1 INTRODUCTION

Nitrous oxide is a gas frequently used in the medical/dental field for anesthesia and analgesic purposes and in the food industry as a spray propellant or foaming agent. Canisters of nitrous oxide are readily available for purchase on the intranet and at grocery stores without restrictions or limitations.¹ Because this chemical compound is easily accessible, relatively inexpensive, and legal to possess, it is abused for recreational purposes. The number of published cases of nitrous oxide abuse has been increasing since 2010.² The lifetime prevalence of nitrous oxide abuse ranges from 2% to 15.8%.² Inhalation of nitrous oxide causes a feeling of euphoria, relaxation, and occasional hallucinations for a brief period.³ Large-scale and long-term use of nitrous oxide have been found to cause nerve damage from vitamin B12 deficiency, thromboembolic phenomenon from elevated homocysteine levels, and even death from hypoxia.⁴ This case examines a patient with a neurological complication, subacute combined degeneration of the spinal cord (SACD), secondary to vitamin B12 deficiency in the setting of nitrous oxide abuse.

2 CASE PRESENTATION

A 44-year-old male patient with a past medical history of recently diagnosed type 2 diabetes, on metformin, presented to the emergency department for 1 month of bilateral upper and lower extremity weakness that worsened over the previous 3 days. He was prompted to seek medical attention after a flight from Florida to New York when he was unable to stand from his seat and required assistance. Additional symptoms included unsteady gait, difficulty voiding, numbness of the lower abdomen, and burning, numbness, and rigidity in all extremities.

On initial physical examination, the patient demonstrated pertinent findings of 2/5 hand strength bilaterally, 4/5 strength in his left upper extremity and right lower extremity, 5/5 strength in right upper and left lower extremities, intact cranial nerves, impaired coordination, ataxic gait, rigidity, and decreased but symmetrical reflexes. He exhibited confusion and was unable to recall the events leading up to his presentation to the emergency department, but was oriented to person, place, time, and situation. Further history obtained from his brother revealed a history of polysubstance use, including nitrous oxide, prompting his family to bring him to New York for rehabilitation.

His neurological work-up in the emergency department showed an unremarkable CT pelvis with IV contrast, CTA head and neck, and CT brain without contrast. A urine toxicology screen was negative for amphetamines, benzodiazepines, cocaine, barbiturates, methadone, opiates, cannabinoids, and phencyclidine. Blood work showed RBC 3.56 × 10⁶/μl, hemoglobin 12.5 g/dl, and MCV 98.3 fl (Table 1).

During a later conversation, the patient elaborated on his substance use. He reported a history of cocaine and opioid abuse but had not used these substances in “a long time.” He also admitted using nitrous oxide for “many years” with heavier use in the last several months prior to presentation. He reported using 50–100 canisters per day to obtain a feeling of relaxation and euphoria. He continued to exhibit some memory deficiencies and was unable to provide a more detailed history.

Further work-up revealed a borderline vitamin B12 level of 168 pg/ml, an elevated A1c of 10.4%, an elevated homocysteine level of 97.5 μmol/ml, an elevated methylmalonic acid level of 2920 nmol/ml, a negative intrinsic factor blocking antibody, and negative Lyme disease antibody (Table 2). His creatinine level was 0.71, which was within normal limits. His copper, vitamin E, vitamin B6, and vitamin B9 levels were within normal limits (Table 2). Repeat CBC showed hemoglobin 12.1 g/dl, MCV 101.2 fl (Table 3). MRI of the cervical and lumbar spine showed mild disc protrusion. MRI Brain showed a 3 mm linear hyperintense focus within the subcortical white matter. MRI of the thoracic spine revealed an abnormal T2 signal within the central portion of the spinal cord extending from the lower thoracic region into the upper and mid thoracic cord (Figure 1).The patient was diagnosed with subacute combined degeneration secondary to nitrous oxide use.

