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.

Metformin-Induced Vitamin B12 Deficiency among Type 2 Diabetes Mellitus' Patients: A Systematic Review.

BACKGROUND: Type 2 diabetes mellitus is one of the most globally common chronic diseases. Metformin is the most popular prescribed medication for the treatment of diabetes. Studies suggest that metformin is associated with vitamin B12 deficiency, which may impart adverse health complications. OBJECTIVE: This review screens the literature to clarify the effect of metformin on vitamin B12 deficiency among type 2 diabetes mellitus patients. METHODS: Google Scholar, PubMed, Research Gate, and Semantic Scholar, were searched for the association between metformin intake and vitamin B12 deficiency in type 2 diabetes mellitus patients using relevant keywords and their combinations. Selected studies were those conducted on patients taking metformin with no vitamin B12 supplement. Nineteen studies (fifteen observational studies and four randomized controlled trials) met the inclusion criteria. These studies were assessed for design, setting, study population, and overall quality. RESULTS: There is a positive correlation between metformin intake and vitamin B12 deficiency. This has been accompanied by increased homocysteine and decreased folate levels. Despite the refuting of the findings, most studies showed that higher doses of metformin were strongly associated with lower vitamin B12 levels, while the duration of treatment was not. CONCLUSION: Regular measurement of vitamin B12 levels during long-term metformin treatment is recommended. A clear policy should be in place to illuminate the importance of this screening in preventing vitamin B12 deficiency complications. Taking therapeutic supplements or injections of vitamin B12 along with a vitamin B12-rich diet may decrease the incidence of its deficiency in diabetic patients taking metformin.

Metformin-induced vitamin B12 deficiency can cause or worsen distal symmetrical, autonomic and cardiac neuropathy in the patient with diabetes.

Metformin blocks the absorption of vitamin B12 through a mechanism that has not been established but could be because of interference with the calcium-dependent binding of the intrinsic factor vitamin B12 complex to the cubam receptor in the terminal ileum. The subsequent deficiency of vitamin B12 may cause or accelerate distal symmetrical and autonomic neuropathy in the patient with diabetes. Several observational studies and meta-analyses have reported a significant association between metformin utilization and vitamin B12 deficiency. Prospective studies have shown that not only do metformin utilizers have lower vitamin B12 levels but they also have higher frequencies of distal symmetrical polyneuropathy and autonomic neuropathy (including cardiac denervation, which is associated with increased incidences of cardiac arrhythmias, cardiac events and mortality). Therefore, periodic monitoring of vitamin B12 is recommended in all patients who utilize metformin, particularly if metformin has been used for over 5 years at which stage hepatic stores of vitamin B12 would probably be depleted. Factors that accelerate the loss of hepatic vitamin B12 stores are proton pump inhibitors, bariatric surgery, being elderly and having an increased turnover of red blood cells. If serum vitamin B12 levels are borderline, measurement of methylmalonic acid and homocysteine levels can detect vitamin B12 deficiency at its earliest stage. Therapies include prophylactic calcium and vitamin B12 supplements, metformin withdrawal, replenishing vitamin B12 stores with intramuscular or oral vitamin B12 therapy and regular monitoring of vitamin B12 levels and vitamin B12 supplements if metformin continues to be utilized. With adequate vitamin B12 replacement, while symptoms of neuropathy may or may not improve, objective findings of neuropathy stabilize but do not improve.

Analysis of clinical characteristics and prognostic factors in 110 patients with nitrous oxide abuse.

PURPOSE: To review the clinical symptoms, auxiliary examination findings, and outcomes of patients with nitrous oxide (N2 O) abuse, and analyze the factors that affect outcomes. METHODS: Patients with N2 O abuse treated in the Department of Neurology between January 2018 and December 2020 were included. The clinical data of these patients were collected, and follow-up was conducted to determine the outcomes. RESULTS: The average age of the 110 patients with N2 O abuse was 21.4 ± 4.2 years (range: 14-33 years). Clinical presentation primarily included neurological symptoms, such as limb numbness and/or weakness (97%), psychiatric symptoms, changes in appetite, and skin hyperpigmentation. Laboratory test results were characterized by vitamin B12 deficiency (60%, 34 out of 57 cases) and high homocysteine level (69%, 31 out of 45 cases). Electromyography indicated mixed axonal and demyelination injury (92%, 80 out of 87 cases). Motor and sensory nerves were simultaneously involved, and injury primarily involved the lower limbs. One hundred and seven (97%) patients were clinically diagnosed with peripheral neuropathy, of whom 26 (24%) exhibited spinal abnormalities on magnetic resonance imaging, supporting a diagnosis of subacute combined degeneration. Treatment included N2 O withdrawal and vitamin B12 supplementation. Reexamination of six patients indicated that treatment was effective. Follow-up was completed for 51 patients. Thirty-four patients (67%) recovered completely, 17 patients (33%) had residual limb numbness, and only one patient experienced relapse. Sex was an independent prognostic factor; the outcomes of female patients were better than that of male patients. CONCLUSION: The recreational use of N2 O has largely expanded among youth in recent decades, which has become a growing public health concern in China. It highlights the importance of the recognition of various clinical symptoms, particularly limb numbness and/or weakness related to the cases of N2 O abuse. The therapeutic administration of vitamin B12 supplementation and N2 O withdrawal can make the overall prognosis good, especially for female patients.

