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A 19-year-old man presented to the emergency department (ED) after falling down a flight of stairs. He denied any health problems or medication use. However, he told clinicians that for the past month or more, he had been experiencing an increasing problem with numbness in his hands and feet. This worsened and he found that his sense of balance was affected. He also noted weakness in his lower legs.

Clinicians initially suspected that the patient's symptoms might be due to Guillain-Barre syndrome, neurological infection, or another neuropathic condition. They performed an extensive workup that included a lumbar puncture, electroneuronography, and an MRI of the medulla totalis. Results of these tests were normal, and there was no evidence of pathology changes on the MRI.

Most lab test results were within reference range, except for his homocysteine and methylmalonic acid levels:

• Homocysteine: 92 μmol/L (reference range <10 μmol/L)
• Methylmalonic acid: >10 μmol/L (range 0.08-0.28 μmol/L)
• Folate: 21 nmol/L (range >9 nmol/L)
• Vitamin B12: 234 pmol/L (range 200-600 pmol/L)
• Creatinine: 61 μmol/L (range 60-105 μmol/L)

Results of the lab tests and diagnostic workup led to a diagnosis of severe sensorimotor neuropathy. After considering the patient's history and all exam results, ED physicians concluded that his sensorimotor neuropathy was due to functional vitamin B12 deficiency.

His self-reported history of recreational use of nitrous oxide up to 10 times within recent months, mainly on weekends, likely triggered his neuropathy, they determined. The patient had told several members of the ED staff that he had used nitrous oxide about twice per week within recent months (maximum of 50-75 cartridges per time). He said he did not use any other recreational drugs.

The patient was treated with oral vitamins, including 1 mg once daily of vitamin B12, 5 mg once daily of folate (vitamin B9), and 300 mg once daily of thiamine (vitamin B1); he also started physiotherapy treatment.

His symptoms improved over the course of the following 14 days, and he was prepared for discharge to a rehabilitation center. Just before his release from hospital, he began experiencing acute non-radiating chest pain, which worsened when he breathed deeply.

Vital signs included blood pressure of 112/64 mm Hg, pulse of 86 beats per minute, and oxygen saturation of 98%. Clinicians suspected aortic dissection and performed an acute CT angiography of the aorta. Imaging showed no evidence of dissection; however, it revealed bilateral central pulmonary embolism with signs of pulmonary infarction in both lower lobes with consolidated changes. An MRI scan of the cervical column did not reveal any definite pathological findings.

Given the patient's hemodynamic stability and normal findings on echocardiography, clinicians treated the pulmonary embolism with an oral anticoagulant (20-mg once-daily rivaroxaban). He was discharged from hospital a few days later.

Clinical follow-up assessment 6 months later showed only mild sensory-motor residual symptoms. The patient had no symptoms associated with the pulmonary embolism or anticoagulant treatment he received. He was screened for thrombophilia, but all test results were normal, with no antiphospholipid antibodies or lupus anticoagulant, no genetic polymorphisms, and no lack of natural anticoagulants. In addition, his homocysteine level had returned to normal (9.5 μmol/L). Thus, anticoagulant treatment was discontinued.

Discussion

Clinicians reporting this of a 19-year-old who presented with peripheral neuropathy after several months of occasional recreational use of nitrous oxide, followed by a bilateral central pulmonary embolism during hospitalization, suggested that these were related to functional vitamin B12 deficiency and an increased level of homocysteine associated with nitrous oxide use.

Nitrous oxide, or so-called "laughing gas," has been in use as an anesthetic for more than a century, the case authors noted. However, recent years have seen the of nitrous oxide growing among young people, perhaps due to its "presumed innocent effect combined with an easy and legal availability," they wrote. For example, nitrous oxide can be easily obtained from whipped cream charging bottles.

Daily heavy use (i.e., >200 cartridges) and long-term recreational use of nitrous oxide can lead to functional vitamin B12 deficiency -- resulting in nerve damage and other complications such as macrocytic anemia, thromboembolic phenomena, myocardial infarction, , and even death, presumably due to hypoxia.