The patient was treated with 1000 μg vitamin B12 Intramuscular every other day for 3 doses, followed by 500 μg cyanocobalamin orally daily. It was unclear if his use of metformin contributed to the vitamin b12 deficiency, but it was unlikely as the patient started metformin only 3 weeks prior to presentation. He required multiple urinary catheterizations and foley placement for urinary retention. He was evaluated by physical and occupational therapy who found decreased proprioception, strength, coordination, and ataxic/scissoring gait.

He demonstrated a significant improvement in his neuropathy during his stay. However, he was still dependent in basic transfers, activities of daily living, and mobility and was discharged to acute rehabilitation 6 weeks. During this time, the foley catheter was removed, he received cognitive retraining given his mild deficits in memory and executive functioning and completed physical and occupational therapy. With this treatment, he was able to ambulate with a rolling walker and he was discharged to an inpatient substance abuse rehabilitation program. The patient did not follow-up within our organization as instructed, but there was frequent communication with his primary care physician to facilitate transition of care.

3 DISCUSSION

Vitamin B12 is an important cofactor for two enzymes involved in the preservation of myelin, methionine synthase and Methylmalonyl-CoA mutase.¹ Vitamin B12 deficiency occurs for several reasons including nutritional deficiency, gastrointestinal tract abnormalities, parasitic infection, pernicious anemia, pancreatic disease, and certain medications. Gastric acid suppressants, methotrexate, metformin, and nitrous oxide can all cause vitamin B12 deficiency through different mechanisms. Nitrous oxide causes permanent oxidation of cobalt ions in vitamin B12, effectively inhibiting active vitamin B12 and leading to degeneration of myelin (Figure 2). Heavy and prolonged use of nitrous oxide can result in neurologic and hematologic effects due to functional vitamin B12 deficiency.⁵ Reversible cognitive decline and confusion can also be seen.⁶ Of note, similar symptoms may be seen in copper deficiency and vitamin E deficiency, and these causes should be ruled out.⁷

Vitamin B12 deficiency can lead to subacute combined degeneration, which presents with sensory deficits, weakness, ataxia, spasticity, and gait abnormalities.⁸ SACD is demyelination of the white matter of the spinal cord, specifically the dorsal column and lateral corticospinal tracts, that may be seen on T2-weighted MRI as hyperintense signals in the posterior column of the thoracic spine.⁹ Involvement of the dorsal and lateral corticospinal tracts leads to the loss of vibration sense, proprioception abnormalities, ataxic gait, and loss of two-point discrimination. If the spinothalamic tract is involved, neuropathy of the lower limbs is seen.⁷ In a number of cases, individuals also present with urinary retention, similar to our patient.²

Treatment for SACD should be aggressive and rapid to prevent irreversible neurological deficits. The vitamin B12 deficiency should be corrected with supplementation, first in parenteral form followed oral supplementation.⁸ Additionally, the underlying cause of the deficiency must be addressed. In the case of this patient, cessation of the offending agent, nitrous oxide, was strongly advised. Although laboratory values improve quickly, it may take 3–12 months for the neurological deficits to improve, and some may be permanent.⁸

4 CONCLUSION

Medical providers can easily overlook the use of nitrous oxide, and patients may consider this drug to be relatively harmless. However, nitrous oxide use can lead to vitamin B12 deficiency and, in turn, spinal cord subacute combined degeneration. The deleterious neurological effects can be irreversible if not treated quickly. Given its rapid onset and short half-life, there is no laboratory test for nitrous oxide use. Patients who present with neuropathy and vitamin B12 deficiency should be questioned about drug use, both prescribed and recreational. Thorough history taking is a crucial step to identify nitrous oxide misuse and educate patients about the potential risks.

AUTHOR CONTRIBUTIONS

Both authors contributed equally to the research, writing, and editing of this manuscript.

FUNDING INFORMATION

No funding was provided during the research and writing of this manuscript.

CONFLICT OF INTEREST

All authors declare that they have no conflicts of interest in this manuscript.

CONSENT

Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy