Dialysis-Associated Nonarteritic Anterior Ischemic Optic Neuropathy: A Case Series and Review

Dialysis-associated nonarteritic ischemic optic neuropathy (DA-NAION) occurs secondary to intra-dialytic hypotension often with catastrophic consequences and is one of the rare situations where NAION can recur in the same eye. We describe 3 cases of DA-NAION associated with hypotension, review the current literature on DA-NAION, and provide recommendations for decreasing the risk of intradialytic hypotension.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Dialysis-Associated Nonarteritic Anterior Ischemic Optic Neuropathy: A Case Series and Review Laura Donaldson, MD, PhD, Paul Freund, MD, Ramona Aslahi, MD, Edward Margolin, MD Background: Dialysis-associated nonarteritic ischemic optic neuropathy (DA-NAION) occurs secondary to intradialytic hypotension often with catastrophic consequences and is one of the rare situations where NAION can recur in the same eye. We describe 3 cases of DA-NAION associated with hypotension, review the current literature on DA-NAION, and provide recommendations for decreasing the risk of intradialytic hypotension. Methods: In addition to describing 3 cases of DA-NAION, PubMed was searched for all reports of DA-NAION in adults with documented episodes of hypotension preceding the onset of NAION. A total of 50 eyes of 31 patients were included. Age, visual acuity at presentation, rate of bilateral involvement at presentation, sequential involvement of the fellow eye, and recurrence of NAION in the same eye were analyzed. Results: We found that most cases of DA-NAION occur in relatively young patients (47.7 ± 14.7 years) with a high rate of bilateral involvement at presentation (23%) and bilateral sequential involvement (39%). Vision loss is severe with 64% of patients presenting with 20/200 acuity or worse in the involved eye and 19% of patients with final visual acuity of 20/200 or worse in both eyes. 3 patients (9.7%) had recurrence of NAION in the previously affected eye. Conclusions: Neuro-ophthalmologists have an important role in identifying patients who have suffered DA-NAION and communicating their findings to nephrologists to minimize the chance of involvement of the fellow eye and recurrence in the same eye. Intradialytic blood pressure must be closely monitored, and fluid balance, dialysate composition, and dialysis protocol must be optimized to prevent occur- Department of Ophthalmology and Vision Sciences (LD, PF, EM), University of Toronto, Toronto, Canada; Department of Medicine (RA), Division of Nephrology, University of Toronto, Toronto, Canada; and Department of Medicine (EM), Division of Neurology, University of Toronto, Toronto, Canada. The authors report no conflicts of interest. All authors contributed equally to the preparation and writing of this manuscript. Address correspondence to Edward Margolin, MD, FRCSC, Dipl. ABO, Associate Professor, Department of Ophthalmology and Visual Sciences; and Department of Medicine, Division of Neurology, University of Toronto, 801 Eglinton Avenue West, Suite 301, Toronto, Ontario M5N 1E3; E-mail: [e-mail] e116 rence of intradialytic hypotension, which is the culprit for DANAION. Journal of Neuro-Ophthalmology 2022;42:e116–e123 doi: 10.1097/WNO.0000000000001493 © 2021 by North American Neuro-Ophthalmology Society N onarteritic anterior ischemic optic neuropathy (NAION) is the most common cause of optic nerve swelling and optic neuropathy in adults older than 50 years (1). The typical presentation is sudden painless vision loss with swelling of the optic nerve head accompanied by visual field defect, variable central acuity, and a relative afferent pupillary defect (RAPD). Although the exact pathogenesis of NAION has not been elucidated, the most likely culprit is impaired blood flow through short posterior ciliary arteries (SPCAs) causing ischemia and resultant swelling of the intraocular portion of the optic nerve, leading to the compartment