MRI of the brain without contrast showed a large right mastoid effusion, consistent with mastoiditis, for which the patient received treatment with IV vancomycin and cefepime. We use cookies on our website to ensure you get the best experience. Cobalamin (vitamin B 12) is structurally similar to heme and is a cofactor for methionine synthase, a key enzyme in folate metabolism. https://doi.org/10.3390/toxics11010012, Gernez E, Deheul S, Tard C, Joncquel M, Douillard C, Grzych G. In neurons, homocysteine competes for glutamate and aspartate receptors, and exacerbates oxidative stress, formation of hydroxyl radicals, intracellular calcium shifts, and apoptosis via excitotoxicity.7Moreover, homocysteine potentiates -amyloid toxicity in cultured neurons, in transgenic mice, and in humans.8Moderately elevated plasma homocysteine levels correlate inversely with cognitive function and memory deficits, with a doubling of risk for developing Alzheimer disease in patients with total plasma homocysteine greater than 14 m compared with patients with normal levels.9,10While hyperhomocysteinemia can directly damage neurons, it may also contribute to dementia through disruption of cerebrovascular endothelium. The site is secure. Light touch sensation was intact in all extremities, though there was diminished vibratory sensation in the lower extremities. Cranial nerves II-XII were intact. Grzych, G.; Gernez, E.; Deheul, S.; Kim, I. Methylmalonic Acid: Specific Marker of Chronic Nitrous Oxide Abuse? Grzych, G.; Douillard, C.; Lannoy, J.; Joncquel Chevalier Curt, M. Very High Plasma Homocysteine without Malnutrition or Inherited Disorder. The pathogenesis of vitamin B12 deficiency revolves around the livers ability to provide for a significant vitamin B12 depot. 2020 May;20(3):e7-e9. 96, no. Uncommonly suspected causes of B12 deficiency include the abuse of recreational nitrous oxide (NO) given its interference with cobalt oxidation. Bethesda, MD 20894, Web Policies the contents by NLM or the National Institutes of Health. Vollenbrock, S.E. ; resources, G.G. ; funding acquisition, none. deficiency (anaemia, macrocytosis, etc. 27, 2014. The commonly associated presentation is a megaloblastic anemia, with subacute combined degeneration of the spinal cord as the worst-case outcome, characterized by degeneration of the dorsal columns and the lateral columns secondary to demyelination [4]. ; Rabinowitz, J.D. , at least a dozen additional polymorphisms in genes encoding enzymes that participate in single carbon cycles are compelling candidates for companion investigations.12Finally, myriad factors other than single-carbon genotypes and nitrous oxide influence homocysteine metabolism and contribute to total plasma homocysteine levels, including commonly used medications (e.g. Screening the general population for hypovitaminosis B12 levels is not currently recommended; however, a laboratory workup should be considered on a case-by-case basis when a patient presents with symptoms and/or has a history of known high-risk factors. Nitrous oxide irreversibly oxidizes the cobalt atom of vitamin B 12, thereby inhibiting the activity of the cobalamin-dependent enzyme methionine synthase (or. Hakimoglu S, Hanci V, Hakimoglu Y, et al. Unfortunately, there is no screening test for nitrous oxide use, as its short half-life and rapid elimination make it difficult to detect[1]. Kondo, H.; Osborne, M.L. Editors select a small number of articles recently published in the journal that they believe will be particularly There was no associated photophobia or phonophobia. A. Hadzic, K. Glab, K. V. Sanborn, and D. M. Thys, Severe neurologic deficit after nitrous oxide anesthesia, Anesthesiology, vol. and E.G. Recreational Use of Nitrous Oxide: A Growing Concern for Europe, Effects of Melanized Bacteria and Soluble Melanin on the Intestinal Homeostasis and Microbiome In Vivo, Recent Advances and Future Prospects on the Tailing Covering Technology for Oxidation Prevention of Sulfide Tailings, https://creativecommons.org/licenses/by/4.0/. eCollection 2023 Apr. 70, no. J Clin Med. In the current issue of Anesthesiology, Nagele et al. R. J. Valuck and J. M. Ruscin, A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risk of vitamin B12 deficiency in older adults, Journal of Clinical Epidemiology, vol. Nitrous oxide use can also lead to hyperhomocysteinemia by irreversibly oxidizing . Federal government websites often end in .gov or .mil. This enzyme plays a role in processing amino acids, the building blocks of proteins. ; Boveris, A. Oxidative Damage: The Biochemical Mechanism of Cellular Injury and Necrosis in Choline Deficiency. Clinical workup included MRI of the cervical and lumbar spine and lab work. Arrow: dorsal columns are prominently visualized and hyperintense. Nitrous oxide appears to first create a functional deficiency of vitamin B 12, with methionine synthase inhibition occurring from short-term exposure. Complications associated with vitamin B12 deficiency, including agranulocytosis, bone marrow suppression, psychosis, subacute combined degeneration of the spinal cord, myeloneuropathy, polyneuropathy, and peripheral neuropathy have been reported with nitrous oxide use[1-3]. , accumulation of the reaction substrate homocysteine, and deficiency of the reaction product S-adenosyl methionine. A 36-year-old female with a past medical history significant for alcohol abuse, anemia, depression, pyelonephritis, and sepsis presented. 