To the Editor: 

The recent study of postoperative visual loss after spinal surgery identified long duration anesthesia, male gender, obesity, and the need for larger blood transfusion as risk factors for postoperative visual loss.1The authors believe the core mechanism for visual loss is a vascular one causing optic nerve ischemia. The accompanying editorial emphasized the possible role anesthesia-associated inflammation may play in visual loss and referenced the article of Staff et al.,  who first described postoperative inflammatory neuropathy.2,3The inflammatory neuropathy cases described by Staff et al.  all involved peripheral nerves. Perhaps there is a common risk factor in perioperative visual loss and postoperative inflammatory peripheral neuropathy. That factor could be the use of nitrous oxide. It would be interesting if information on the use of nitrous oxide were available from these two reports' databases.

Nitrous oxide anesthesia increases plasma homocysteine.4Nitrous oxide does this by disrupting a metabolic chain involving folate, vitamin B6, and vitamin B12. Speculatively, the nitrous-oxide–induced increase in homocysteine effects could be greater in individuals who have a preexisting deficiency of these vitamins or a subclinical or undiagnosed variant of the known congenital biochemical abnormalities involving these vitamins, such as hyperhomocystinemia.

Nitrous-oxide–induced increases in plasma homocysteine have been correlated positively with altered endothelial function.4Increased plasma homocysteine concentration have strong association with increased inflammation.5,6Increased homocysteine concentrations are strongly correlated with the microvascular complications of diabetes, including neuropathy.7The ENIGMA trail suggested that if nitrous oxide is used for more than 2 h in patients, it increases their long-term myocardial infarction risk.8Hyperhomocystinemia is also well described as a factor for central retinal artery occlusion and central retinal vein occlusion.9,,11This is precisely what the injury in perioperative visual loss seems to be.

If this speculated link between nitrous oxide use and perioperative vision loss should ever find any more supporting scientific evidence, it could suggest utility of simple protective strategies to avoid both postoperative visual loss and inflammatory peripheral neuropathy. One remedy could be to administer folate and vitamins B6 and B12 as premedication to patients before they undergo long duration surgery, especially spinal surgery, when using nitrous oxide in the anesthetic. In one preoperative study of 390 patients scheduled for major surgery, 0.2% individuals had a preexisting folate deficiency and 7.5% individuals had preexisting increased plasma homocysteine concentrations.12Those individuals could possibly be a higher risk for blindness or postoperative inflammatory neuropathy than are the other patients. The authors proposed administering routine preanesthetic folate and vitamin supplements when nitrous oxide was planned to be used on patients undergoing major surgery. The alternative protective remedy would be to avoid use of nitrous oxide surgeries that present the risk of vision loss.

Nitrous oxide is not devoid of benefits and has been shown to reduce long-term pain, possibly via  its N -methyl-D-aspartic acid receptor blocking effects.13Thus, the overall place of nitrous oxide use in anesthesia remains a matter of debate.

It is likely that multiple risk factors for visual loss after long duration spinal surgery will remain, and all have a complex interplay with no single remedy being able to eliminate the risk of blindness.

Postoperative Visual Loss Study Group: Risk factors associated with ischemic optic neuropathy after spinal fusion surgery. ANESTHESIOLOGY 2012;116:15–24
Warner MA: Cracking open the door on perioperative visual loss. ANESTHESIOLOGY 2012;116:1–2
Staff NP, Engelstad J, Klein CJ, Amrami KK, Spinner RJ, Dyck PJ, Warner MA, Warner ME, Dyck PJ: Post-surgical inflammatory neuropathy. Brain 2010; 133:2866–80
Myles PS, Chan MT, Kaye DM, McIlroy DR, Lau CW, Symons JA, Chen S: Effect of nitrous oxide anesthesia on plasma homocysteine and endothelial function. ANESTHESIOLOGY 2008; 109:657–63
Gori AM, Sofi F, Marcucci R, Giusti B, Franco Gensini G, Abbate R: Association between homocysteine, vitamin B(6) concentrations and inflammation. Clin Chem Lab Med 2007; 45:1728–36
McCully KS: Chemical pathology of homocysteine. IV. Excitotoxicity, oxidative stress, endothelial dysfunction, and inflammation. Ann Clin Lab Sci 2009; 39:219–32
Ambrosch A, Dierkes J, Lobmann R, Kühne W, König W, Luley C, Lehnert H: Relation between homocysteinaemia and diabetic neuropathy in patients with Type 2 diabetes mellitus. Diabet Med 2001; 18:185–92
Leslie K, Myles PS, Chan MT, Forbes A, Paech MJ, Peyton P, Silbert BS, Williamson E: Nitrous oxide and long-term morbidity and mortality in the ENIGMA trial. Anesth Analg 2011; 112:387–93
Pianka P, Almog Y, Man O, Goldstein M, Sela BA, Loewenstein A: Hyperhomocystinemia in patients with nonarteritic anterior ischemic optic neuropathy, central retinal artery occlusion, and central retinal vein occlusion. Ophthalmology 2000; 107:1588–92
Kawasaki A, Purvin VA, Burgett RA: Hyperhomocysteinaemia in young patients with non-arteritic anterior ischaemic optic neuropathy. Br J Ophthalmol 1999; 83:1287–90
Stanger O, Weger M, Obeid R, Temmel W, Meinitzer A, Steinbrugger I, Schmut O, Herrmann W: Impairment of homocysteine metabolism in patients with retinal vascular occlusion and non-arteritic ischemic optic neuropathy. Clin Chem Lab Med 2005; 43:1020–5
Myles PS, Chan MT, Forbes A, Leslie K, Paech M, Peyton P: Preoperative folate and homocysteine status in patients undergoing major surgery. Clin Nutr 2006; 25:736–45
Chan MT, Wan AC, Gin T, Leslie K, Myles PS: Chronic postsurgical pain after nitrous oxide anesthesia. Pain 2011; 152:2514–20