syndrome and eventually apoptosis of involved axons and ganglion cell loss (2). Most patients with NAION have a crowded optic nerve head with a small cup-to-disc ratio (3) and systemic vascular risk factors including hypertension, dyslipidemia, diabetes mellitus, and cardiovascular disease (4,5). NAION can also occur after episodes of severe systemic hypotension, which has been termed shock optic neuropathy (6,7). In younger patients, both chronic renal failure (CRF) and dialysis therapy have an important association with NAION, and 5%–10% of patients who present with NAION younger than 50 years are on dialysis (8,9). Patients with CRF typically have multiple comorbidities including cardiovascular disease and anemia that can also increase their risk of NAION, but often NAION events in this at-risk patient population are preceded by episodes of relative hypotension during dialysis. This review describes the presentation and natural history of dialysis-associated NAION (DA-NAION) and highlights Donaldson et al: J Neuro-Ophthalmol 2022; 42: e116-e123 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution the treatment strategies that can be used to minimize recurrent NAION. METHODS The PubMed database was searched for combinations of “optic neuropathy,” “ischemic optic neuropathy,” “NAION,” and “dialysis,” “hypotension,” or “renal failure.” Pertinent articles’ reference lists were manually reviewed as well. All cases where an episode of NAION occurred immediately after dialysis with confirmed episode of intradialytic hypotension were included. We also describe 3 cases from our practice who fulfilled the same criteria. Age, visual acuity at presentation and at the final follow-up, and rate of recurrence of NAION in the fellow eye and same eye were recorded and analyzed. ments, atrial fibrillation, chronic superior vena cava syndrome, hyperparathyroidism with a parathyroidectomy, and psoriatic arthritis. She recalled noticing blurry vision in LE after an IHD session w7 years ago and was told that she had an “eye stroke.” She now presented with a sudden onset of blurry vision in RE during a HD session during which her systolic blood pressure dipped to 50 mm Hg. Vision was hand motions in RE and 20/25 in LE; she had hyperemic right optic nerve head edema with peripapillary hemorrhages and mild pallor of the left optic disc. AVF in RE demonstrated superior altitudinal defect and severe generalized depression in LE. Six months later, visual acuity and AVFs remained unchanged, but optic nerve head edema in RE resolved, and she now had bilateral optic nerve head pallor. Case 3 CASE DESCRIPTIONS Case 1 A 41-year-old man with a history of 2 failed renal transplants performed for congenital renal disease was undergoing intermittent hemodialysis (IHD). His medications included ASA, bisoprolol, calcitriol, pantoprazole, rosuvastatin, and sevelamer. He smoked half a pack of cigarettes per day for over 20 years. He noticed sudden loss of vision in his left eye (LE) immediately after his last hemodialysis (HD) session. The visual acuity was 20/20 in the right eye (RE) and counting fingers (CF) in LE with left RAPD. Automated visual field (AVF) (24-2 algorithm) was normal in RE and demonstrated diffuse depression in LE. On ophthalmoscopy, the left optic nerve head demonstrated hyperemic edema with peripapillary hemorrhages. The right optic nerve appeared normal with a cup-to-disc ratio of 0.3. MRI of the brain and orbits with contrast and antineuromyelitis optica and antimyelin oligodendrocyte protein antibody titers were also checked because he complained of pain with eye movements and were both negative. His visual acuity 3 months later remained unchanged. Six months later, he experienced acute painless loss of vision in the superior portion of his right visual field also within 30 minutes of his last IHD session. Visual acuity remained unchanged at 20/20 in RE and CF in LE; however, AVF now demonstrated diffuse depression in RE and with