Nitrous Oxide-induced Myeloneuropathy Due to Recreational Abuse.

BACKGROUND: The recreational use of nitrous oxide (N2O) has increased in recent years with a noticeable surge in the incidence of nitrous oxide-related myeloneuropathy. OBJECTIVES: To raise awareness of increasing myeloneuropathy due to recreational nitrous oxide misuse in Israel. METHODS: We conducted a case series documenting the clinical and investigative features of eight patients presenting with nitrous oxide-induced myeloneuropathy who were admitted to our departments. RESULTS: Paresthesia was the chief complaint in all patients, with sensory gait ataxia being a common feature, which was often accompanied by Romberg's sign and mild lower limb weakness. Vitamin B12 levels were below the normal range in seven patients, accompanied by elevated homocysteine and methylmalonic acid levels. Magnetic resonance imaging scans revealed hyperintense signals in the dorsal columns of the cervical spine. All patients improved following vitamin B12 injections. CONCLUSIONS: Enhancing awareness, prompting the use of appropriate investigations, and advocating for timely treatment are needed to overcome the risks associated with nitrous oxide misuse.

Vitamin B12 deficiency in diabetic patients treated with metformin: A cross-sectional study.

Metformin is a cornerstone medication in the management of type 2 diabetes. Metformin is safe, effective, and inexpensive; however, it is associated with vitamin B12 deficiency. This study set out to evaluate the rate of vitamin B12 deficiency in Vietnamese patients with type 2 diabetes who were treated with metformin and to investigate factors associated with vitamin B12 deficiency. This is a cross-sectional study that was conducted in Vinmec Central Park Hospital from February to June 2023. The clinical and paraclinical characteristics of the participants were recorded, and the levels of vitamin B12 and folate were measured. The rate of vitamin B12 deficiency in patients treated with metformin was found to be 18.6%. Further, the duration of diabetes, duration of metformin use, metformin dose, and hemoglobin levels were statistically associated with vitamin B12 deficiency with OR (95% CI) = 1.12 (1.03-1.19), 1.01 (1.00-1.02), 1.002 (1.001-1.002), 0.74 (0.55-0.99), respectively. After adjusting for covariates, a metformin dose greater than the median dose remained the only parameter associated with vitamin B12 deficiency, with OR (95% CI) = 4.10 (1.62-10.36). Moreover, when combining both long-term use of metformin and a metformin dose greater than the median dose, the OR increased to 5.25 (95% CI: 2.11-13.15). These results demonstrate that vitamin B12 deficiency in patients treated with metformin is quite prevalent in Vietnam and that those with long-term use of metformin (48 months or more) and high metformin dose (1000 mg/day or more) are at high risk of experiencing this adverse effect and so require screening.

Vitamin B12 status and hyperhomocysteinemia in patients with Rheumatoid arthritis treated with methotrexate and folic acid.

BACKGROUND: Rheumatoid arthritis (RA) is an inflammatory arthritis in which the immune system targets synovial joints. Methotrexate serves as the mainstay of treatment for RA due to its efficacy. However, patients treated with methotrexate are uniquely at risk for vitamin B12 deficiency and hyperhomocysteinemia due to coincident disease risk factors and the fact that methotrexate use is associated with malabsorption. The objective of this study was to assess for vitamin B12 deficiency among patients with RA treated with methotrexate and folic acid. METHODS: This cross-sectional study included 50 patients with RA treated with methotrexate and folic acid and 49 patients with RA treated with other therapies. Patients were matched by age, sex, race, renal function, and disease activity. We compared plasma vitamin B12, methylmalonic acid, and homocysteine levels between these two groups utilizing quantitative and categorical analyses. RESULTS: Thirty-seven (74%) RA patients on methotrexate and folic acid had elevated plasma homocysteine levels compared with only 27 (55%) RA patients receiving other therapies (P < 0.05). The proportion of patients with low vitamin B12 and high methylmalonic acid levels did not differ between the two groups. CONCLUSIONS: Our data show high plasma homocysteine levels among RA patients treated with methotrexate and folic acid. While plasma vitamin B12 levels were similar between the two groups, high plasma homocysteine is also a sensitive marker of vitamin B12 deficiency. Additional studies should evaluate for the presence of clinical features of vitamin B12 deficiency and hyperhomocysteinemia among RA patients treated with methotrexate and folic acid.