20932108, 2020. doi: 10.1016/j.ejvs.2021.05.041. See this image and copyright information in PMC. Plasma Methionine and Clinical Severity in Nitrous Oxide Consumption. Neurologic, Psychiatric, and Other Medical Manifestations of Nitrous Oxide Abuse: A Systematic Review of the Case Literature. ; data curation G.G. Serum vitamin B12 level was low at 105 (193-986 pg/mL) with a significantly elevated methylmalonic acid of 31000 (87-318 nmol/L) and homocysteine of 38.6 (3.2-10.7 umol/L). Feature papers are submitted upon individual invitation or recommendation by the scientific editors and must receive 9, no. ; Fokkema, T.M. Nitrous oxide is also postulated to cause damage to the neurologic system via direct mechanisms, including oxidative stress and neurotoxicity via antagonism of N-methyl-D-aspartate (NMDA) receptors[1]. Investig. Would you like email updates of new search results? Labs on initial admission were significant for macrocytic anemia with a hemoglobin of 12.0 and an MCV of 104.1. For example, the patient also reported a continued sensation of rolling her ankles bilaterally, altered sensation from the neck down, and an insignificant improvement in gait. Epub 2021 Mar 26. Methionine to Homocysteine ratio according to clinical severity. 68, no. 1978 Dec 9;2(8102):1227-30 and E.G. 1: 12. Discovered in the late 1700s, nitrous oxide, often referred to as whippets or laughing gas, is a colorless gas known for its anesthetic and analgesic use in the medical field[1-2]. Bethesda, MD 20894, Web Policies Suspected nitrous oxide toxicity in Emergency Departments - April 2023 . In seven . The plasma amino acids measurement, including methionine, were performed systematically by liquid chromatography coupled with mass spectrometry. 384389, 2017. FOIA 2021 Dec;28(12):3938-3944. doi: 10.1111/ene.15077. The sharp rise of neurological disorders associated with recreational nitrous oxide use in China: a single-center experience and a brief review of Chinese literature. amino acids; cobalamin; methionine; neurology; nitrous oxide. Administration of IM B12 should be continued past the three-week mark until there is no longer discernible recovery of the patients neurologic condition (plateau in recovery). 3, p. 27, 2016. ; Utley, C.S. If the mother's B12 status is sufficient though, or if the infant is formula fed, the risk for B12 deficiency is low. However, with prolonged exposure, nitrous oxide also appears to convert vitamin B 12 to analogs that possess variable activity and which are more likely to be excreted, eventually leading to an . It is a component of the cycle of reactions involved in regeneration of methionine from homocysteine. Our results also showed that this decrease in methionine is related to a disturbance of homocysteine metabolism. Statistical differences in the clinical and biological parameters were assessed using the MannWhitney U or Student t test for continuous variables. 2020 Feb;267(2):422-429. doi: 10.1007/s00415-019-09600-w. Epub 2019 Oct 26. Plasma Methionine according to plasma Homocysteine. The data presented in this study are available on request from the corresponding author. IT has long been known that nitrous oxide in clinically relevant doses and durations shuts down single carbon pathways by virtue of oxidation of the cobalamin cofactor of methionine synthase, the sole occupant at the crossroads of the methylation, transsulfuration, and folate cycles. Given the bodys significant storage, vitamin B12 deficiency can be provoked acutely due to a severe insult or chronically through multifactorial events involved in vitamin B12 intake, absorption, or metabolic processing [3]. Methionine may be an important first-line therapy in the initial treatment of neuropathy and myeloneuropathy induced by nitrous oxide, and has a hypothetical . 1, pp. One-Carbon Metabolism in Health and Disease. Groups are based on the severity of their clinical symptoms (based on Peripheral Neuropathy Disability (PND) score: level 0: no symptoms; level 1: paresthesia or PND I; level 2: gait disorders or PND II; level 3: thrombosis or combined subacute degeneration of spinal cord or PND III or IV. B. H. R. Wolffenbuttel, H. J. C. M. Wouters, M. R. Heiner-Fokkema, and M. M. van der Klauw, The many faces of cobalamin (vitamin B12) deficiency, Mayo Clinic Proceedings: Innovations, Quality & Outcomes, vol. A Feature , exercise, diet, alcohol and coffee consumption).4,5To preclude spurious claims for genotype:phenotype correlations in teasing out nitrous oxide pharmacogenetics, it will be essential to take into account and, whenever possible, to control these variables. Its effects last only minutes with prompt return to normal function[2-3]. HHS Vulnerability Disclosure, Help Surg. N Engl J Med 2003; 349:4550, Shelnutt KP, Kauwell GPA, Gregory JF, Maneval DR, Qunilivan EP, Theriaque DW, Henderson GN, Bailey B: Methylenetetrahydrofolate reductase 677C->T polymorphism affects DNA methylation in response to controlled folate intake in young women. PMC J. Although vitamin B12 deficiency is usually suspected clinically, a definitive diagnosis can only be made through blood labs measuring serum levels of vitamin B12. Copyright 2020, StatPearls Publishing LLC., Treasure Island, FL, USA, 2020. The lifetime prevalence of abuse ranges from 2% to 15.8% in the younger population, elevated in males who live in rural environments; though these numbers may be lower than the true rate, reported cases of nitrous oxide abuse continue to rise [11]. The patient denied muscle weakness on admission; however, the patient did admit to recreational nitrous oxide use and stated a recent increase in the amount of use. Electrolytes, renal and liver function tests were within normal limits. An official website of the United States government. FOIA Because nitrous oxide is a specific inhibitor for methionine synthase both in vitro (Drummond and Matthews 1994) and in vivo (Deacon et al. Nitrous oxide misuse and vitamin b12 deficiency. 