central sparing. Review of intradialytic blood pressure recordings demonstrated that his intradialytic systolic blood pressures dipped to 80 mm Hg before the first event and 60 mm Hg before the second event. Six months later, his visual acuity and AVFs were unchanged, but he now developed bilateral optic nerve head pallor. Case 2 A 41-year-old woman underwent IHD for medullary cystic kidney disease. Her medical history was significant for coronary artery disease with 2 prior coronary stent placeDonaldson et al: J Neuro-Ophthalmol 2022; 42: e116-e123 A 35-year-old man with a history of hypertension and CRF due to anabolic steroid use was undergoing IHD and daily peritoneal dialysis. His medications were bisoprolol, telmisartan, amlodipine, and pantoprazole. He noticed sudden loss of vision in RE immediately after the last IHD session. Vision was light perception in RE and 20/20 in LE with severe right optic nerve head swelling and peripapillary hemorrhages. The right optic nerve had a cup-to-disc ratio of 0.2 and appeared normal. AVF demonstrated severe generalized depression in RE and was normal in LE. MRI of the brain and orbits with contrast was unremarkable. On detailed review, his systolic blood pressure during the last IHD session dropped to 50 mm Hg. On our recommendation, treatment of long-standing anemia with erythropoietin commenced, dialysate temperature was reduced, and midodrine was administered during the HD sessions. The dose of oral antihypertensive medications was adjusted as well. Despite these measures to reduce chances of further episodes of intradialytic hypotension, he returned 3 months later with acute painless loss of vision in LE during his last HD session when his systolic blood pressure dropped to 48 mm Hg. The visual acuity was now only light perception in RE and 20/30 in LE. Fundus examination demonstrated diffuse optic nerve pallor RE and diffuse hyperemic optic disc edema with peripapillary hemorrhages in LE. Duration of HD sessions was shortened, and frequency increased from 3 to 6 times weekly. Despite these modifications, 1 month later, he experienced a third episode of visual loss affecting his LE during HD session when his systolic blood pressure dropped to 60 mm Hg. Vision was now light perception only in each eye. There was segmental edema of the left optic nerve. AVF demonstrated severe generalized depression in each eye. Three months later, visual acuity and AVFs were unchanged, and both optic nerves demonstrated diffuse pallor. RESULTS Including the cases presented here, a total of 31 cases of DA-NAION associated with intradialytic hypotension were e117 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution found in the literature (Table 1). The mean age at presentation was 47.7 years, and 18 patients (58.1%) were male. Overall, there was bilateral involvement in 19 patients (61.3%) which was simultaneous at presentation in 7 (22.6%) and sequential in 12 (38.7%). Three patients (9.7%) had a recurrent episode within a previously affected eye. Most of the cases (27, 87.1%) occurred in patients undergoing HD with the remaining 4 (12.9%) in those on peritoneal dialysis. Anemia was present in 20 of 22 cases (91%) where these data were available. Presenting visual acuity was available for 44 eyes and was 20/200 or worse in 28 eyes (63.6%). Final visual acuity was worse than 20/200 in 25 of 42 eyes (59.5%) and hand motions or worse in 15 eyes (35.7%); 19.0% of patients were worse than 20/200 in both eyes at the final follow-up. The pattern of visual field defect was specified in 34 eyes, and of these, 55.9% were primarily inferior, 35.3% were central or diffuse depression, and 8.8% were primarily superior. DISCUSSION Pathophysiology of Nonarteritic Anterior Ischemic Optic Neuropathy The pathophysiology of NAION is not completely understood, but it is accepted that relative hypoperfusion of the optic nerve head supplied by the SPCAs leads to edema and infarction of optic nerve axons, more commonly