Nitrous oxide induced subacute combined degeneration of the spine cord: A case report.

RATIONALE: In recent years, recreational use of inhaled nitrous oxide (N2O) is on the increase among young people, accompanied by a corresponding rise in reports about its toxicity. Subacute combined degeneration of the spine cord (SCD) is the typical clinical picture of the nervous system disorder caused by N2O intoxication, as a result of metabolic disturbance of vitamin B12. PATIENT CONCERNS, DIAGNOSES, INTERVENTIONS AND OUTCOMES: We report a 28-year-old female of SCD due to prolonged use of N2O, presented with paresthesia and unsteady in walking progressing within 1 month. Symptoms gradually improved with the treatment of intramuscular injections of hydroxocobalamin combined with N2O abstinence, and the patient recovered completely with normal neurological examination after 4 months of follow-up. LESSONS: Clinicians should be aware of the clinical features and pathogenesis of SCD caused by N2O intoxication in order to lead effective treatment as soon as possible. Recreational N2O use should always be considered as an etiology when dealing with patients presented with myelopathy and/or neuropathy suspected of vitamin B12 deficiency.

Subacute Combined Degeneration of the Spinal Cord Induced by Nitrous Oxide Abuse: A Rare Patient Presentation to a Spine Surgery Clinic: Illustrative Case.

Subacute combined degeneration (SCD) of the spinal cord is a disease involving the lateral and posterior columns of the spinal cord that can manifest in patients with vitamin B12 deficiency. Nitrous oxide (N2O)-induced SCD of the spinal cord is a result of N2O interfering with the metabolism of vitamin B12 and results in nervous system demyelination. This is an infrequent complication of N2O anesthesia; however, cases are rising with recreational N2O use. This case report describes a patient with SCD of the spinal cord induced by recreational N2O abuse. The patient presented to a spine surgery clinic with a 3-week history of progressive global weakness and paresthesias. After a detailed history and physical examination, the diagnosis was made and supported by various tests and imaging findings. Despite marked neurologic deficits, the patient's symptoms improved markedly with therapy and vitamin B12 supplementation. Spine surgery clinicians may be confronted with these cases and should be aware of this atypical presentation of SCD. As in our case, patients may present with neurologic deficits of unclear etiology. Neurologic dysfunction may be irreversible; therefore, accurate diagnosis, medical treatment, and complete neurologic evaluation are of the utmost importance to prevent additional progression.

Not a Laughing Matter: When Nitrous Oxide Causes Functional Vitamin B12 Deficiency.

Subacute combined degeneration (SCD) is an acquired neurologic complication from prolonged vitamin B12 deficiency. As a result of dorsal and lateral spinal cord column degeneration, patients present with a range of neurological symptoms, including paresthesias, ataxia, and muscle weakness. Without prompt treatment, irreversible nerve damage occurs. Here we present a young man who developed progressive ascending paresthesias and lower extremity weakness after escalated nitrous oxide use. This case highlights the importance of considering SCD from nitrous oxide toxicity when patients present with progressive ataxia, paresthesia, and lower extremity weakness.

Neurological complications of excessive recreational nitrous oxide use: a case series based on a text mining algorithm.

BACKGROUND: The recreational use of nitrous oxide (N2O) has gained popularity over recent years. We present a case series of excessive N2O users with neurological complications. METHODS: In this retrospective three-centre study, we used a text mining algorithm to search for patients who used N2O recreationally and visited a neurologist. RESULTS: We identified 251 patients. The median duration of N2O use was 11 months (interquartile range [IQR], 3-24) and the median amount of N2O used per occasion 1.6 kg (IQR 0.5-4.0). Clinically, polyneuropathy (78%), myelopathy (41%), and encephalopathy (14%) were the most common diagnoses. An absolute vitamin B12 deficiency of < 150 pmol/L was found in 40% of cases. In 90%, at least one indicator of functional vitamin B12 status (vitamin B12, homocysteine, or methylmalonic acid) was abnormal. MRI showed signs of myelopathy in 30/55 (55%) of cases. In 28/44 (64%) of those who underwent electromyography, evidence of axonal polyneuropathy was found. Most (83%) patients were treated with vitamin B12 supplementation, and 23% were admitted to the hospital. Only 41% had follow-up for ≥ 30 days, and 79% of those showed partial or complete recovery. CONCLUSIONS: In this case series of excessive N2O users, we describe a high prevalence of polyneuropathy, myelopathy, and encephalopathy. Stepwise testing for serum levels of vitamin B12, homocysteine, and methylmalonic acid may support the clinical diagnosis. Due to low sensitivity, MRI of the spinal cord and electromyography have limited value. Effective treatment should incorporate supplementation of vitamin B12 and strategies to prevent relapses in N2O use.