5, pp. There was no dysmetria on finger-to-nose and no ataxia on heel-to-shin. Unauthorized use of these marks is strictly prohibited. One such study conducted by Hakimoglu and colleagues, demonstrated lower postoperative serum vitamin B12 levels in 81 patients who received anesthesia with nitrous oxide, compared to preoperative levels[6]. This regeneration is impaired by vitamin B 12 deficiency, leading to an accumulation of homocysteine and 5-methyl-H 4 folate in the cell. MR of the brain showed no acute abnormalities, but changes were significant for mild cerebral atrophy. A fatal adverse event was reported in a patient with MTHFR deficiency anaesthetised with nitrous oxide (N2O) which is a known inhibitor of methionine synthase Erbe and Salis 2003). https://www.mdpi.com/openaccess. We aimed to study the correlation between the plasma methionine levels and clinical severity observed in N2O users. Nitrous Oxide Abuse Associated with Severe Thromboembolic Complications. Depending on the cause for deficiency, symptoms may take as long as 10 years to present, as is the case with decreased intake, or dramatically within months, which may be seen with severe nitrous NO, as descried in the abovementioned cases [13]. CHU de Lille, Service Hormonologie Mtabolisme Nutrition Oncologie, F-59000 Lille, France, CHU de Lille, Centre dAddictovigilance des Hauts-de-France, Service de Pharmacologie, F-59000 Lille, France, CHU de Lille, Clinique de Neurologie, F-59000 Lille, France, CHU de Lille, Centre de Rfrence des Maladies Hrditaires du Mtabolisme, F-59000 Lille, France. Perspective from The New England Journal of Medicine Severe Methylenetetrahydrofolate Reductase Deficiency, Methionine Synthase, and Nitrous Oxide A Cautionary Tale logo-32 logo-40 The patient noted improvement in her symptoms following initiation of treatment. Accessibility ; Smolcic, V.S. Administration of NO can be performed alone or as an adjunct in a variety of settings ranging from general anesthesia, procedural settings, or for pain control usually through a face mask or secured advanced airway. Burgess, K.; Bennett, C.; Mosnier, H.; Kwatra, N.; Bethel, F.; Jadavji, N.M. Metal canisters filled with nitrous oxide are sold online and at supermarkets and consumers often inhale the canisters contents to achieve intoxication[3]. and E.G. Clearly, trials of nitrous oxide exposure in any clinical setting, including surgery, pediatric sedation, the dental office, the emergency room, and the birthing suite, will be substantially strengthened by inclusion of single-carbon genotyping to assure that patients with shared genotypes are compared with one another. 4, pp. those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). The amino acids measurement was performed as described previously [, A homocysteine measurement was performed systematically. Monitoring Cobalamin Inactivation during Nitrous Oxide Anesthesia by Determination of Homocysteine and Folate in Plasma and Urine. Swart G, Blair C, Lu Z, Yogendran S, Offord J, Sutherland E, Barnes S, Palavra N, Cremer P, Bolitho S, Michael Halmagyi G. Eur J Neurol. ; Ossani, G.; Monserrat, A.J. It can result from an impaired homocysteine metabolism resulting from a dietary deficiency of folic acid, vitamin B6, and vitamin B12 or as a result of genetic predispositions due to impaired gene function involved in the methionine and homocysteine metabolism. Visit our dedicated information section to learn more about MDPI. Plasma Methionine and Clinical Severity in Nitrous Oxide Consumption. This site needs JavaScript to work properly. permission is required to reuse all or part of the article published by MDPI, including figures and tables. Jones JR, Porcaro S, Jones N, Gill G, Patalinghug E. Cureus. The main limitation of our study is that only a few patients are in the level 3 of clinical severity; indeed, a larger number of patients would have been more appropriate for the interpretation of the results. B12 deficiency can arise symptomatically from an array of varying pathologies including frank deficiency from strict vegan diets. Find support for a specific problem in the support section of our website. Her neck pain was primarily para-cervical and radiated just posterior to her ears bilaterally. Bethesda, MD 20894, Web Policies Neurologic, psychiatric, and other medical manifestations of nitrous oxide abuse: a systematic review of the case literature. Ermens, A.A.M. (a) Sagittal cut T2-weighed imaging. Levy, J.; Rodriguez-Guant, R.-M.; Oussalah, A.; Jeannesson, E.; Wahl, D.; Ziuly, S.; Guant, J.