Nitrous oxide abuse induced subacute combined degeneration despite patient initiated B12 supplementation.

INTRODUCTION: Nitrous oxide (N2O) is a commonly used inhaled anesthetic that is legal to purchase as a food additive and is popular as a recreational euphoric drug. Abuse causes a functional B12 deficiency, leading to clinical features and imaging consistent with subacute combined spinal cord degeneration (SCD). CASES: Poison Center medical records from four patients are reviewed in this series. Four patients presented with lower extremity weakness, paresthesias and gait abnormalities in the setting of chronic N2O abuse. Each reported using 50-150 N2O cartridges ("whippets") almost daily for months to years, and reported supplementing with oral B12 at the recommendation of other users and online forums. None reported prior B12 deficiency or dietary restrictions, and none exhibited hematologic abnormalities. RESULTS: All patients had clinical signs of neurotoxicity including weakness and ataxia. Additionally, all had elevated methylmalonic acid and homocysteine concentrations with normal B12 indicating a functional B12 deficiency. Three had imaging consistent with SCD despite home supplementation The MRI in the fourth case was inconclusive due to movement artifact. CONCLUSION: We report four cases of subacute combined degeneration induced by recreational nitrous oxide abuse despite self-administered vitamin B12 supplementation.

Extensive Cerebral Venous Thrombosis Secondary to Recreational Nitrous Oxide Abuse.

Nitrous oxide, colloquially known as "whippets," is a commonly abused inhalant by adolescents and young adults. There are limited data describing the adverse effects of this abuse. We present a 16-year-old girl with no medical history who presented to the emergency department for confusion, hallucinations, weakness, and headaches. Imaging revealed extensive cerebral thrombosis. She had no prior history of venous or arterial thrombosis. Hypercoagulability workup demonstrated an elevated homocysteine level. She was treated with effective anticoagulation and vitamin B12 folate supplementation. To our knowledge, there are a very few cases in the medical literature of cerebral venous thrombosis following the use of nitrous oxide. The pathophysiology of the disorder appears to be linked to the metabolism of vitamin B12 inducing hyperhomocysteinemia and a procoagulant state.

A rise in cases of nitrous oxide abuse: neurological complications and biological findings.

BACKGROUND: The recent lockdown due to the COVID-19 pandemic has been linked to a higher incidence of psychiatric manifestations and substance abuse. The recreative use of nitrous oxide is more and more widespread and neurological complications are frequent. METHODS: We report clinical characteristics and biological findings of five consecutive patients presenting to our tertiary care center between April 2020 and February 2021 with various neurological symptoms occurring after recent nitrous oxide abuse. RESULTS: Our patients presented with subacute combined degeneration of the spinal cord (4/5 patients) or with acute inflammatory demyelinating polyneuropathy (1/5 patients). No patient had reduced vitamin B-12 titer, but all had elevated blood levels of homocysteine and methylmalonic acid. This reflects the functional deficit in vitamin B-12 that can be linked to nitrous oxide consumption. After vitamin B-12 supplementation, clinical signs regressed at least partially in all 5 patients. CONCLUSION: We report an elevated incidence of neurological complications of nitrous oxide abuse occurring during the recent COVID-19 lockdown. Nitrous oxide abuse should be tracked down in patients presenting with compatible neurological symptoms and elevated homocysteinemia. Vitamin B-12 should be supplemented as soon as the diagnosis is made.

Cerebral venous sinus thrombosis: a complication of nitrous oxide abuse.

Nitrous oxide (NO) is an inhalant that has become increasingly popular as a recreational drug. While it is presumed to be harmless, a number of adverse effects of NO have been described. We discuss the case of a 24-year-old man with no medical history, who initially presented to the emergency department with progressive polyneuropathy caused by vitamin B12 deficiency after NO abuse. Two days after being discharged with hydroxocobalamin supplementation, the patient returned with a severe headache, blurry vision and slurred speech. Imaging revealed cerebral venous sinus thrombosis. Hypercoagulability workup showed slightly elevated homocysteine and normalised vitamin B12 after supplementation. Genetic testing showed a heterozygous prothrombin G20210A mutation. He was treated with low-molecular-weight heparin followed by dabigatran. We hypothesise that NO use may increase the risk of developing cerebral venous thrombosis, especially in patients with multiple risk factors and elevated homocysteine levels.