The case authors noted that peripheral neuropathy has been associated with recreational use of nitrous oxide in the past, mainly after . Chronic use of nitrous oxide causes irreversible inactivation of vitamin B12, thus resulting in functional vitamin B12 deficiency, they said.

Active vitamin B12 is required for the conversion of methylmalonic acid and the degeneration of homocysteine to methionine; therefore, persistent inactivation of vitamin B12 by use of nitrous oxide results in elevated levels of methylmalonic acid and homocysteine, the authors explained (Figure).

Because methionine is necessary for all methylations, inactivation of vitamin B12 resulting from nitrous oxide inhalation can cause nerve damage due to lack of myelination of the nerve cell axons, the group explained.

They suggested that this mechanism likely resulted in their patient's peripheral neuropathy, given the elevated levels of methylmalonic acid and homocysteine shown in lab tests at admission, and concurrent normal plasma levels of vitamin B12, folate, and creatinine.

Regarding the fact that the patient's vitamin B12 level was normal, the authors explained that since cobalamin must bind to transcobalamin to be available for circulation, the levels available for the cells can still be suboptimal; this could explain the symptoms observed in their patient, whose transcobalamin was not measured. In addition, the MRI showed no conclusive evidence of pathology, they added.

When the patient stopped using nitrous oxide, vitamin B12 inactivation no longer persisted, the authors noted; thus, blood levels returned to normal and nerve cell myelination was restored. The rapid fall/normalization in homocysteine level supports their theory that use of nitrous oxide caused the significant increase in homocysteine level, they said.

Furthermore, they suggested that the patient's pulmonary embolism may have been related to his remaining in his room (despite being able to walk) for the 2 weeks after admission, since immobilization is known to increase the risk for thromboembolic complications. The patient's nitrous oxide use may also have been a contributing factor in the development of the pulmonary embolism, they said.

The authors cited a of pulmonary embolism following recreational use of nitrous oxide, although this patient had long-term use.

They noted several factors that may increase risk of thromboembolic complications: the greatly increased level of homocysteine, which has been reported to affect hemostasis by causing endothelium dysfunction; platelet activation; and impaired fibrinolysis, which can also increase the risk of myocardial infarction.

In addition to the effects of increased homocysteine on hemostasis, they pointed to a of a recreational user of nitrous oxide who developed a blood clot in the aortic arch. Given its location in the artery of a patient with no other risk factors for thrombosis, this supported the possibility that nitrous oxide contributed to a hypercoagulable state.

The authors of the present case also referenced another report of a patient with after long-term recreational use of nitrous oxide, whose homocysteine level was normal upon admission. However, regarding their patient, the authors cautioned that the 2-week gap between his cessation of nitrous oxide use and development of the pulmonary embolism leaves the direct contributing effect of nitrous oxide uncertain.

"This report shows that even moderate recreational use of nitrous oxide can lead to severe peripheral neuropathy due to functional vitamin B12 deficiency and can be associated with pulmonary embolism, even in young and previously healthy individuals," the group concluded. As in their patient's case, completely stopping nitrous oxide use and receiving treatment with relevant vitamins can lead to a rapid recovery.

According to the , the largest survey of recreational drug use in the world, findings from 74,864 respondents showed that use of nitrous oxide is very common, particularly in the U.K. and U.S. (38.6% and 29.4% lifetime prevalence, respectively).

"Nitrous oxide was generally consumed via gas-filled balloons, at festivals and clubs where use of other substances was common," the survey study authors wrote. Most use is infrequent and not associated with significant harm, they added, although a subgroup of heavy users may be using in a dependent pattern. Analysis of last-year users (n=4,883) showed that use was associated with hallucinations (27.8%), confusion (23.9%), persistent numbness (4.3%), and accidental injury (1.2%), with the latter linked with the highest number of "hits" per session, suggesting a dose-response relationship.

Due to the GDS's noted increasing popularity of recreational nitrous oxide consumption among young people, the case authors urged awareness among healthcare professionals when treating patients who develop unexplained neuropathy or thromboembolic events. Furthermore, they urged clinicians to inform young people about the risks of adverse effects from the recreational use of nitrous oxide.

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