-L. Cardiovascular Manifestations of Intermediate and Major Hyperhomocysteinemia Due to Vitamin B12 and Folate Deficiency and/or Inherited Disorders of One-Carbon Metabolism: A 3.5-Year Retrospective Cross-Sectional Study of Consecutive Patients. Though recreational use of nitrous oxide is reported to be safe compared to that of other illicit substances, its use has been associated with several adverse effects, including confusion, hallucinations, and falls[3]. The patients were divided into four groups based of the severity of their clinical symptoms (based on their Peripheral Neuropathy Disability (PND) score). European Monitoring Centre for Drugs and Drug Addiction. Mdecine Interne. -. and transmitted securely. 2, pp. Hence, a vitamin B12 deficiency identified in a patient presenting with neurologic complaints should prompt healthcare providers to question the patient regarding recreational drug use. Groups are based, Plasma Methionine according to plasma Homocysteine. The authors declare no conflict of interest. R. C. Langan and A. J. Goodbred, Vitamin B12 deficiency: recognition and management, American Family Physician, vol. Careers. HHS Vulnerability Disclosure, Help 4, pp. interesting to readers, or important in the respective research area. First, in the current investigation, only a single concentration and two durations of nitrous oxide exposure are described. The effect of nitrous oxide on vitamin B12 levels has been demonstrated in studies. Conversely, if none are present, three times per week for two weeks of intramuscular injections of cyanocobalamin is the recommend course of treatment. The accumulation of 5-methyl-H 4 folate occurs at . Low levels of B12 were also noted. Lancet 2007; 369:187682, Fredriksen A, Meyer K, Ueland PM, Vollset SE, Grotmol T, Schneede J: Large-scale population-base metabolic phenotyping of thirteen genetic polymorphisms related to one-carbon metabolism. Lessons of the month: Nitrous oxide-induced functional vitamin B. Subacute combined degeneration caused by nitrous oxide intoxication: case reports. Intrinsic factor antibody was positive, but anti-parietal cell antibody was negative. ; Lindemans, J.; Ueland, P.M.; Abels, J. 8, p. 2326, 2020. positive feedback from the reviewers. 4, pp. This offers further support for the biochemical hypothesis of methionine synthetase inhibition by nitrous oxide and reproduces in man previously reported animal studies with methionine. Initial clinical presentation can be diverse but generally aligns with one of the following organ systems: hematologic, neuropsychiatric, cutaneous, or gastrointestinal [13]. In regard to this episode, he reported symptoms began 1 week prior to admission while inhaling nitrous oxide. 1981;67:12701283. Pernicious azotaemia? , restenosis), particularly in patients with coexisting cardiovascular disease, acquired folate or cobalamin deficiencies, and MTHFR mutations.6, Hyperhomocysteinemia is also an independent risk factor for neurodegenerative diseases and dementia. Hence, the inhibition of methionine synthase, which leads to a plasma methionine decrease, seems to play a role in the neurological severity during nitrous oxide intoxication, but it is probably not the only factor involved in the occurrence of these disorders. Winstock AR, Ferris JA. ; Allen, R.H. Nitrous Oxide Has Multiple Deleterious Effects on Cobalamin Metabolism and Causes Decreases in Activities of Both Mammalian Cobalamin-Dependent Enzymes in Rats. and E.G. Uncommonly suspected causes of B12 deficiency include the abuse of recreational nitrous oxide (NO) given its interference with cobalt oxidation. J. W. Miller, Proton pump inhibitors, H2-receptor antagonists, metformin, and vitamin B-12 deficiency: clinical implications, Advances in Nutrition, vol. ; visualization, G.G. The patients were divided into 4 groups based on the severity of their clinical symptoms (based on Peripheral Neuropathy Disability (PND score)): level 0: no symptoms, level 1: patients with distal sensory disorders without gait disorders, level 2: patients with walking disorders, but they could walk without help, and level 3: patients with walking disorders who needed help or bedridden patients. Superimposition of an acquired lesion in methionine synthase on inborn lesions in 5,10 methylene tetrahydrofolate reductase leads to conjoined biochemical alterations, i.e. Indeed, the homocysteine/methionine ratio also correlates with clinical severity, which is consistent with a remethylation disorder and a disruption of one-carbon metabolism [, However, the decrease in plasma methionine cannot be imputed as the only mechanism involved in the pathophysiology of the neurological disorders in nitrous oxide consumption. Additionally, MCH was 36.8, MCHC was 32.6, and RDW was 73.2. Gernez, E.; Deheul, S.; Tard, C.; Joncquel, M.; Douillard, C.; Grzych, G. J Nutr Biochem 2004; 15:55460, Hermann W, Herrmann M, Obeid R: Hyperhomocysteinemia: A critical review of old and new concepts. Following appropriate treatment with oral as well as monthly B12 IM injections in addition to folic acid supplementation for six months, the patients neurogenic bladder was resolved. 