A case of functional vitamin B12 deficiency after recreational nitrous oxide use.

The recreational use of nitrous oxide as laughing gas becomes a real public health issue among adolescents and young adults. Chronic use is deleterious and can lead to severe neurological disorders. Nitrous oxide inactivates vitamin B12, and the functional defect of vitamin B12 plays a major role in the pathogenesis of nitrous oxide-related neurological disorders. Here we report the case of a 22-year-old woman who came to the hospital after an unexplained loss of consciousness. She exhibited typical features of vitamin B12 or folate deficiency such as macrocytic anemia and hypersegmented neutrophils. However, serum concentrations of folate and vitamin B12 were normal. In contrast, circulating concentrations of total homocysteine and methylmalonic acid were significantly increased. These results clearly indicated a defect in vitamin B12 functions. The reason for this defect was clarified when she revealed that she had been consuming nitrous oxide recreationally for over a year. The present case points out the challenges in diagnosing vitamin B12 deficiency in the context of nitrous oxide abuse due to normal concentrations of total serum vitamin B12 in a significant proportion of cases. The medical community should be aware of how difficult it can be to interpret B12 status in this specific population.

Functional vitamin B12 deficiency is a consistent feature in hospital admissions for neurological disorders due to the use of nitrous oxide.

Introduction: Misuse of inhaled nitrous oxide is a growing concern in France. It is known to alter concentrations of vitamin B12, which is required as a cofactor for methionine synthase and methylmalonyl-CoA mutase activity. Hence, measurement of the concentrations of cobalamin metabolism biomarkers, including vitamin B12, homocysteine, and methylmalonic acid, could assist in the management of patients with a complex clinical presentation or in those who deny the consumption of nitrous oxide.Methods: We retrospectively collected clinical and biological data in patients hospitalized for nitrous oxide use in a university hospital in southern France between January 2020 and October 2022.Results: Thirty-one patients were identified during 34 months; 79% were men with a median age of 23.7 years. Most (97%) presented with peripheral polyneuropathy and/or myelopathy. The median vitamin B12 concentration was 134.6 pmol/L, with 17 of 31 patients having values less than 145 pmol/L (the lower limit of the normal range). The median plasma folate concentration was 20.1 nmol/L, which is within the normal range. The median plasma homocysteine concentration was 87.7 µmol/L (normal range <15 µmol/L), and the median plasma methylmalonic acid concentration was 3.8 µmol/L (normal range <0.5 µmol/L).Conclusion: Nitrous oxide use is an emerging public health problem in France, as shown by the number of patients admitted to our hospital. The presence of a functional vitamin B12 deficiency was a consistent feature that could be helpful in diagnosis in complex cases.

Subacute combined degeneration of the spinal cord in a patient with nitrous oxide use and autoimmune atrophic gastritis.

Nitrous oxide is among the most common drugs used by adolescents and young adults, and its neuropsychiatric sequelae are severe but reversible with timely treatment. The causal mechanism relates to impaired metabolism of vitamin B12, which is necessary for the development and maintenance of the myelin sheath. Individuals most susceptible to neuropsychiatric manifestations are those with a secondary cause of vitamin B12 deficiency, including nutritional deficiency and impaired absorption, or an alternative cause of impaired metaboclism. We describe the case of a man in his thirties who developed subacute combined degeneration of the spinal cord and polyneuropathy in the setting of recreational nitrous oxide use and autoimmune atrophic gastritis. Our case highlights clinical pearls for diagnosis and treatment, differential diagnosis, common concomitant aetiologies and the importance of screening for substance use disorder and psychiatric comorbidities.

