Important reminder: nitrous oxide (N₂O) as a cause of functional vitamin B₁₂ deficiency

Abstract

A 32-year-old woman who misused multiple substances, including nitrous oxide (N₂O), sought medical advice after she subacutely developed bilateral lower extremity weakness without a sensory level but with ataxia—her significant other developed similar symptoms with vitamin B₁₂ deficiency due to N₂O intake. Laboratory results revealed macrocytic anaemia despite normal B₁₂ and folate levels, with serum markers pointing towards functional cobalamin deficiency. Spinal MRIs and cerebrospinal fluid analysis were unremarkable. Our patient was treated with vitamin B₁₂ supplementation with an encouraging response.

Background

Vitamin B₁₂, which is also called cobalamin, plays an essential role in DNA and RNA synthesis and is crucial for the well-being of the human body. Its deficiency is known to cause haematological diseases like macrocytic anaemia.¹ At the same time, low levels of vitamin B₁₂ are associated with severe neurological problems, including but not limited to cognitive impairment and acute/subacute combined degeneration of the cord.² Older adults are more prone to developing low levels of vitamin and related complications.³ Other age groups can be affected as well. Multiple factors can lead to a lack of cobalamin in the body; these are low dietary intake, factors related to malabsorption, some medications and increased demand for cobalamin, like what happens in pregnancy and hemodialysis.⁴

One of the circumstances that need attention from clinicians is functional rather than actual deficiency of vitamin B₁₂, where the blood levels of the nutrient are within normal limits, but the vitamin is not doing its tasks. The seriousness of this situation is that it can be easily missed during practice, and the complications are not addressed immediately, leading to significant permanent harm. Useful parameters in detecting functional vitamin B₁₂ deficiency are methylmalonic acid and the amino acid homocysteine.⁵ In addition, high values in the blood can point to failing cobalamin despite normal blood values.

Nitrous oxide (N₂O) is an inhaled gas that can be used in anaesthesia.⁶ Occasional use is to improve oxygenation for people with acute respiratory distress syndrome on mechanical ventilators. In addition, some people use N₂O, which is also called ‘laughing gas’, for recreational purposes for its anxiolytic effect; it is thought to increase the efficacy of γ-aminobutyric acid type A receptors.⁷ Whip-its, whippits and whippets are all the same, and they are slang names for the small metal containers filled with N₂O, which are used to recharge reusable whipped cream dispensers. These usually are the sources for N₂O abuse. The containers are also known as chargers, and the slang names are thought to be related to the containers’ intended use.⁸

N₂O is highly toxic and can be fatal.⁹ In addition, it can lead to decreased effectiveness of cobalamin by targeting the enzyme methionine synthase, adversely affecting cobalamin metabolism and eventually leading to functional deficiency of the vitamin.¹⁰

Case presentation

We are presenting the case of a 32-year-old Caucasian woman with a medical history significant for anxiety and polysubstance abuse, including tobacco smoking, alcohol and N₂O for recreational purposes. Continuously over the 2 months before her presentation, our patient had been using whip-its (N₂O battery or cartridge) and would inhale the gas together with her husband. She also had a history of seizures related to alcohol withdrawal but was not on any anti-seizure medications.

Our patient presented to the hospital with difficulty ambulating due to lower extremities weakness and unsteadiness on her feet after experiencing numbness and a tingling sensation which started suddenly 1 week before the presentation. She denied any bowel or bladder incontinence or diplopia, dysphagia or dysarthria. She had no fever, no known significant head or back trauma, and no recent changes in medications. Likewise, she had no known prior similar spells, transient ischaemic attacks or acute strokes. She also had no known recent history of infection or significant stress and no heat intolerance. Of note, our patient’s spouse was recently diagnosed with upper and lower extremity weakness secondary to vitamin B₁₂ deficiency due to N₂O intake and was receiving treatment in the same facility.

On arrival to the hospital, our patient was fully awake, alert and oriented, and hemodynamically stable. A neurological examination showed a wide-based ataxic gait and power of 4/5 in the right lower extremity and 5/5 in the left lower extremity; no sensory level was detected. Deep tendon reflexes showed hyperreflexia in bilateral lower extremities. Bilateral upper extremities examination was normal.

Investigations

Neurology recommended MRIs of the back, including cervical and thoracic areas, but unfortunately, they were limited because of the patient’s excessive movements during the examination despite suitable sedation. Hyperintense areas were noticed in the cervical region (figure 1). Extensive blood work was done; complete blood count did show macrocytic anaemia with a haemoglobin level of 11.8 g/dL (normal 12.0–16.0 g/dL) and increased mean corpuscular volume at 113 fL (normal 80–100 fL). Other relevant tests were significant for increased homocysteine level at 34.8 µmol/L (normal 5.0–13.0 µmol/L) and methylmalonic acid at 1.16 µmol/L (normal <0.40 µmol/L), levels highly suggestive for vitamin B₁₂ functional deficiency despite normal serum vitamin B₁₂ levels at 312 ng/mL (normal 211–911 pg/mL) and a folate level of 13.06 ng/mL (normal 5.40–20.00 ng/mL).¹¹ A lumbar puncture was done, and cerebrospinal fluid (CSF) analysis was within normal limits.

Figure 1.

MRI revealing transverse linear hyperintensities involving the cervical spinal cord at the mid-cervical level.