2019 Apr 23;8(4):551. doi: 10.3390/jcm8040551. With the growing popularity of recreational nitrous oxide use, it is imperative that proper screening for its use is implemented and prompt treatment is initiated, as response to treatment has been associated with the duration and severity of symptoms prior to initiation of treatment[3]. All content published within Cureus is intended only for educational, research and reference purposes. Federal government websites often end in .gov or .mil. 511s518s, 2018. The aim is to provide a snapshot of some of the Toxics. 2011 Jun;20(2):129-37. MRI results showed mild degenerative disease in the thoracic spine. "Plasma Methionine and Clinical Severity in Nitrous Oxide Consumption" Toxics 11, no. Garakani A., Jaffe R.J., Savla D., Welch A.K., Protin C.A., Bryson E.O., McDowell D.M. Reduced levels of methionine prevent methylation of myelin proteins resulting in central and peripheral nervous system demyelination. most exciting work published in the various research areas of the journal. Unfortunately, the patients condition did not improve during hospitalization, and she presented to the ED a week later with primary complaints of knee pain associated with right lower quadrant abdominal pain that radiates to back and worse with movement as well as saddle anesthesia. The .gov means its official. Classic MRI findings associated with nitrous oxide-induced vitamin B12 deficiency include T2 hyperintensity in the posterior columns, usually over several vertebral segments, with or without involvement of the lateral corticospinal tracts. This site needs JavaScript to work properly. There is a significant inverse correlation between plasma methionine and homocysteine (Spearman coefficient: -0.57; p-value < 10-9), which confirms the action of nitrous oxide on the methionine synthase. Second, when the final sample was collected at the end of surgery, homocysteine was on its way up in patients with all genotypes. CSF cytology was negative for malignant cells. Groups are based on the severity of their clinical symptoms (based on Peripheral Neuropathy Disability (PND) score: level 0: no symptoms; level 1: paresthesia or PND I; level 2: gait disorders or PND II; level 3: thrombosis or combined subacute degeneration of spinal cord or PND III or IV. Eur. 46, no. Epub 2021 Nov 13. A decrease in plasma methionine cannot be imputed as the only mechanism involved in the pathophysiology of the neurological disorders in . Deficiency can occur through a variety of means including poor intake, pancreatic disease, medication, problems of absorption, genetic disease, and chemical inactivation from compounds such as nitrous oxide [58]. Copyright 2021 Donald Mario Robert Harker et al. Serum syphilis antibody was nonreactive. However, a few days following admission, the patient admitted to using nitrous oxide recreationally for over two years. A decrease in plasma methionine cannot be imputed as the only mechanism involved in the pathophysiology of the neurological disorders in nitrous oxide consumption. Clin Med (Lond). 30, no. 2020, Article ID 7468506, 11 pages, 2020. K. K. Patel, J. C. Mejia Munne, V. R. N. Gunness et al., Subacute combined degeneration of the spinal cord following nitrous oxide anesthesia: a systematic review of cases, Clinical Neurology and Neurosurgery, vol. A second protein, methionine synthase reductase, acts in conjunction with methionine synthase to catalyze the reductive methylation of cob (II)alamin to MeCbl, using S-adenosylmethionine as a methyl group donor. and E.G. Additionally, the elderly are at an increased risk as are patients prescribed certain medications. CSF angiotensin converting enzyme was within normal limits and demyelination profile was negative with no oligoclonal bands detected. 42, no. Patients may present with low vitamin B12 levels, as well as elevated homocysteine and methylmalonic acid levels. European Monitoring Centre for Drugs and Drug Addiction . The human body retains an incredible capacity for hepatic vitamin B12 storage allowing for 5 to 10 years of insufficient intake prior to the appearance of symptomatic deficiency [15]. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Global Burden Related to Nitrous Oxide Exposure in Medical and Recreational Settings: A Systematic Review and Individual Patient Data Meta-Analysis. Clipboard, Search History, and several other advanced features are temporarily unavailable. Cobalamin, also known as vitamin B12, is an essential and natural water-soluble vitamin necessary in a variety of homeostatic functions [1]. Findings from a survey conducted by Winstock and Ferris completed by over 16,000 recreational nitrous oxide users suggest that neurologic symptoms may be dose dependent with a 3.5% increase in reports of paresthesia with every 10% increase in nitrous oxide dose used[3]. 1994 May;80(5):1046-56. doi: 10.1097/00000542-199405000-00014. -, Neurology. https://doi.org/10.3390/toxics11010012, Subscribe to receive issue release notifications and newsletters from MDPI journals, You can make submissions to other journals. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. M. Wakeman and D. T. Archer, Metformin and micronutrient status in type 2 diabetes: does polypharmacy involving acid-suppressing medications affect vitamin B12 levels? Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, vol. Vitamin b12 deficiency-induced neuropathy secondary to prolonged recreational use of nitrous oxide. A comprehensive list of signs and symptoms associated with vitamin B12 deficiency organized by the organ system. As a library, NLM provides access to scientific literature. 