Evaluation level of serum vitamin B12 in Iraqi patients with diabetes mellitus type 2, who used the metformin drug as a hypoglycemic agent.

Diabetes mellitus type 2 is characterized by insulin resistance, which can be combined with relatively decrease secretion of insulin hormone in the body. Metformin is usually recommended as a first-line treatment for diabetes mellitus-type 2, as it has a significant role in decrease mortality. This study aims to evaluate the B12 levels in Iraqi patients with type 2 diabetes, who were using the metformin drug in short-, medium- and long-term periods. The study included 202 patients, who were classified into four groups, according to their use of the Metformin drug as a hypoglycemic agent, while the fourth group did not use metformin and was termed as 'the standard group'. The results showed that the levels of vitamin B12 in patients using Metformin drugs in short-, medium- and long-term periods were, (444.4±17.21)pg/ml, (403.0±20.34)pg/ml and (261.7±14.70)pg/ml, respectively, compared to the standard group (469.7±26.37)pg/ml. The conclusion of this study was that a significant reduction was seen in the level of vitamin B12 in patients using the Metformin drug for medium- and long-term periods compared to the standard group, who did not use the Metformin drug.

Effect of Metformin Use on Vitamin B12 Deficiency Over Time (EMBER): A Real-World Evidence Database Study.

OBJECTIVE: To examine the extent to which metformin increases the risk of vitamin B12 deficiency and borderline deficiency over time in participants with type 2 diabetes mellitus (T2DM). METHODS: Using the All of Us database, adults aged ≥18 years with T2DM and a documented history of metformin use were included for the evaluation of B12 deficiency. Those with B12 deficiency before metformin use were excluded. Adjusted logistic regression models were used to evaluate the association between metformin use and long-term metformin use (≥4 years) and the risk of B12 deficiency. We conducted a subgroup analysis comparing differences in borderline B12 deficiency in metformin and non-metformin users. RESULTS: Of 36 740 participants with T2DM, 6221 (16.9%) had documented metformin use. The mean age of metformin users was 65.3 years. B12 deficiency was confirmed in 464 (7.5%) metformin users, and 1919 of 30 519 participants (6.3%) did not use metformin. Metformin users had a 4.7% increased risk of developing B12 deficiency compared with nonmetformin users (P = .44). Each additional year of metformin use was associated with 5% increased likelihood of deficiency (P < .05). Metformin use for ≥4 years resulted in a 41.0% increased odds of B12 deficiency, compared with those who used <4 years of metformin (P < .05). Metformin use increased the odds of borderline B12 deficiency by 27.0% (P < .05). CONCLUSION: Long-term metformin use was associated with an increased risk of B12 deficiency in patients with T2DM, with compounding risk over time.

The effects of daily dose and treatment duration of metformin on the prevalence of vitamin B12 deficiency and peripheral neuropathy in Chinese patients with type 2 diabetes mellitus: A multicenter cross-sectional study.

AIMS: To evaluate the prevalence of vitamin B12 deficiency in Chinese patients with type 2 diabetes mellitus receiving metformin treatment and to investigate the effects of metformin daily dose and treatment duration on the prevalence of vitamin B12 deficiency and peripheral neuropathy (PN). MATERIALS AND METHODS: In this multicenter cross-sectional study, 1027 Chinese patients who had been taking ≥1000 mg/day metformin for ≥1 year were enrolled using proportionate stratified random sampling based on daily dose and treatment duration. Primary measures included the prevalence of vitamin B12 deficiency (<148 pmol/L), borderline B12 deficiency (148 pmol/L-211 pmol/L), and PN. RESULTS: The prevalence of vitamin B12 deficiency, borderline deficiency, and PN were 2.15%, 13.66%, and 11.59%, respectively. Patients receiving ≥1500 mg/day metformin had significantly higher prevalence of borderline vitamin B12 deficiency (16.76% vs. 9.91%, p = .0015) and serum B12 ≤221 pmol/L (19.25% vs. 11.64%, p < .001) than patients receiving <1500 mg/day metformin. No difference was found in prevalence of borderline vitamin B12 deficiency (12.58% vs. 15.49%, p = .1902) and serum B12 ≤221 pmol/L (14.91% vs. 17.32%, p = .3055) between patients receiving metformin for ≥3 and <3 years. Patients with vitamin B12 deficiency had numerically higher PN prevalence (18.18% vs. 11.27%, p = .3192) than patients without it. Multiple logistic analyses revealed that HbA1c and metformin daily dose were associated with the prevalence of borderline B12 deficiency and B12 ≤221 pmol/L. CONCLUSIONS: High daily dosage (≥1500 mg/day) played an important role in metformin-associated vitamin B12 deficiency while not contributing to the risk of PN.

