# Reply to letter on What biological markers could be used for diagnosis and monitoring of nitrous oxide abuse

Etienne Fortanier, Edouard Berling, Adrien Zanin, Adrien Le Guillou, Joelle

Micaleff, Guillaume Nicolas, Pierre Lozeron, Shahram Attarian

► To cite this version:

Etienne Fortanier, Edouard Berling, Adrien Zanin, Adrien Le Guillou, Joelle Micaleff, et al.. Reply to letter on What biological markers could be used for diagnosis and monitoring of nitrous oxide abuse. European Journal of Neurology, 2024, 31 (3), 10.1111/ene.16187. hal-04931277

HAL Id: hal-04931277

https://hal.science/hal-04931277v1

Submitted on 14 Feb 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
LETTER TO THE EDITOR

european journal
of neurology

The official journal of the european academy of neurology

Reply to letter on What biological markers could be used for
diagnosis and monitoring of nitrous oxide abuse

Dear Editor,

We would like to thank you for the opportunity to respond to the remarks presented in the letter "What biological markers could be used for diagnosis and monitoring of nitrous oxide abuse?" We would also like to thank Gernez et al. for their interest and contribution to our article [1].

The authors proposed some suggestions about the different bio-
logical biomarkers in nitrous oxide (N₂O) intoxication by highlighting
the relevance of homocysteine and methylmalonic acid (MMA) over
serum vitamin B12 measurement.

The primary objective of our study was to help clinicians to rap-
idly discriminate between N₂O-induced neuropathy (N₂On) and its
main differential diagnosis, namely, Guillain–Barré syndrome [2],
by characterizing the most efficient clinical, biological, and electro-
physiological biomarkers. As mentioned by the authors, the diagno-
sis is mainly based on discriminating clinical features, and we tried
to describe the typical N₂On patient in the first part of the Results
section. However, as detailed in the article, the diagnosis can be
challenging, with equivocal clinical presentations and hidden N₂O
misuse at first interview, requiring the analysis of biological and elec-
trophysiological biomarkers.

With regard to biological biomarkers, vitamin B12 serum level was reduced in only half of our patients, as reported recently in the literature [3]. Nevertheless, the use of a slightly different threshold presented a good sensitivity and specificity to distinguish between the two groups of patients, which was the purpose of our work.

We agree with the authors' observations on the relevance of ho-
mocysteine and MMA in N₂O intoxication. However, as mentioned
in the article, the average time to obtain these results in our three
centers was approximately 7 days, making it difficult to use them as
differential biomarkers in this context.

MMA has been correlated to the clinical severity of N₂O intox-i-
cation in a previous study [4]. In our cohort, there was no correlation
between homocysteine or MMA serum levels and clinical severity.
This may be due to some missing data concerning MMA serum lev-
els, resulting in a lack of statistical power. Larger national cohorts
will undoubtedly enable us to better assess the correlation between
biological and clinical biomarkers in the future.

Finally, we agree with the authors in their recommendation to
perform a combination of biological tests (at least vitamin B9 and

B12, homocysteine, and MMA) as quickly as possible, another issue
being the fairly rapid correction of some markers after vitamin sup-
plementation, which is sometimes carried out in emergency depart-
ments before any blood testing.

AUTHOR CONTRIBUTIONS

**Etienne Fortanier:** Conceptualization; writing – review and editing; writing – original draft. **Edouard Berling:** Writing – review and editing. **Adrien Zanin:** Writing – review and editing. **Adrien Le Guillou:** Writing – review and editing. **Joelle Micaleff:** Writing – review and editing; supervision. **Guillaume Nicolas:** Supervision; writing – review and editing. **Pierre Lozeron:** Supervision; writing – review and editing. **Shahram Attarian:** Supervision; writing – review and editing.

CONFLICT OF INTEREST STATEMENT

None of the authors has any conflict of interest to disclose.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from
the corresponding author upon reasonable request.

Etienne Fortanier<fnref n="1" />

Edouard Berling<sup>2,3</sup>

Adrien Zanin<sup>4,5</sup>

Adrien Le Guillou⁶

Joelle Micaleff<sup>7,8</sup>

Guillaume Nicolas<sup>2,3</sup>

Pierre Lozeron<sup>4,5</sup>

Shahram Attarian<sup>1,9</sup>

<footnote n="1">¹Reference Center for Neuromuscular Diseases and amyotrophic
lateral sclerosis, La Timone University Hospital, Aix-Marseille
University, Marseille, France</footnote>

<footnote n="2">²APHP, Service de Neurologie, Hôpital Raymond Poincaré,
Centre de Référence Nord-Est-Ile-de-France, FHU PHENIX,
Garches, France</footnote>

<footnote n="3">³Université de Versailles Saint-Quentin-en-Yvelines, U1179
INSERM, Paris-Saclay, France</footnote>

<footnote n="4">⁴Service de Physiologie Clinique-Explorations Fonctionnelles,
DMU DREAM, APHP, Hôpital Lariboisière, Paris, France</footnote>
⁵Laboratory for Vascular Translational Science, INSERM, U1148,
Université de Paris, Paris, France

⁶Department of Epidemiology, Emory University, Atlanta,
Georgia, USA

⁷Marseille University Hospital, Clinical Pharmacology and
Pharmacosurveillance, Regional Addictovigilance Center of
Marseille, Marseille, France

⁸INSERM UMR1106, Aix-Marseille University, Marseille, France

⁹INSERM, GMGF, Aix-Marseille University, Marseille, France

**Correspondence**

Etienne Fortanier, Reference Center for Neuromuscular
Diseases and amyotrophic lateral sclerosis,, La Timone
University Hospital, Aix-Marseille University, 264 rue Saint
Pierre, 13385 Marseille, France.

Email: etienne.fortanier@ap-hm.fr

REFERENCES

1. 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.

2. Qin X, Kang L, Liu X, et al. Acute nitrous oxide-induced neuropathy mimicking Guillain-Barré syndrome. *J Peripher Nerv Syst.* 2022;27(3):189-196. doi:10.1111/jns.12503

3. Ruijter BJ, de Mooij MJ, Bruijnes JE, van Oosterhout WPJ, Kwa VIH. Neurological complications of excessive recreational nitrous oxide use: a case series based on a text mining algorithm. *J Neurol.* 2023. doi:10.1007/s00415-023-12061-x. Epub ahead of print.

4. Grzych G, Deheul S, Gernez E, et al. Comparison of biomarker for diagnosis of nitrous oxide abuse: challenge of cobalamin metabolic parameters, a retrospective study. *J Neurol.* 2023;270(4):2237-2245.