Nitrous Oxide-Induced Neuropathy

By Michael Rubin, MD

Professor of Clinical Neurology, Weill Cornell Medical College

SYNOPSIS: Nitrous oxide-induced neuropathy presents with a rapidly progressive sensorimotor neuropathy that may mimic Guillain-Barré syndrome. The pattern of clinical weakness and progression, as well as electrophysiological features, can help to rapidly distinguish the two disorders.

SOURCE: Fortanier E, Berling E, Zanin A, et al. How to distinguish Guillain-Barré syndrome from nitrous oxide-induced neuropathy: A 2-year, multicentric, retrospective study. Eur J Neurol 2023;30:3296-3306.

Known colloquially as “laughing gas,” “nangs,” “whippets,” or “hippy crack,” nitrous oxide (N₂O) is a faintly sweet-smelling gas whose recreational misuse has become a worldwide public health issue because it is inexpensive, legal, and easily purchased online. Used as a propellant in canisters of whipped cream, it usually is inhaled from a balloon, with chronic exposure resulting in neurologic toxicity, including neuropathy, ataxia, and psychosis, similar to the subacute combined degeneration syndrome associated with pernicious anemia. Neuropathy may be severe and come on rapidly, mimicking Guillain-Barré syndrome (GBS). N₂O neuropathy (N₂On) usually is axonal, as opposed to the usually demyelinating GBS, but exceptions exist on both sides. How might the two best be differentiated?

Data were collected retrospectively from three neuromuscular disease referral centers in France (Hôpital La Timone, Hôpital Lariboisière, and Hôpital Raymond-Poincaré) on all N₂On patients admitted between June 2020 and June 2022, and compared to all GBS patients hospitalized in the first referral center during the same time period. Inclusion criteria for N₂On included an acute or subacute sensorimotor peripheral neuropathy presentation, confirmed by electrodiagnostic studies, with recurrent recreational N₂O use for at least four weeks prior to symptom onset. GBS patients satisfied Brighton criteria levels 1 or 2, validated by two experts from the referral centers.¹

No patient in either group had any prior history of neuromuscular disease. Data collected encompassed clinical history and examination, blood studies including vitamin B12, homocysteine, and methylmalonic acid, cerebrospinal fluid (CSF) cell count and protein level, spinal magnetic resonance imaging (MRI), and electrodiagnostic studies (nerve conduction studies and needle electromyography). Statistical analysis comprised the Shapiro-Wilk and Mann-Whitney tests, and chi-square and Fisher’s exact test, with significance set at P < 0.05.

Among 58 N₂On patients included in the study, proprioceptive ataxia was the presenting symptom in 88%, with sensory deficits limited to the legs in 34.5%, compared to 14.9% in the GBS group. Motor weakness also was predominantly in the legs, with tibialis anterior weakness accounting for at least half of the Medical Research Council (MRC) sum score reduction in 60.4%, compared to 0.07% in the GBS cohort.

Dysphagia was not seen in any N₂On patient, compared to 36.2% in the GBS group, and diffuse areflexia was present in 17%, compared to 68%, respectively. Dyspnea was present in 3.4% (n = 2) vs. 21.3%, and only one N₂On patient had cranial nerve involvement (facial paresthesiae) compared to 55.3% of GBS patients. Hence, the typical N₂On presentation (56.7%) comprised distal paresthesia (100%), proprioceptive ataxia (88%), predominantly distal leg weakness (60.4%), no arm weakness (74.1%), areflexia only in the legs (74.5%), and no cranial nerve involvement (98.1%), swallowing difficulties, or dyspnea (100%).

The vitamin B12 level was low (< 200 pmol/L) in only three (7%) GBS patients, compared to 82% of N₂On patients, with elevated homocysteine in 40.4% and 88%, respectively. Albuminocytologic dissociation in CSF was seen in 18.2% of N₂On patients. Electrodiagnostic studies typically showed a predominantly sensorimotor axonal neuropathy, mostly involving the legs, with decreased motor and sensory amplitudes, and a neurogenic pattern on needle electromyography, with 62% demonstrating spontaneous activity in leg muscles.

Only 6.9% of N₂On patients met demyelinating neuropathy criteria, compared to 74.5% of GBS patients, with conduction block being the most striking finding, seen in only one (1.7%) of the former, vs. 70.2% of the latter. Serum B12 levels < 200 pmol/L and the absence of conduction block are the two most sensitive biomarkers for rapidly distinguishing N₂On from GBS.

COMMENTARY

N₂O oxidizes the vitamin B12 cobalt ion, disrupting cobalamin function, with resultant impaired myelin sheath synthesis and consequent demyelination of white matter in the brain, spinal cord, and peripheral nerve, resulting in gait ataxia, paresthesiae, autonomic dysfunction, and cognitive impairment.²

Among 20 hospitalized patients with N₂O-related neurological complaints between January 2016 and March 2021 at the West China Hospital of Sichuan University, Chengdu, Sichuan, China, parameters that significantly correlated with disability, as measured by the functional disability rating score, included decreased hemoglobin, decreased red blood cell count, and increased mean corpuscular volume. Such parameters noted on admission correlate with a more severe clinical presentation.³

REFERENCES

1. Ghazanfar H, Qazi R, Ghazanfar A, Iftekhar S. Significance of Brighton criteria in the early diagnosis and management of Guillain-Barré syndrome. Cureus 2020;12:e8318.
2. Edigin E, Ajiboye O, Nathani A. Nitrous oxide-induced B12 deficiency presenting with myeloneuropathy. Cureus 2019;11:e5331.
3. Gao H, Wang R, Zeng Y, et al. Nitrous oxide-induced neurotoxicity: Clinical characteristics and impacts on overall neurological impairments. Front Neurol 2023;14:1132542.