Nitrous oxide-induced myeloneuropathy.

BACKGROUND AND PURPOSE: Nitrous oxide misuse is a recognized issue worldwide. Prolonged misuse inactivates vitamin B12, causing a myeloneuropathy. METHODS: Twenty patients presenting between 2016 and 2020 to tertiary hospitals in Sydney with myeloneuropathy due to nitrous oxide misuse were reviewed. RESULTS: The average age was 24 years, and mean canister consumption was 148 per day for 9 months. At presentation, paresthesias and gait unsteadiness were common, and seven patients were bedbound. Mean serum B12 was normal (258 pmol/L, normal range [NR] = 140-750) as was active B12 (87 pmol/L, normal > 35). In contrast, mean serum homocysteine was high (51 µmol/L, NR = 5-15). Spinal magnetic resonance imaging (MRI) showed characteristic dorsal column T2 hyperintensities in all 20 patients. Nerve conduction studies showed a predominantly axonal sensorimotor neuropathy (n = 5). Patients were treated with intramuscular vitamin B12, with variable functional recovery. Three of the seven patients who were bedbound at presentation were able to walk again with an aid at discharge. Of eight patients with follow-up data, most had persistent paresthesias and/or sensory ataxia. Mobility scores at admission and discharge were not significantly correlated with the serum total and active B12 levels or cumulative nitrous oxide use. There were no significant trends between serum active B12 level and cumulative nitrous oxide use (Spearman rho = -0.331, p = 0.195). CONCLUSIONS: Nitrous oxide misuse can cause a severe but potentially reversible subacute myeloneuropathy. Serum and active B12 can be normal, while elevated homocysteine and dorsal column high T2 signal on MRI strongly suggest the diagnosis. Neurological deficits can improve with abstinence and B12 supplementation, even in the most severely affected patients.

Inhaled nitrous oxide-induced functional B12 deficiency.

Recreational nitrous oxide (N2O) is commonly used among young people partly due to its low cost and accessibility, and awareness of its potential adverse effects is poor in this group. One such adverse effect is degeneration of the spinal cord due to its disruption of DNA synthesis by inactivating cobalamin (B12).A 19-year-old man presented to the emergency department with a 4-week history of worsening paraesthesia in his fingers and lower limbs, and weakness in the hands and lower limbs for 2 weeks. On examination, he had an ataxic gait, reduced power of grip strength and ankle movements, and impaired sensation in the lower limbs. An MRI brain and spine revealed myelopathy of the cervical and thoracic cord.On further questioning, he reported recreational N2O inhalation. His symptoms improved after stopping this and he was treated with supplementation of B vitamins. Education strategies regarding the risks of N2O misuse are indicated.

Acute cognitive disorder as the initial manifestation of nitrous oxide abusing: a case report.

Nitrous oxide (N2O) is a colorless, odorless gas used as an anesthetic and analgesic. It is also abused as a recreational drug, and such abuse is associated with neurological disorders and psychiatric complications such as myelopathy and, rarely, cognitive impairment. Its abuse has not been associated with acute cognitive decline. Here, we report a young girl who presented with acute cognitive impairment after excessive recreational inhalation of nitrous oxide and who recovered completely after vitamin B12 supplementation. We conclude that nitrous oxide abuse can cause acute cognitive impairment, and that this diagnosis should be considered if a patient initially presents with acute cognitive decline.

Association between metformin dose and vitamin B12 deficiency in patients with type 2 diabetes.

BACKGROUND: Metformin can cause serum vitamin B12 deficiency, but studies on the influence of its duration and dose are lacking. We investigated vitamin B12 deficiency in patients with type 2 diabetes using metformin, in conjunction with other related factors. METHOD: This cross-sectional study included 1111 patients with type 2 diabetes who took metformin for at least 6 months. Serum vitamin B12 levels were quantified using a competitive-binding immunoenzymatic assay, and vitamin B12 deficiency was defined as serum B12 <300 pg/mL. Information on metformin use and confounding variables were collected from records or questionnaires and interviews. RESULT: Serum vitamin B12 deficiency occurred in 22.2% of patients (n = 247). After adjusting for confounders, a 1 mg increase in daily metformin dose was associated with a 0.142 pg/mL decrease in vitamin B12 (P < .001). Compared with a daily dose of <1000 mg, the adjusted odds ratios for 1000 to 1500, 1500 to 2000, and ≥2000 mg metformin were 1.72 (P = .080), 3.34 (P < .001), and 8.67 (P < .001), respectively. Vitamin B12 deficiency occurred less often in patients taking multivitamins (odds ratio 0.23; P < .001). After adjusting for confounding factors, there was no correlation between B12 deficiency and duration of metformin use. Serum homocysteine levels showed significant negative correlation with vitamin B12. CONCLUSION: Metformin at ≥1500 mg/d could be a major factor related to vitamin B12 deficiency, whereas concurrent supplementation of multivitamins may potentially protect against the deficiency. Serum homocysteine levels were negatively correlated with vitamin B12 levels, suggesting that B12 deficiency due to metformin use may occur at the tissue level. However, this hypothesis will require further study.