in the superior half of the ONH (2,10,11). Crowded optic nerve heads with a small cup-to-disc ratio, typically ,0.3, or a socalled “disc at risk,” have been long recognized to be associated with NAION and are present in the fellow eye of nearly all cases of patients with NAION who are not associated with shock/severe hypotension (3). In a disc at risk, optic nerve head edema induced by ischemic injury is believed to cause compression of neighboring axons within a small and rigid scleral tunnel, which, in turn, leads to propagation of edema and compression of more axons. Optic disc drusen are believed to contribute to axonal compression within the tight confines of the ONH by decreasing the available space within the scleral canal (12). Several systemic factors have also been recognized to increase the risk of NAION including male gender, hypertension, and diabetes mellitus (4,5). Obstructive sleep apnea has been recognized more recently to also be an independent risk factor for NAION, which is believed to be related to dysfunctional autoregulation of the blood flow within the optic nerve head (13). NAION has also been reported in association with the use of phosphodiesterase 5 inhibitors (14); however, the mechanism and strength of this association is unclear (15). e118 Nonarteritic Anterior Ischemic Optic Neuropathy in Dialysis Patients Multiple factors including pathophysiology of ESRD and its treatment can all contribute to the development of NAION in patients undergoing dialysis. Diabetes and hypertension are 2 of the most common causes of end-stage kidney disease and similarly contribute to the vascular dysfunction in the retina and optic nerve head, thus constituting a significant risk factor for development of NAION in these patients (16). Anemia reduces the blood’s oxygen-carrying capacity and is very common in patients with ESRD. Increased risk of NAION has been reported in patients with chronic anemia; thus, anemia is also an independent risk factor for DANAION (17,18). Finally, intradialytic hypotension, whether peritoneal or HD, is the most common complication of dialysis and can cause significant morbidity and mortality. Depending on the definition used, intradialytic hypotension could occur in 5–30% of all dialysis treatments (19–21). An absolute intradialytic nadir systolic ,90 mm Hg is most strongly associated with overall mortality of patients on HD (22). Intradialytic hypotension can also cause reduced perfusion of the ONH and is likely the most important risk factor for development of DA-NAION. Many factors contribute to intradialytic hypotension: rapid or excessive ultrafiltration, a rapid reduction in plasma osmolality, incorrectly low prescribed target weight, autonomic neuropathy, and poor cardiac reserve (19,20,23–25). Use of antihypertensive medications (26), ingestion of a meal during dialysis (27,28), dialysis temperature (29), and dialysate compositions (30,31) are other contributing factors. In addition, inappropriately low plasma vasopressin levels (32) and increased synthesis of endogenous vasodilators such as nitric oxide (33) have been shown to cause hypotension during dialysis. Prevention of Dialysis-Associated Nonarteritic Ischemic Optic Neuropathy Acute management of intradialytic hypotension includes decreasing or holding the ultrafiltration rate, repositioning the patient in the Trendelenburg position, infusion of saline or albumin, lowering blood flow (Qb) and dialysate flow (Qd) rate, and even discontinuing dialysis if necessary (34). If hypotension persists despite the above measures, the patient should be evaluated for serious underlying medical conditions such as sepsis, cardiac emergencies, GI bleeding, and allergic reactions. To prevent recurrent episodes of intradialytic hypotension, a stepwise approach has been recommended to be considered (35). First, reassessment of the prescribed target weight by physical examination and use of objective modalities such as bioimpedance