Nitrous oxide (N2O) is a weak anesthetic gas that was first used in 1844 in the field of dental anesthesia. However, currently, N2O is being abused for entertainment purposes in the form of N2O-filled balloons, called funky balls, which can cause many adverse effects, especially nervous system injury. This study aimed to investigate the detailed clinical and subclinical features associated with N2O intoxication. We retrospectively reviewed 47 patients diagnosed with N2O intoxication, from May 2018 to July 2019, and collected demographic data, clinical and laboratory tests, and spinal cord magnetic resonance imaging (MRI) findings. The mean time of funky ball use was 8.8 months, with a mean use of 36.3 balls per day. All patients presented with superficial sensory disorders. Reductions in muscle strength, decreased vibration sensation, and decreased or lost tendon reflexes were the most common clinical signs of N2O intoxication. Romberg sign and Lhermitte sign were observed in 39 patients (83%) and 21 patients (44.7%), respectively. Spinal cord lesions on MRI were observed in 32 patients (68.1%), which mostly presented with an inverted V sign. The total duration of N2O use, the number of days of using N2O per week, and the presence of Lhermitte sign (P<0.05) were significantly different between patients with and without spinal cord lesions on MRI. Serum levels of homocysteine and vitamin B12 were significantly different between the time of admission and discharge (P<0.05). Our study indicated that the days of using N2O per week was significantly associated with Spinal Cord Injuries (SCI) on MRI. According to the Receiver Operating Characteristic (ROC) curve analysis, a cutoff days of using per week value of 2.5 days could predict SCI with a sensitivity of 81.3%, a specificity of 73.3%, and an area under the ROC curve (AUC) of 0.813. Changes in the serum levels of homocysteine and vitamin B12 were effective markers for the evaluation of treatment response.

1. Garakani A, Jaffe RJ, Savla D, Welch AK, Protin CA, Bryson EO, McDowell DM. Neurologic, psychiatric, and other medical manifestations of nitrous oxide abuse: A systematic review of the case literature. Am J Addict 2016;25:358–69.
2. Kaar SJ, Ferris J, Waldron J, Devaney M, Ramsey J, Winstock AR. Up: The rise of nitrous oxide abuse. An international survey of contemporary nitrous oxide use. J Psychopharmacol 2016;30:395–401.
3. Emmanouil DE and Quock RM. Advances in Understanding the Actions of Nitrous Oxide. Anesth Prog 2007;54:9–18.
4. Jalbert ER, Fahmi A, Li C, Goshtasbi M, Zaman M. Subacute Combined Degeneration of the Dorsal Columns in A Patient With Nitrous Oxide Induced B12 Inactivation: A Case Report. J Neurol Neurosci 2016;6:3.
5. Ilniczky S, Jelencsik I, Kenez J, Szirmai I. MR findings in subacute combined degeneration of the spinal cord caused by nitrous oxide anaesthesia - two cases. Eur J Neurol 2002;9:101–4.
6. Safari A, Emadi F, Jamali E, Borhani-Haghighi A. Clinical and MRI manifestations of nitrous oxide induced vitamin B12 deficiency: A case report. Iran J Neurol 2013;12:111–3.
7. Singer MA, Lazaridis C, Nations SP, Wolfe GI. Reversible nitrous oxide–induced myeloneuropathy with pernicious anemia: Case report and literature review. Muscle Nerve 2008;37:125–9.
8. Yuan JL, Wang SK, Jiang T, Hu WL. Nitrous oxide induced subacute combined degeneration with longitudinally extensive myelopathy with inverted V-sign on spinal MRI: a case report and literature review. BMC Neurol 2017;17:222.
9. Hathout L, El-Saden S. Nitrous oxide-induced B12 deficiency myelopathy: Perspectives on the clinical biochemistry of vitamin B12. J Neurol Sci 2011;301:1–8.
10. Lan SY, Kuo CY, Chou CC, Kong SS, Hung PC, Tsai HY, Chen YC, Lin JJ, Chou IJ, Lin KL; PCHAN Study Group. Recreational nitrous oxide abuse related subacute combined degeneration of the spinal cord in adolescents – A case series and literature review. Brain Dev 2019;41:428–35.
11. Wang YY, Wang RB, Hong W, Jiao JS, Peng DT, Liu ZJ, Tian ZH, Jin M, Dong MR, Duan XH, Liu L, Sun Q, Sun SJ, Wang L. [Clinical features of long segmental myelopathy cause by nitrous oxide]. Beijing Da Xue Xue Bao Yi Xue Ban 2019;51:288–92.
12. Patel KK, Mejia Munne JC, Gunness VRN, Hersey D, Alshafai N, Sciubba D, Nasser R, Gimbel D, Cheng J, Nouri A. Subacute combined degeneration of the spinal cord following nitrous oxide anesthesia: A systematic review of cases. Clin Neurol Neurosurg 2018;173:163–8.
13. Li HT, Chu CC, Chang KH, Liao MF, Chang HS, Kuo HC, Lyu RK. Clinical and electrodiagnostic characteristics of nitrous oxide-induced neuropathy in Taiwan. Clin Neurophysiol 2016;127:3288–93.
14. Oussalah A, Julien M, Levy J, Hajjar O, Franczak C, Stephan C, Laugel E, Wandzel M, Filhine-Tresarrieu P, Green R, Guéant JL. Global Burden Related to Nitrous Oxide Exposure in Medical and Recreational Settings: A Systematic Review and Individual Patient Data Meta- Analysis. J Clin Med 2019;8:551.
15. Onrust MR, Frequin ST. Subacute Combined Spinal Cord Degeneration by Recreational Laughing Gas (N2O) Use. J Cent Nerv Syst Dis 2019;11:1179573519838277.
16. Garakani A, Welch AK, Jaffe RJ, Protin CA, McDowell DM. Psychosis and Low Cyanocobalamin in a Patient Abusing Nitrous Oxide and Cannabis. Psychosomatics 2014;55:715–9.
17. Manavifar L, Nemati Karimooy H, Jamali J, Talebi Doluee M, Shirdel A, Nejat Shokohi A, Fatemi Nayyeri M. Homocysteine, Cobalamin and Folate Status and their Relations to Neurocognitive and Psychological Markers in Elderly in Northeasten of Iran. Iran J Basic Med Sci 2013;16:772–80.
18. Nappo F, De Rosa N, Marfella R, De Lucia D, Ingrosso D, Perna AF, Farzati B, Giugliano D. Impairment of endothelial functions by acute hyperhomocysteinemia and reversal by antioxidant vitamins. JAMA 1999;281:2113–8.
19. Chen HJ, Huang CS. Nitrous Oxide-induced Subacute Combined Degeneration Presenting with Dystonia and Pseudoathetosis: A Case Report. Acta Neurol Taiwan 2016;25:50-5.
20. Narra R, 1 Adinarayana M, Naganarasimharaju J, Pradeep G. “Inverted V sign” in sub-acute combined degeneration of cord. J Clin Diagn Res. 2015;9:TJ01.