Peripheral Neuropathy Linked to Recreational Nitrous Oxide Use: A Case Report

Introduction

Apart from its intended uses in automotive performance and anesthesia, nitrous oxide (N2O) is often misused recreationally with lifetime prevalence reported as 29.4% in the United States [1]. Its most common colloquialisms are “laughing gas” and “whippets”, and N2O is often directly inhaled from cylindrical metal containers or balloons [2]. Contrary to general belief among users, N2O exposure can have dangerous effects, including demyelinating neuropathies and myelopathies due to vitamin B12 inactivation [3]. B12 acts as a cofactor for use in anabolic pathways, including methylation of neuronal lipids and proteins [4]. N2O irreversibly oxidizes the cobalt core of vitamin B12, potentially causing symptoms within days due to disruption of cellular metabolism [5,6]. This established role explains the neurologic sequelae of B12 deficiency, most commonly manifesting as paresthesia, unsteady gait, and weakness which can be due to peripheral neuropathy or degeneration of the spinocerebellar, lateral corticospinal, and dorsal column tracts of the spinal cord [7].

Low levels of B12 are common, seen in about 6% of people under age 60 and 20% over age 60 in the United States and United Kingdom and has many possible causes, including malabsorption, dietary insufficiency, and processes that limit intrinsic factor activity [8]. Vitamin B12 deficiency can be diagnosed by decreased serum B12 level or, in uncertain cases, by using methylmalonic acid levels, which demonstrates increased sensitivity [9,10]. Parenteral or high-dose oral vitamin B12 supplementation is an effective treatment, especially with early initiation [10].

Although back injury from trauma, such as from a motor vehicle collision (MVC), and N2O-induced B12 deficiency can overlap in neurologic manifestations, an important distinction is that the presentation with N2O is more delayed compared to the immediate acuity of a mechanical injury. This report describes the case of a 24-year-old man with a history of recreational N2O inhalation use presenting with lower limb weakness and paresthesia due to vitamin B12 deficiency.

Case Report

A 24-year-old man with no medical history presented with low back pain and bilateral lower extremity numbness and tingling starting 3 days prior to his presentation. The patient noted that he was involved in an MVC 5 days prior to his presentation, so 2 days before the onset of his symptoms. He was the passenger in a rear-ended vehicle, denying loss of consciousness, head trauma, or difficulty ambulating immediately after. Following the MVC, the patient went to a party later that night. In addition to the delayed-onset neurologic symptoms, he reported difficulty with ambulation, prompting the use of a crutch. There was no saddle anesthesia or urinary or fecal incontinence. He had no prior history of similar issues. In the initial interview, he admitted to social alcohol use and marijuana as a sleep aid.

Vitals upon presentation were: blood pressure, 166/94 mmHg; heart rate, 94 bpm; respiratory rate, 18 breaths per minute; O2 saturation, 97% on room air; body temperature, 36°C. On physical examination, the patient was alert and oriented to person, place, and time. His pupils were equal, round, and reactive to light, and all extraocular movements were intact. His facial sensation was intact throughout with no facial droop. His hearing was normal bilaterally. The palate, uvula, and tongue were midline. Full strength was exhibited in shoulder shrugging, head-turning, and all extremities showed normal sensation and vibration perception throughout. Proprioception was intact. Signs of cerebellar dysfunction were absent. Deep tendon reflexes were 2+ throughout. Notably, we observed an apraxic gait and positive Romberg sign. Laboratory tests were remarkable for erythrocyte sedimentation rate (ESR) 38 mm/h (reference 0–10 mm/h), C-reactive protein (CRP) 1.37 mg/dL (reference <0.5 mg/dL), and vitamin B12 <150 pg/mL (reference 250–1100 pg/mL). Additionally, the patient was mildly anemic at 11.7 g/dL (reference 13–17 g/dL) and although within the normal range, mean corpuscular volume was 96 (reference 80–100) which was near the upper limit, and is consistent with B12 deficiency. The remainder of the blood work is shown in Table 1. Urine toxicology was positive for marijuana and cocaine. Imaging – chest X-ray, non-contrast CTs of the head and spine (cervical, thoracic, and lumbar), CT angiograms of the neck and chest with intravenous contrast, and MRI of the lumbar spine – showed no acute disease processes.

At this juncture, we suspected the neurologic symptoms were more likely attributable to the severely low B12 level than the MVC with unclear etiology. Common causes of B12 deficiency – dietary insufficiency, gastric bypass, and medications – had been ruled out through comprehensive interviewing, absence of abnormal lab values, and lack of imaging study findings. The patient consumed a regular diet, had no surgical history, and denied use of medications on a regular basis. The patient denied any family history of similar symptoms.

Autoimmune pernicious anemia was also a possible differential diagnosis. However, given the acute nature of the neurologic symptoms, the clinical context was deemed to favor B12 deficiency rather than classic pernicious anemia, which typically presents in older adults and is associated with chronic symptoms, and macrocytic anemia [11]. Serological exclusion of autoimmune pernicious anemia was therefore not completed. His lab values were within normal limits, with the exception of low hemoglobin and hematocrit. Additionally, the patient denied any history of B12 deficiency. The patient was administered 1000 mcg of vitamin B12 intramuscularly.