spectroscopy, if available (36), should be performed. Patients should be educated to avoid consuming food during dialysis and to limit their overall salt intake to less than 6 g/day (37,38). Other important considerations are adjustment of antihypertensive regimens, reassessment of Donaldson et al: J Neuro-Ophthalmol 2022; 42: e116-e123 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Cases of dialysis-associated nonarteritic anterior ischemic optic neuropathy (DA-NAION) Age Sex Current Current Current 41 41 35 Male Female Male Sequential Sequential Sequential Jain et al (49) Sabt (50) Sabt, 2013 Sabt, 2013 Maio et al (51) Bartlett et al (52) Servilla and Groggel (53) Connolly et al (54) Prat et al (55) Kirmizis et al (56) Michaelson et al (57) Haider et al (58) Nieto and Zapata (59) Nieto and Zapata Korzets et al (60) Korzets et al 45 24 30 72 50 42 30 39 63 75 23 53 26 56 77 70 Female Female Female Male Male Female Male Male Female Male Female Male Male Male Male Female Sequential Right Sequential Left Right Sequential Simultaneous Left Sequential Left Sequential Left Sequential Simultaneous Right Right Hemodialysis Hemodialysis Hemodialysis and peritoneal Hemodialysis Hemodialysis Hemodialysis Peritoneal Hemodialysis Hemodialysis Hemodialysis Hemodialysis Hemodialysis Hemodialysis Peritoneal Hemodialysis Hemodialysis Peritoneal Hemodialysis Hemodialysis Basile et al (18) Jackson et al (61) Al Zubidi et al (62) Al Zubidi et al Sabeel et al (63) Basri and Shaheen (64) Cuxart et al (65) Tay et al (66) Tay et al Tay et al Bansal et al (67) Bansal et al 49 58 55 48 40 40 58 53 62 37 39 49 Male Male Male Male Female Female Female Female Male Male Female Male Sequential Left Left Left Sequential Simultaneous Simultaneous Sequential Left Simultaneous Simultaneous Simultaneous Hemodialysis Peritoneal Hemodialysis Hemodialysis Hemodialysis Hemodialysis Hemodialysis Hemodialysis Hemodialysis Hemodialysis Hemodialysis Hemodialysis Author Current Current Current Jain et al (49) Sabt (50) Final VA LE VF RE CF Affected Eye Presenting VA RE Author VF LE Dialysis Type 20/400 20/25 LP 20/20 CF LP 20/200 20/200 NS — 20/50 NLP 20/30 — 20/33 — 20/20 — 20/30 20/400 LP 20/200 HM — NS NS — HM 20/20 20/800 HM “Total blindness” 20/25 20/20 20/200 HM — — NS — — — NLP NLP 20/100 20/60 NS 20/200 CF NLP NLP NLP 20/400 20/80 CF HM 20/32 NLP 20/200 NS 20/30 — 20/100 NLP 20/30 — HM — CF — NLP CF NS 20/ 1,200 NS — — — NLP NLP 20/50 20/20 — 20/20 20/30 LP 20/20 20/17 NLP Anemia Hemoglobin Hypotension Diffuse Yes 100 Dialysis 20/25 Diffuse LP Diffuse Inf NFB Inf NFB Yes No 87 116 Dialysis Dialysis Diffuse — Yes NS 95 NS Nocturnal Dialysis Diffuse NS Donaldson et al: J Neuro-Ophthalmol 2022; 42: e116-e123 Final VA RE 20/20 HM 20/30 Sup alt HM — Presenting VA LE Dialysis Indication Other Notes Congenital kidney — disease Cystic kidney disease — Anabolic steroidRecurrent induced kidney episode failure in LE DM and Htn — Chronic reflux Recurrent RE NAION, Hx PION LE, and ocular ischemia OU e119 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution (Continued ) Author Final VA LE VF RE VF LE Anemia Hemoglobin Hypotension Sabt, 2013 NS Inf NFB Inf alt NS NS Dialysis Sabt, 2013 Maio et al (51) NS — — — Inf alt Inf NFB NS Yes NS 101 Yes Dialysis NS Sup alt Yes Yes 71 NS Yes Yes Bartlett et al (52) Servilla and Groggel (53) Connolly et al (54) Prat et al (55) Kirmizis et al (56) Michaelson et al (57) HM NS 20/20 Diffuse 20/ 100 CF — — Yes Ht 23% Dialysis — Sup alt No Ht 39% Yes 20/50 — Yes 96 NS NS Nocturnal, dialysis Yes Diffuse then inf alt 20/25 Inferote Diffuse mporal Dialysis Indication Other Notes Glomeru Hx PION LE lonephritis Glomerulonephritis — Congenital — malformation IgA nephropathy — Chronic — glomerulonephritis Congenital — obstruction Hypertension On a PDE5 inhibitor Chronic — glomerulonephritis Poststreptococcal Optic disc drusen glomerul onephritis Polycystic kidneys — Chronic reflux — Unknown — DM2 — Uremia and fluid — overload Unknown — Nephrocalcinosis — Haider et al (58) Nieto and Zapata (59) Nieto and Zapata Korzets et al (60) Korzets et al — NLP HM — — — — Inf alt — Inf Inf NFB — Diffuse — — Yes Yes NS NS NS 90 NS NS NS NS Yes Yes Yes Yes Dialysis Basile et al (18) Jackson et al (61) — — — Inf alt Yes Yes NS 104 Yes Nocturnal Al Zubidi et al (62) NS 20/ 200 CF — Yes NS Dialysis DM — Al Zubidi et al NS — Yes NS Dialysis Unknown — Sabeel et al (63) Basri and Shaheen (64) Cuxart et al (65) NLP NLP — — Central and inferot emporal Diffuse and dense inferonasal — — NS Yes NS 74 Yes Yes Unknown Unknown — — — Yes 107 Dialysis Interstitial nephritis — Diffuse Central Diffuse Inf alt Yes Yes Yes Yes 117 92 111 75 Dialysis Dialysis Dialysis Nocturnal Inf alt and Super onasal NS NS Yes Tay et al (66) Tay et al Tay et al Bansal et al (67) 20/ — 100 20/60 Inf NFB CF — HM Inf alt 20/30 Inf alt Bansal et al 20/32 Diffuse Unknown Unknown Unknown Congenital malformation Unknown — — — Recurrent episode in RE — HM, hand motions; Ht, hematocrit; NLP, no light perception; NS, not specified; RE, right eye; LE, left eye. e120 Donaldson et al: J Neuro-Ophthalmol 2022; 42: e116-e123 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution ultrafiltration rate (23,39), and a review dialysate composition including sodium, calcium, magnesium, and bicarbonate. If these measures prove ineffective, patients should be assessed for underlying cardiac disease. Cooling of dialysate may be used using empiric fixed-temperature reduction or isothermic techniques (29) and is believed to work by stimulating the sympathetic nervous system. Individual treatment session times may need to be lengthened or their frequency increased (35). Third-level interventions include the use of pharmacologic agents to increase blood pressure including midodrine (40), L carnitine (41,42), and sertraline (43). Dialysis modality may need to be changed if hypotension is refractory (44). Treatment There is no effective treatment for NAION. There is a great deal of interest in using a neuroprotective strategy; however, this approach relies on the assumption that retinal ganglion cell death is not immediate but can be prevented within a time window in which therapy can be administered and axonal integrity preserved (45). The most recent clinical trial using a short interfering RNA compound targeting caspase 2 stopped enrollment after interim analysis was not indicative of any positive treatment effect (46). Prognosis In typical NAION, many patients have relatively preserved central acuity, with almost 54% of cases in one large series seeing 20/40 or better (2). Hand motion or worse vision is uncommon (2,47). Approximately 30% of patients improve in their central acuity by 3 or more lines and 20% decline 3 or more lines (48). Visual field defects show minimal changes after onset (11). By contrast, prognosis is much more guarded in DA-NAION with 35.7% of eyes having final visual acuity of hand motions or worse. Fellow eye involvement and recurrence within an affected eye are both more common in DANIAON, with bilateral involvement in 61.3% and recurrent episodes in 9.7% of patients in our series. CONCLUSIONS DA-NAION is a well-described complication of HD. Patients with DA-NAION have worse visual outcomes and high rate of involvement of the fellow eye and recurrence in the same eye compared with patients with non–dialysis-associated NAION. The most important therapeutic measure for preventing NAION occurrence in the fellow eye and recurrence in the same eye is prevention of intradialytic hypotension, and nephrologists must be alerted about the importance of modifying dialysis protocols to reduce its incidence. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: E. Margolin, L. Donaldson, R. Aslahi, and P. Freund; b. Acquisition of data: E. Margolin, L. Donaldson, and P. Freund; c. Analysis and interpretation of data: Donaldson et al: J Neuro-Ophthalmol 2022; 42: e116-e123 E. 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