Arnold AC. Current concepts in the diagnosis, pathogenesis and management of nonarteritic anterior ischaemic optic neuropathy. Eye. 2015;29:65-79. 10. Katz B, Hoyt WF. Intrapapillary and peripapillary hemorrhage in young patients with incomplete posterior vitreous detachment. Ophthalmology. 1995;102:349-354. 219 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.