Given the history of substance use, we postulated N2O use as a possible cause for the B12 deficiency, prompting further interviewing of the patient. He then reported recreational N2O inhalation on the night of the MVC, as well as chronic use within the past year without specifying any details. The patient noted that he woke up with the new reported neurologic symptoms 2 days after using N2O. Several hours after B12 administration, he noted significant symptomatic improvement, such as cessation of paresthesias and restoration of normal gait. Thus, the need for further workup, such as homocysteine and methylmalonic acid levels, pernicious anemia workup, and electromyogram/nerve conduction studies was deemed unnecessary due to clinical improvement. Similarly, since the patient was not reporting any neck pain and there was evidence of clinical improvement, a cervical MRI was not obtained.

Considering the updated social history, symptom improvement after B12 repletion, and unremarkable imaging, the bilateral lower extremity paresthesia was clinically attributed to B12 deficiency secondary to N2O use. The low back pain was deemed a soft tissue strain caused by the MVC. The patient was advised to take over-the-counter B12 supplements, educated on the effects of N2O, and prescribed physical therapy for his lumbar strain. Since the patient improved clinically and was medically stable, he was deemed stable for discharge from the emergency department without admission. The patient was advised to follow-up with his primary care physician for further management.

Given this diagnostic challenge, the patient agreed to our presentation of his rare case in the medical literature to highlight the importance of considering substance use when evaluating a patient with unexplained neurologic signs and symptoms. A patient Consent-to-Disclose Form was signed. Ethical approval was obtained from Arrowhead Regional Medical Center’s Institutional Review Board committee (Case Study 25-03).

Discussion

This patient presented with lower back pain, gait instability, and bilateral lower extremity paresthesia in the setting of a recent MVC. The initial workup focused on ruling out structural spinal cord damage and other medical emergencies. CT of the cervical, thoracic, and lumbar spine and MRI of the lumbar spine were all unremarkable with no evidence of myelopathy or radiculopathy. Post-traumatic neuropathy was also consistent with his presentation as MVC trauma can cause paresthesias and gait instability, with the MVC itself accounting for musculoskeletal back pain, which is seen frequently after MVCs [12]. However, although post-traumatic neuropathy is consistent with this patient’ onset of symptoms within a few days of his accident, the rapid resolution of symptoms is uncommon and the timing of improvement after vitamin B12 supplementation, in addition to complete blood count notable for low hemoglobin and slightly elevated mean corpuscular volume along with unremarkable imaging, supports B12 deficiency as a more likely diagnosis.

As opposed to common causes of B12 deficiency, such as malabsorption, dietary insufficiency, and pernicious anemia, an abrupt onset of symptoms should prompt consideration of N2O as a possible cause [13]. This is especially relevant in areas with high prevalence of N2O use, and there are increasing numbers of case reports documenting subacute combined degeneration or severe peripheral neuropathy following recreational N2O abuse [13–17]. While the literature often focuses on cases with clear-cut vitamin B12 deficiency, our case highlights a diagnostic challenge where symptoms were initially confounded by recent trauma. Such diagnostic challenges are frequently compounded by incomplete patient histories and, similar to our experience, previous reports have noted that N2O use is often not disclosed during initial patient interviews and may only be identified through repeated, directed questioning [13,17]. This underscores the importance of maintaining a high index of suspicion and proactively screening for inhalant use, particularly as serum B12 levels may remain within reference ranges. In uncertain cases or cases of functional B12 deficiency, elevated methylmalonic acid levels serve as a more sensitive diagnostic marker [15,18]. Guidelines call for treating all cases of B12 deficiency immediately, with a straightforward approach: direct repletion to address the underlying cause. In cases with neurologic manifestations, aggressive repletion is prudent since such deficits can be irreversible [19]. Parenteral administration is advised to ensure rapid absorption; however, in patients without concern for malabsorption, data suggests that oral dosing is equivalent or possibly superior in correcting serum levels and neurologic symptoms [10]. B12 dosing recommendations include 1000 mcg for at least 3 days over 1–2 weeks, followed by either 1 month of weekly doses or dosages every 1–3 months. Throughout treatment, frequent monitoring for full resolution of symptoms and eradication of the cause can guide when to discontinue supplementation [10].

Specifically following N2O-induced deficiency, systematic data regarding the neurologic response to B12 correction is not well documented. However, across all causes of B12 deficiency-induced neurotoxicity, vitamin correction consistently provides improvement in deficits, with response reliably beginning within the first 3 months of treatment. With B12 correction, the degree of neurologic symptom reversibility relates inversely to the duration of the deficiency and its clinical severity [10,20]. These phenomena boded well for our patient, who presented relatively promptly after onset and with mild symptoms, with the likely cause withdrawn.

Strengths of this case include a systematic approach to rule out alternative causes of B12 deficiency and the timely recognition of a reversible cause. Limitations include self-reported N2O use, limited generalizability, and lack of long-term follow-up since the patient was treated in the emergency department without admission to the hospital.

In this case, clinical recognition of this timing led to focused questioning, which revealed the presence of N2O use not initially disclosed. His paresthesia improved after B12 administration, and he was counseled on the risks of further N2O use. Given the potential long-term consequence of subacute combined degeneration due to B12 deficiency, recognizing this clinical picture is key to reaching a prompt diagnosis, treatment course, and counseling to reduce the risk of long-term sequelae.

Conclusions

Vitamin B12 deficiency is an important cause of neurological conditions. While it may be intuitive to attribute acute onset neurologic symptoms to trauma, physicians should be aware of the risk of prematurely coming to this conclusion, and should routinely screen for substance abuse. Similarly, when an easily identifiable cause of B12 deficiency is not apparent and the onset of neurologic symptoms is rapid, N2O use should be investigated, especially in young patients with known recreational drug use. B12 supplementation can lead to impressive symptomatic improvement, and educating the patient on N2O’s harms can lower the risk of associated neurologic complications that are not always reversible.