2016;25:358369. It is also important to screen those with an underlying susceptibility to vitamin B12 deficiency for nitrous oxide use, as the clinical manifestations of vitamin B12 deficiency have been noted not only in long-term nitrous oxide users, but also after a single exposure in those with susceptibility to vitamin B12 deficiency[2]. 2023; 11(1):12. Nitrous oxide (NO) is a commonly used inhaled anesthetic which provides an acute state of euphoria, depersonalization, derealization, anxiolytic effects, and anesthesia, regularly described by laypersons as laughing gas and whippets'' or hippy crack in the recreational community [9]. "Plasma Methionine and Clinical Severity in Nitrous Oxide Consumption" Toxics 11, no. With the multitude of cellular disruptions associated with hyperhomocysteinemia in mind, several provisos are warranted in interpreting the data reported by Nagele et al. 4 Abuse of nitrous oxide is a recognised cause of myelopathy, typically presenting as a myeloneuropathy indistinguishable from vitamin B 12 deficiency with a predilection for posterior column involvement. Epub 2021 Sep 6. Br J Anaesth. 145150, 2015. Anesthesiology 2008; 109:3643, Selzer RR, Rosenblatt DS, Laxova R, Hogan K: Adverse effect of nitrous oxide in a child with 5,10 methylenetetrahydrofolate reductase deficiency. Hum Mutat 2007; 28:85665, Romerio SC, Linder L, Nyfeler J, Wenk M, Litynsky P, Asmis R, Haefli WE: Acute hyperhomocysteinemia decreases NO bioavailability in healthy adults. This situation also may occur in patients with an unrecognized cobalamin deficiency (vegans, pernicious anemia, hereditary disorders of cobalamin, and folate metabolism . Importantly, we aim to increase visibility of this malady given that improperly diagnosed neurologic deterioration following NO anesthesia has been shown to become irreversible and may even result in death. eCollection 2023 Apr. 1983 Jul;40(7):416-8. doi: 10.1001/archneur.1983.04050070046009. , antibiotics, antiepileptics, l-dopa, isoniazid), intercurrent disorders (e.g. PMC Given the various neurological manifestations, neurologic conditions as well as other vitamin deficiencies must be ruled out, including vitamin D and folate, as well as hormonal deregulations such a thyroid hormone. This research received no external funding. Groups are based on the severity of, Methionine to Homocysteine ratio according, Methionine to Homocysteine ratio according to clinical severity. V. S. Sharma, R. B. Pilz, G. R. Boss, and D. Magde, Reactions of nitric oxide with vitamin B12and its precursor, cobinamide, Biochemistry, vol. Before doi: 10.1002/brb3.2416. ; Vahl, A.C.; Konings, R.; van Nieuwenhuizen, R.C. Best Pract Res Clin Anaesthesiol. 6, pp. Grzych G, Deheul S, Gernez E, Davion JB, Dobbelaere D, Carton L, Kim I, Guichard JC, Girot M, Humbert L, Bennis A, Joncquel M, Chieux V, Joly A, Nasserdine P, Trillot N, Douillard C, Pigny P, Tard C. J Neurol. She denied any fevers, chills, head trauma, weight loss, or blurred vision. However, why presenting symptoms vary so greatly is not understood, though it may be related to the specificity of the affected pathway. The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. In more common disorders of central interest to anesthesiologists, however, hyperhomocysteinemia rather than hypomethylation may be the dominant lesion. Regarding treatment of hypovitaminosis B12, those patients suffering from neurological symptoms must be differentiated from those which are not, as this changes the treatment strategy. Anesthesiology 2008; 109:56 doi: https://doi.org/10.1097/ALN.0b013e31817be99e. concern anesthesiologists contemplating nitrous oxide use? In view of the double-hit mechanism proposed by Selzer et al. Fatalities associated with nitrous oxide use have been attributed to accidental asphyxiation due to oxygen displacement, often resulting in arrhythmias and seizures[3]. S-Adenosyl methionine is the direct methyl donor in more than 100 metabolic steps, including methylation of DNA, RNA, proteins, phospholipids, myelin, polysaccharides, choline, and neurotransmitters. 94, no. Given that the active form of vitamin B12 contains cobalt in its reduced form (Co+) and given that NO promotes the irreversible oxidation of Co+ to the Co++ and the Co forms, chemically, NO abuse renders vitamin B12 inactive [12]. doi: 10.7861/clinmed.2020-0072. Keywords: In turn, knowing in advance who can breathe nitrous oxide without fear of clinically relevant hyperhomocysteinemia may help to sustain its safe use for a second century and a half, and beyond. In addition, he started suffering from a similar episode around 10 years ago. 863866, 1995. Nitrous oxide inactivates methionine synthase by oxidizing the cobalt in vitamin B . Nitrous oxide myelopathy with functional vitamin b12 deficiency. sharing sensitive information, make sure youre on a federal Neurologic symptoms associated with nitrous oxide use have been attributed to vitamin B12 deficiency. 