Nitrous oxide myelopathy with functional vitamin B 12 deficiency.

Recreational use of nitrous oxide as a 'legal high' is increasing in the UK. Physicians should be 'street wise' to this increasing prevalence and aware of the potential neurological complications which may result from misuse. We describe a 17-year-old male patient who presented to neurology with a severe myelopathy following prolonged recreational use of nitrous oxide. MRI demonstrated characteristic changes affecting the dorsal columns and blood tests demonstrated a 'functional' B12 deficiency. Clinical and radiological improvement was noted following initiation of vitamin B12 replacement.

One month of nitrous oxide abuse causing acute vitamin B 12 deficiency with severe neuropsychiatric symptoms.

A 21-year-old university student studying abroad in the USA presented to the emergency department with double vision, lower extremity weakness with difficulty ambulating and other neuropsychiatric symptoms. MRI of the brain and spinal cord were normal. Vitamin B12 was 78 pg/mL (58 pmol/L, reference 211-911 pg/mL). The patient had been using nitrous oxide capsules used for whipped cream recharging, which she obtained from other students, a few times daily for a month for the purpose of anxiety relief. The patient was not a vegan or vegetarian. The patient was treated with intramuscular vitamin B12 repletion with partial resolution of neurologic symptoms and discharged on vitamin B12 supplementation.

Recreational nitrous oxide abuse related subacute combined degeneration of the spinal cord in adolescents - A case series and literature review.

BACKGROUND: Nitrous oxide (N2O) is a commonly used inhaled anesthetic in outpatient dental procedures. However, the increasing recreational use of N2O may result in vitamin B12 deficiency-related neurologic and psychiatric symptoms. The aim of this study was to demonstrate the clinical features of chronic N2O abuse in pediatric patients. METHODS: Patients under 20 years of age who were diagnosed with N2O-induced subacute combined degeneration of the spinal cord from 2012 to 2018 were enrolled in this study. Clinical presentations, laboratory, imaging, ancillary studies, treatments and outcomes were analyzed. RESULTS: Nine patients were included, all of whom presented with symptoms of myeloneuropathy including limb numbness, limb weakness or unsteady gait. Six patients had low or low-normal vitamin B12 (cyanocobalamin) levels. Eight patients had evidence of subacute combined degeneration of the spinal cord via neuroimaging studies. All of the patients received vitamin B12 supplementation as treatment. All had full recovery of muscle power within 2 months. Five patients had persistent sensory deficits. CONCLUSION: Chronic N2O abuse can cause permanent neurological damage if not treated promptly. Clinical staff should be aware of the various presentations of neurotoxicity related to N2O abuse.

Imaging appearance of myelopathy secondary to nitrous oxide abuse: a case report and review of the literature.

Purpose The abuse of nitrous oxide (N2O) can induce Vitamin B12 deficiency that subsequently leads to central nervous demyelination, myelopathy and peripheral neuropathy. Although myelopathy has been reported in the past, the specific locations and prognosis of the disease are still unclear. MATERIALS AND METHODS: We report the case of a 22-year-old male who presented with quadriplegia that began after a 3-month history of inhalation of N2O. We summarized the clinical data of this entity and performed a comprehensive literature review of various presentations and MRI features of myelopathy secondary to N2O abuse. RESULTS: In combination with previous reports of 14 cases, we found that the onset of the disease was usually subacute, and the majority of patients (92.85%) were young men. There was no definite relationship between myelopathy and the amount or duration of N2O inhalation. The most common clinical manifestation was sensory ataxia, and the cervical spinal cord was the most frequently impaired area of the whole spinal cord. The spinal cord lesions had a high signal intensity on T2-weighted MRI and usually involved more than three spinal segments and impaired the posterior column more significantly. Most patients recovered well after vitamin B12 supplementation. CONCLUSIONS: Myelopathy secondary to N2O abuse is generally seen in young men. The clinical diagnosis mainly depends on a history of N2O inhalation and the characteristic imaging changes in the posterior cervical spinal cord. Early diagnosis and intervention are important for a satisfactory prognosis.