Nitrous Oxide-Induced Funicular Myelopathy: A Case Report and Pathophysiological Insights

Case Presentation

A young adult presented to the emergency department with progressive sensory disturbances and weakness in both arms and legs. There were no signs of bladder dysfunction, infection, prior significant medical conditions, or a vegetarian diet. The patient reported recreational nitrous oxide (N₂O) use over the past six months, with approximately 150 applications, several times per week.

Clinical and Diagnostic Findings

Neurological examination revealed a transverse spinal cord syndrome, with symptoms more pronounced in the lower extremities and a defined sensory level at thoracic segment T8. Magnetic resonance imaging (MRI) of the cervical spine (T2-weighted) demonstrated a long segment of intramedullary hyperintensity from vertebral body C2 to C5. Axial images showed a characteristic inverted “V” pattern in the posterior columns—typical for subacute combined degeneration (SCD) or funicular myelopathy. There was no radiological or clinical evidence of peripheral nerve demyelination.

Laboratory Results:

Vitamin B12: 122.9 pmol/L – at the lower end of the reference range or slightly reduced
Folic acid: 13.74 µg/L – within normal range
Homocysteine: 40.3 µmol/L – significantly elevated
Methylmalonic acid (MMA): 330 µg/L – significantly elevated
Cerebrospinal fluid (CSF): unremarkable

Despite the near-normal B12 levels, the elevations in homocysteine and MMA indicated a functional vitamin B12 deficiency—a metabolic state in which serum B12 is present but not bioavailable at the cellular level.

Pathophysiology of Nitrous Oxide-Induced B12 Inactivation

Nitrous oxide exerts its neurotoxic effect by oxidizing the cobalt ion within vitamin B12, rendering it inactive. This inactivation primarily disrupts the function of methionine synthase, a B12-dependent enzyme critical for:

DNA and RNA synthesis
Myelin maintenance
Conversion of homocysteine to methionine

Disruption of this enzymatic process leads to accumulation of homocysteine and methylmalonic acid, and ultimately results in myelin sheath damage, especially in the posterior and lateral columns of the spinal cord.

Importantly, nitrous oxide use can induce this dysfunction even in patients with normal or near-normal B12 levels, as seen in this case. Functional B12 deficiency must therefore be evaluated through metabolic markers like homocysteine and MMA, which are more sensitive indicators of intracellular vitamin B12 activity.

Biochemical Markers: Clinical Relevance

Homocysteine

Homocysteine is an intermediate amino acid that is normally remethylated to methionine in a process that requires both vitamin B12 and folate. Elevated levels indicate a disruption in this pathway, commonly due to deficiencies in these cofactors or enzyme dysfunction.

Methylmalonic Acid (MMA)

MMA is produced during the metabolism of odd-chain fatty acids and amino acids. It is metabolized exclusively via a B12-dependent enzyme (methylmalonyl-CoA mutase). Elevated MMA is a specific marker for B12 deficiency, especially in distinguishing it from folate deficiency.

Broader Implications of Hyperhomocysteinemia

Persistent elevation of homocysteine (hyperhomocysteinemia) is associated with multiple health risks, regardless of the underlying cause:

Causes:

Nutritional deficiencies (vitamin B12, B6, folate)
Genetic conditions (e.g., homocystinuria, MTHFR mutations)
Chronic diseases (e.g., renal failure, hypothyroidism)
Lifestyle factors (smoking, alcohol use, aging)
Certain medications (e.g., anti-epileptics, methotrexate)

Health Risks:

Cardiovascular disease: Elevated homocysteine may damage endothelial cells, promoting atherosclerosis, thrombosis, and increased risk of myocardial infarction or stroke.
Venous thromboembolism: Hypercoagulability associated with high homocysteine can lead to deep vein thrombosis or pulmonary embolism.
Neurodegenerative diseases: Chronic elevation has been linked to cognitive impairment, Alzheimer’s disease, and other neuropsychiatric disorders, although causality remains under investigation.

Vegetarian Diet and Vitamin B12 Deficiency

Although the patient in this case did not follow a vegetarian diet, vegetarianism and veganism are among the most common dietary causes of vitamin B12 deficiency and are thus highly relevant to the broader discussion of subacute combined degeneration and funicular myelopathy.

1. Absence of Natural B12 Sources

Vitamin B12 is naturally found only in animal-derived foods (meat, fish, dairy, eggs). Plant-based diets, unless supplemented or fortified, typically lack adequate amounts of bioavailable B12. Claims that certain fermented or plant products (e.g., seaweed, spirulina) contain B12 often refer to inactive analogs that may even inhibit B12 absorption.

2. Depletion of Body Stores

The liver stores several years’ worth of B12, which can delay the onset of symptoms after switching to a vegetarian or vegan diet. For this reason, deficiency may not manifest until 2–5 years later, potentially leading to a delayed or missed diagnosis.

3. Neurological Complications

Vitamin B12 deficiency can lead to subacute combined degeneration of the spinal cord, affecting both the posterior and lateral columns. Neurological symptoms may include:

Paresthesia (tingling, numbness)
Gait disturbance and ataxia
Lower limb weakness
Cognitive changes and mood disorders

If not promptly diagnosed and treated, such damage may become irreversible, even with B12 repletion.

4. Functional vs. Absolute Deficiency

Some individuals may present with functional B12 deficiency, in which serum levels appear normal but intracellular utilization is impaired. This can occur in vegetarians due to poor absorption (e.g., intrinsic factor deficiency, atrophic gastritis), inadequate supplementation, or interference (e.g., nitrous oxide exposure). Elevated MMA and homocysteine are essential in diagnosing such cases.

5. Prevention and Monitoring

To prevent B12 deficiency, vegetarians and vegans should:

Take B12 supplements: Recommended doses are 250–500 µg daily or 1000 µg several times per week.
Consume fortified foods: Such as B12-enriched plant-based milks, breakfast cereals, and nutritional yeast.
Monitor B12 status regularly, especially in high-risk populations (pregnant women, children, elderly, or those with absorption issues).

Therapeutic Implications and Public Health Concerns

This case highlights the potentially severe, yet underrecognized, consequences of chronic nitrous oxide use. In some instances, early diagnosis and treatment with high-dose parenteral vitamin B12 can lead to partial or full recovery. However, irreversible neurological damage is possible, particularly if the exposure continues or treatment is delayed.

Given the increasing recreational use of nitrous oxide, especially among young adults, there is a strong public health imperative to re-evaluate its availability and regulation. Education on its neurotoxic potential is critical for both the public and healthcare providers.

Conclusion

Chronic nitrous oxide abuse can cause significant neurological injury through the inactivation of vitamin B12, leading to functional B12 deficiency and funicular myelopathy. Importantly, serum B12 levels may be misleading, making metabolic markers like homocysteine and methylmalonic acid crucial for diagnosis.

Vegetarian and vegan individuals, though not affected in this case, represent another major at-risk population for B12 deficiency. Awareness, screening, and preventive strategies are essential to mitigate neurological complications in both groups.

This case underscores the need for clinical vigilance, appropriate diagnostic testing, and public health interventions to address the rising incidence of nitrous oxide-induced neurotoxicity and dietary B12 deficiency.

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