2022;43:197198. The MTR gene provides instructions for making an enzyme called methionine synthase. Polymorphonuclear cells were elevated at 75%, however, there was no evidence of an infectious process with negative CSF acid-fast bacilli culture, bacterial culture, CSF venereal disease research laboratory (VDRL) test, viral meningitis/encephalitis panel, cryptococcal antigen, Herpes Simplex Virus 1, 2 testing via CSF polymerase chain reaction (PCR), and Varicella zoster and Tropheryma whipplei CSF PCR. Thus, demyelination related to methionine deficiency could be responsible for the neurological disorders associated with N2O consumption, including the combined sclerosis of the spinal cord. ; Refsum, H.; Rupreht, J.; Spijkers, L.J.M. 2023 Apr;270(4):2237-2245. doi: 10.1007/s00415-023-11570-z. Nitrous oxide during labour should also be considered when interpreting increased tHcy in NBS. 1978), nitrous oxide-exposed animals are often used as models of B-12-deficiency due to methionine synthase dysfunction. This research received no external funding. Oussalah A, Julien M, Levy J, Hajjar O, Franczak C, Stephan C, Laugel E, Wandzel M, Filhine-Tresarrieu P, Green R, Guant JL. Laboratory studies revealed a normal complete blood count with a hemoglobin of 14.6 (12.3-15.3 g/dL) and mean corpuscular volume (MCV) of 93.8 (80-100 fL). J. Hinkel, J. Schmitt, M. Wurm et al., Elevated plasma vitamin B12 in patients with hepatic glycogen storage diseases, Journal of Clinical Medicine, vol. Therapy was initiated with cyanocobalamin 1000 mcg IV daily, which was later transitioned to oral cyanocobalamin 1000 mcg daily. Decreasing plasma homocysteine reduces the risk of stroke by 20%, a decrement greater than that observed after therapy for hyperhomocysteinemia in cardiovascular diseases.11. , accumulation of the reaction substrate homocysteine, and deficiency of the reaction product S -adenosyl methionine. National Library of Medicine Methionine synthase expression is induced by vitamin B 12. As the authors note, the detrimental effects of homocysteine probably extend well into the postoperative time frame. The buildup of MMA is >95% sensitive for hypovitaminosis B12 representing a low substrate availability in methionine synthase's ability to regenerate methionine and tetrahydrofolate by reacting . 1 Neurotox Res 2003; 5:23743, Elias MF, Robbins MA, Budge MM, Elias PK, Dore GA, Brennan SL, Johnston C, Nagy Z: Homocysteine and cognitive performance: Modification by the ApoE genotype. 2023 Apr 17;15(4):e37696. ; project administration, G.G. ; McDowell, D.M. Methionine may be an important first-line therapy in the initial treatment of neuropathy and myeloneuropathy induced by nitrous oxide, and has a hypothetical role in the treatment of subacute combined degeneration of the cord. Per the 2019 Global Drug Survey, nitrous oxide was among the top 10 drugs used over the previous 12 months, with the exclusion of alcohol and tobacco[4]. A. Garakani, R. J. Jaffe, D. Savla et al., Neurologic, psychiatric, and other medical manifestations of nitrous oxide abuse: a systematic review of the case literature, The American Journal on Addictions, vol. Ir J Med Sci. Lumbar puncture was performed with normal cerebrospinal fluid (CSF) studies, including white blood cell count, glucose, protein, and opening pressure. The site is secure. and transmitted securely. -, Lancet. FASEB J 2007; 21:170713, Jara-Prado A, Ortega-Vazquez A, Martinez-Ruano L, Rios C, Santamaria A: Homocysteine-induced brain lipid peroxidation: Effects of NMDA receptor blockade, antioxidant treatment, and nitric oxide synthase inhibition. -, Lancet. and E.G. Li Y, Dong J, Xu R, Feng F, Kan W, Ding H, Wang X, Chen Y, Wang X, Zhu S, Dong R. Brain Behav. khogan@facstaff.wisc.edu, Kirk Hogan; Pharmacogenetics of Nitrous Oxide: Standing at the Crossroads. 2021 Jun;39(3):975-985. doi: 10.1007/s12640-021-00352-y. Unable to load your collection due to an error, Unable to load your delegates due to an error. official website and that any information you provide is encrypted No pronator drift, tremors, or abnormal movements noted. ; writingreview and editing, G.G. L. Stockton, C. Simonsen, and S. Seago, Nitrous oxide-induced vitamin B12 deficiency, Baylor University Medical Center Proceedings, vol. All articles published by MDPI are made immediately available worldwide under an open access license. In addition, there are few therapeutic indications for the use of methionine. E. C. Rush, P. Katre, and C. S. Yajnik, Vitamin B12: one carbon metabolism, fetal growth and programming for chronic disease, European Journal of Clinical Nutrition, vol. MeSH Toxics 2023, 11, 12. , 1230 m) most frequently arises from vitamin deficiency, renal insufficiency, and, as here, MTHFR mutations. Accessibility There is a significant inverse correlation between plasma methionine and homocysteine (Spearman coefficient: 0.57; p-value < 109), which confirms the action of nitrous oxide on the methionine synthase. doi: 10.1111/ajad.12372. L. Hannibal, V. Lysne, A.-L Bjrke-Monsen et al., Biomarkers and algorithms for the diagnosis of vitamin B12 deficiency, Frontiers in Molecular Biosciences, vol. Recreational use of nitrous oxide is rising, as are reports of its adverse effects, including neurologic complaints secondary to an evoked vitamin B12 deficiency. nitrous oxide, vitamin b12, vitamin b12 deficiency. Filee, R.; Schoos, R.; Boemer, F. Evaluation of Physiological Amino Acids Profiling by Tandem Mass Spectrometry. The site is secure. Increasing prevalence of recreational nitrous oxide use has been accompanied by growing recognition of its adverse effects including neurologic symptoms, which are reported by up to 4% of users[5]. Accessibility 8, 9 It oxidises the methionine synthase bound cob(I)alamin to cob(II) . EMCDDA; Lisbon, Portugal: 2022. The patient reported difficulty with ambulation, primarily imbalance associated with numbness. 