Vitamin B12 deficiency and use of proton pump inhibitors: a systematic review and meta-analysis.

BACKGROUND: Proton pump inhibitors (PPI) may impact the absorption of vitamin B12. We performed a systematic review to ascertain if PPI use increases risk of vitamin B12 deficiency. METHODS: Electronic databases (PubMed, Embase, Scopus) were searched on first of September 2022. We selected studies that compared the frequency of vitamin B12 deficiency in PPI users and non-users. Pooled Odds Ratio (OR) was calculated for the occurrence of vitamin B12 deficiency in PPI users compared to non-users. The risk of bias was assessed using the Newcastle Ottawa scale. RESULTS: Twenty-five studies were included. The pooled OR of vitamin B12 deficiency among PPI users (2852 participants) was higher than non-users (28070 participants) (OR 1.42, 95% CI: 1.16-1.73; I2 = 54%). Overall risk of PPI use among vitamin B12 deficient individuals was higher than those without deficiency (OR 1.49, 1.20-1.85; I2 = 68%). Most studies found no difference between serum vitamin B12 levels among PPI users compared to non-users. CONCLUSION: Although the pooled OR of vitamin B12 deficiency was slightly increased in PPI users, but there was significant heterogeneity, and the pooled OR was too low to imply an association clearly. Better-designed prospective studies in long-term users may clarify the issue. REGISTRATION: This study was not registered on PROSPERO.

Nitrous oxide misuse: a clue not to be missed in young patients with venous thromboembolism.

A 27-year-old man presented with altered mental status and unilateral right lower limb swelling. Brain imaging and cerebrospinal fluid analysis were unremarkable. He reported history of nitrous oxide misuse after he recovered from his delirium. The diagnosis of drug induced psychosis was made. The right lower limb swelling was found to be due to extensive deep vein thrombosis. In another case, a 21-year-old woman presented with headache, vomiting and dipoplia. Brain imaging showed extensive cerebral venous sinus thrombosis. She also misused nitrous oxide. Both cases had low-normal vitamin B12 and elevated methylmalonic acid, consistent with nitrous oxide misuse. The woman was found to have elevated homocysteine because of functional vitamin B12 deficiency. Homocysteine was not measured in the man. Raised homocysteine is associated with increased thrombosis risk. Fourteen cases of nitrous oxide misuse associated arterial and venous thrombosis have been reported. These two cases highlighted the importance of inquiring about recreational drug use in young patients who presented with apparently unprovoked venous thromboembolism.

Nitrous oxide-induced subacute combined degeneration of the cord: diagnosis and treatment.

Recreational use of nitrous oxide (N2O) has increased rapidly in recent years and is now the second most commonly used recreational drug among young people in the UK. There has been a corresponding rise in cases of nitrous oxide-induced subacute combined degeneration of the cord (N2O-SACD), a pattern of myeloneuropathy usually associated with severe vitamin B12 deficiency. This can cause serious and permanent disability in young people but, if recognised early, may be effectively treated. All neurologists should be aware of N2O-SACD and its treatment; however, there are currently no agreed guidelines. Based on our experience in East London, an area of high N2O use, we provide practical advice on its recognition, investigation and treatment.

Comparison of biomarker for diagnosis of nitrous oxide abuse: challenge of cobalamin metabolic parameters, a retrospective study.