Differential diagnosis

Several diagnoses were considered. We ruled out transverse myelitis as there was no sensory level and spinal MRIs and CSF analysis were negative for any abnormality. Guillain-Barré syndrome was excluded because of the clinical presentation and normal CSF analysis.

Treatment

The patient initially started on a course of cyanocobalamin (vitamin B₁₂) 1000 µg/mL intramuscular injection, once daily for three consecutive days, then switched to cyanocobalamin (vitamin B₁₂) tablet 1000 µg once daily along with physical therapy. However, methylcobalamin (bioidentical form) is often preferred due to its superior bioavailability, safety, and costs.¹²

Outcome and follow-up

Our patient’s condition started to improve on the vitamin B₁₂ supplementation regimen, which was started on her admission to the hospital and continued for 9 days. Also, physical and occupational therapists started working with her from the beginning. Gradually, she started regaining strength in her lower extremities, became more stable on her feet and was able to ambulate to the bathroom without assistance towards the end of her hospital stay. Unfortunately, she insisted on being discharged from the hospital before the complete resolution of her symptoms as she wanted to go home and take care of her daughter. She was discharged on oral vitamin B₁₂ in the form of cyanocobalamin with instructions to take it for 3 months and to follow up with her primary care physician and neurologist within 2 weeks. Unfortunately, she was lost to follow-up despite repeated attempts to contact her.

Discussion

Vitamin B₁₂ is a water-soluble B vitamin required by hematopoietic cells to develop and mature and serve as a valuable co-transporter for numerous metabolic reactions. The prevalence of B₁₂ deficiency increased with age and occurred as frequently as 6% in patients over 60 years. Vegetarianism, chronic alcoholism, autoimmune malabsorption syndromes, metformin, proton-pump inhibitors and various types of gastritis are most commonly known to cause B₁₂ deficiency; however, more causes are being elucidated with time.¹²

Recreational N₂O was seen in 29.4% of a global drug survey (USA—38.6% and UK—30%). It is insufflated into canisters of N₂O into reusable whipped cream dispensers known as ‘whippets’. Chronic heavy use can result in neuropathies, notably myeloneuropathies.^{13 14} This case highlights the growing cases of myelopathies from abusing N₂O. A dose-dependent relationship has been established over weeks and months that interferes with homocysteine degradation to methionine, a crucial step in myelin protein production. This leads to demyelination of both the central and peripheral nervous systems manifesting as neurological dysfunction.

A similar case was reported in a young male suspected of having inhaled N₂O toxicity and sensory symptoms of the upper extremities, however, with near-normal vitamin B₁₂ levels. The authors noted rapid and significant improvements of his neurological symptoms in 2 weeks, suggesting that normal B₁₂ levels can mask this presentation. However, the authors reported that methylmalonic acid and homocysteine levels were not drawn, which might have accurately reflected B₁₂ stores. This suggests that the change in clinical outcomes after patients receive vitamin B₁₂ supplements may be important to consider when supporting the diagnosis, even when the laboratory investigation shows normal vitamin levels.¹⁵ Another case report of N₂O abuse demonstrated increased methylmalonic acid and homocysteine levels, but the patient tested positive for intrinsic factor antibodies, which is highly specific for pernicious anaemia.¹⁶ Our patient was not tested for intrinsic factor antibodies. These cases illustrate the highly variable clinical and objective findings of N₂O and B₁₂ deficiency.

Multiple cases were reported that demonstrated how N₂O could lead to vitamin B₁₂ deficiency,^15–17 which physicians can easily miss as it is rare in clinical practice. Extra attention is needed in this area as the complications can be severe and permanent. With the emerging recreational use of N₂O and its association with functional vitamin B₁₂ deficiency, we suggest taking a comprehensive history in addition to physical and neurological examination besides carrying on investigations that focus on the amount of vitamin B₁₂ in the body and also look into its function of the vitamin. Patients must start vitamin B₁₂ supplements as soon as possible to avoid long-lasting complications.^{18 19} Fortunately, our case was diagnosed early, and the treatment started promptly because of the patient’s spouse’s similar diagnosis in the same facility. In addition, good social history helped elucidate the diagnosis.

Follow-up is an essential part of management. Our patient failed to do so after receiving initial treatment, which is something reported in previous case reports. Therefore, for patients experiencing neurological complications due to N₂O effect on vitamin B₁₂the degree of severity may dictate the frequency of blood work and repeat imaging needed to assess treatment response (functional disability rating scale). Finally, for all patients, appropriately counselling about the dangers of N₂O toxicity and increasing public awareness of the abuse and toxic potentials of N₂O are critical to attenuate the burden on the population.

Patient’s perspective.

I am so happy with the apparent improvement in my symptoms. Now I understand how bad it is to inhale nitrous oxide, and I have no intention to go back to it. However, with the help of my mother, I can use a walker for mobility, and I can take care of my daughter.

Learning points.

• Vitamin B₁₂ (cobalamin) deficiency can lead to severe complications, primarily neurological; some of them can be permanent if not recognised early and promptly addressed.

• Nitrous oxide (N₂O), a gas with medical uses, can be consumed recreationally as an anxiolytic.

• N₂O can affect the metabolism of vitamin B₁₂, impacting its ability to carry on a significant role in the human body.

• The deficiency in vitamin B₁₂ can be functional, making it challenging to be discovered unless a high index of suspicion is present.

• Proper treatment by replacing the vitamin can lead to significant improvement if administered early on.

Ethics statements

Patient consent for publication

Obtained.