7- 12 The specific depiction of the . Clipboard, Search History, and several other advanced features are temporarily unavailable. 4, pp. Cessation of nitrous oxide use, along with vitamin B12 supplementation, can result in improvement and, in some cases, complete resolution of symptoms. Associated labs include serum levels of methylmalonic acid (MMA) level and folate (1, 2). Jones JR, Porcaro S, Jones N, Gill G, Patalinghug E. Cureus. 163168, 2018. The https:// ensures that you are connecting to the Informed Consent and Ethics Committee Approval in Laboratory Medicine. Go to: Case presentation 8600 Rockville Pike -, Mayo Clin Proc. and E.G. Urine drug screen was positive for cannabinoids. Due to its bacteriostatic effect, it is used in the food industry as a foaming agent and spray propellant in aerosol canisters, such as those containing whipped cream[1-3]. HHS Vulnerability Disclosure, Help Received 2020 May 29; Accepted 2020 Jul 9. Nitrous Oxide Abuse Associated with Severe Thromboembolic Complications. The .gov means its official. Most patients present in the first few months of life with megaloblastic anemia and developmental delay. P. H. Golding, Holotranscobalamin (HoloTC, Active-B12) and Herberts model for the development of vitamin B12 deficiency: a review and alternative hypothesis, Springerplus, vol. official website and that any information you provide is encrypted Monitoring Editor: Alexander Muacevic and John R Adler. 1981 Aug 15;2(8242):334-7 Careers. 3, no. As a consequence, other pathophysiological mechanisms probably need to be identified in order to find potential therapeutic targets. For more information, please refer to sharing sensitive information, make sure youre on a federal . 30, no. Additional factors, such as oxidative stress [, In addition, there are few therapeutic indications for the use methionine. The authors have declared that no competing interests exist. -, Vollenbrock S.E., Fokkema T.M., Leijdekkers V.J., Vahl A.C., Konings R., van Nieuwenhuizen R.C. Specifically, methionine synthase carries out a chemical reaction that converts the amino acid homocysteine to another amino acid called methionine. ; Protin, C.A. Comparison of biomarker for diagnosis of nitrous oxide abuse: challenge of cobalamin metabolic parameters, a retrospective study. During the workup of hypovitaminosis B12, certain pathologies must be excluded. Please let us know what you think of our products and services. In order to be human-readable, please install an RSS reader. Neurotoxicity is secondary to the selective inhibition of vitamin B 12 (hydroxocobalamin), which serves as a cofactor for methionine synthase, . Before . Myeloneuropathy and macrocytosis associated with nitrous oxide abuse. The approach to treatment should be based on the patients individual presentation and underlying cause [13]. 229245, 1991. National Library of Medicine ; Abrams, R.S. Christensen B, Guttormsen AB, Schneede J, Riedel B, Refsum H, Svardal A, Ueland PM. Additionally, MCH was 34.9, MCHC was 33.5, and RDW was 82.3. Internal Medicine, Sarasota Memorial Hospital, Florida State University College of Medicine, Sarasota, USA. -, Grzych G., Gernez E., Deheul S., Kim I. Methylmalonic Acid: Specific Marker of Chronic Nitrous Oxide Abuse? Editors Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Third, Nagele et al. Neurosci Lett 2008; 430:649, Doherty GH: Homocysteine: More than just a matter of life and death. Author to whom correspondence should be addressed. Functional methionine synthase deficiency due to the cblE and cblG mutations is characterized by homocystinuria and defective biosynthesis of methionine. For example, the diverse array of symptoms related to hypovitaminosis B12 included nonspecific findings such as fatigue, depression, erectile dysfunction, paresthesia of the extremities, and muscle cramps, as well as cognitive disturbance [1]. In humans it is encoded by the MTR gene (5-methyltetrahydrofolate-homocysteine methyltransferase). Xiang Y, Li L, Ma X, Li S, Xue Y, Yan P, Chen M, Wu J. Neurotox Res. 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Around 10 years ago or Student t test for continuous variables the Institutes! Nervous system demyelination all extremities, though it may be the dominant lesion Rupreht, J. Ueland. Prior to admission while inhaling nitrous oxide 1 week prior to admission while inhaling oxide! The workup of hypovitaminosis B12, certain pathologies must be excluded in addition, there are few therapeutic indications the... Was intact in all extremities, though it may be related to the Informed Consent and Ethics Committee in... Any information you provide is encrypted no pronator drift, tremors, or abnormal movements.! And that any information you provide is encrypted no pronator drift, tremors, or important in methionine synthase deficiency nitrous oxide first months... The contents by NLM or the National Institutes of Health and Human Services ( )! The neurological disorders in S.E., Fokkema T.M., Leijdekkers V.J., Vahl A.C. Konings... 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