BACKGROUND: Recreational use of nitrous oxide (N2O) leads to neurological disorders including combined subacute degeneration of spinal cord, psychological disorders, and thrombosis. Serum or urine N2O assays could not be routinely performed. Hence, it is necessary to investigate other biological markers such as metabolic markers. We aimed here to challenge the three main biological markers used for the diagnosis of nitrous oxide abuse as total vitamin B12, homocysteine, and methylmalonic acid. METHODS: We retrospectively collected clinical and biological data from 52 patients with known, documented chronic N2O abuse and associated clinical signs (peripheral neuropathy disability score or thrombosis event). Sera and plasma total vitamin B12, methylmalonic acid (MMA), and homocysteine were performed to identify the most specific marker of chronic N2O intoxication and related clinical outcomes. RESULTS: Plasma homocysteine was almost consistently increased in case of N2O chronic consumption, whereas MMA increase and total vitamin B12 decrease are not systematically found. Our results showed that none of the markers are correlated with levels of N2O consumptions. However, homocysteine and MMA are correlated with clinical severity, but MMA seems to be a better marker of clinical severity. CONCLUSION: There is no specific marker of nitrous oxide abuse according to levels of consumption, total vitamin B12 decrease could not be used either as consumption or as severity marker. However, we showed that homocysteine is consistently increased and could be used as marker of recent N2O consumption. On the other hand, we showed that MMA could be used as a marker of clinical gravity.

Nitrous oxide abuse leading to extreme homocysteine levels and thrombosis in young adults: a case series.

BACKGROUND: Neurologic complications from recreational use of nitrous oxide (N2O), which are attributed to vitamin B12 deficiency, have been well documented. With increasing dosages and frequency of N2O use, an additional association with thromboembolisms is becoming apparent. OBJECTIVES: To assess thrombotic complications of recreational N2O use. METHODS: All medical charts at the largest hospital in Amsterdam were searched for N2O use and subsequent neurologic and/or thrombotic events. For patients with thrombotic events, we extracted data on the risk factors for arterial and venous thrombosis as well as serum vitamin B12 and homocysteine concentrations. RESULTS: Between January 2015 and May 2021, 326 patients who reported recreational use of N2O were identified; of these, 17 (5%) patients presented with severe thrombotic events associated with N2O (71% men; median age, 26 years [range, 18-53 years]), 5 patients presented with arterial thrombosis (3 with acute coronary syndrome, 1 with femoral artery thrombosis, and 1 with middle cerebral artery thrombus), and 12 patients presented with venous thromboembolisms (10 with pulmonary embolisms, 1 with portal vein thrombosis and 1 with cerebral vein thrombosis). Additionally, homocysteine were concentrations severely increased (median, 125 µmol/L [range, 22-253 µmol/L]; reference, <15 µmol/L). Patients reported use of 400 to 6000 g (ie, 50-750 balloons) of N2O in 1 day. Fifty percent of these patients had experienced neurologic symptoms before the thrombotic event. CONCLUSION: We describe an alarming incidence of serious thrombotic events among young adults after excessive recreational use of N2O, accompanied by extremely high homocysteine concentrations. The upward trend in the recreational use of N2O warrants more awareness of its dangers among both users and medical professionals. Furthermore, these findings could reopen the discussion on possible associations between hyperhomocysteinemia and thrombosis mediated through N2O.

The antidiabetic drug metformin aids bacteria in hijacking vitamin B12 from the environment through RcdA.

Years of use of the antidiabetic drug metformin has long been associated with the risk of vitamin B12 (B12) deficiency in type 2 diabetes (T2D) patients, although the underlying mechanisms are unclear. Accumulating evidence has shown that metformin may exert beneficial effects by altering the metabolism of the gut microbiota, but whether it induces human B12 deficiency via modulation of bacterial activity remains poorly understood. Here, we show that both metformin and the other biguanide drug phenformin markedly elevate the accumulation of B12 in E. coli. By functional and genomic analysis, we demonstrate that both biguanides can significantly increase the expression of B12 transporter genes, and depletions of vital ones, such as tonB, nearly completely abolish the drugs' effect on bacterial B12 accumulation. Via high-throughput screens in E. coli and C. elegans, we reveal that the TetR-type transcription factor RcdA is required for biguanide-mediated promotion of B12 accumulation and the expressions of B12 transporter genes in bacteria. Together, our study unveils that the antidiabetic drug metformin helps bacteria gather B12 from the environment by increasing the expressions of B12 transporter genes in an RcdA-dependent manner, which may theoretically reduce the B12 supply to T2D patients taking the drug over time.