Nitrous oxide-induced subacute combined degeneration of the spinal cord

Abstract

The differential diagnoses of a patient presenting with motor weakness is broad and requires a systematic approach at the Emergency Department when evaluating its underlying cause. While nitrous oxide neurotoxicity is uncommon, it is important to consider it as a possible differential in patients with preceding exposure, as treatment is readily available. We present a case report with magnetic resonance imaging images of subacute combined degeneration of the spinal cord due to nitrous oxide induced vitamin B12 deficiency.

Introduction

Nitrous oxide (N₂O), commonly known as laughing gas, is a colorless gas with a slightly sweet odor. It is an N- methyl-D-aspartate (NMDA) receptor antagonist with rapid onset and short duration of action that is commonly used in the medical field for its analgesic properties and at higher concentrations, as an adjunctive inhalational anesthetic agent.^1,2 Nitrous oxide is also commercially available in the food industry in cartridges known as ‘whipped cream chargers’ used to produce whipped cream and for flavoring beverages. ¹ Its accessibility and low cost have contributed to its increased recreational use referred to as ‘nanging’, particularly in the setting of parties or music festivals, to induce a state of euphoria, hallucinations or anxiolysis in recent years.^1,3,4

Acute adverse effects of nitrous oxide use include disorientation, hypoxia, barotrauma-related lung injuries and cold burns.^1,2 While occasional, low-dose use generally carries limited and reversible risks, prolonged, frequent use or use at high doses is associated with serious adverse effects, particularly that of neurotoxicity and anemia.^1,2,4 This case report details a patient presenting with lower limb weakness and numbness secondary to nitrous oxide-induced neurotoxicity.

Case report

A 24-year-old male with no significant medical history presented to the Emergency Department with three days of progressive lower limb weakness and numbness resulting in inability to ambulate. He denied any upper limb weakness or numbness, headache, dizziness, urinary or bowel incontinence, joint pain, rash, and preceding trauma. There was no family history of neurological pathology.

On physical examination, he was found to have predominantly left sided weakness in his lower limbs (Medical Research Council (MRC) Scale for Muscle strength grading 4/5 over left lower limb L2-S1 myotomes, 4/5 over right lower limb L2 myotome, and 5/5 over the remaining right lower limb myotomes). The sensation of fine touch was decreased over bilateral L4-S1 dermatomes. There was hypertonia and hyperreflexia of bilateral lower limbs with upgoing plantar reflexes. Abdominal reflexes were preserved, and examination of both upper limbs and cranial nerves were normal. There was no nuchal stiffness or weakness of neck flexors. A digital rectal examination performed to assess anal tone and saddle anesthesia was also normal. There was a palpable bladder and his post void residual urine was 300 milliliters, therefore an indwelling urinary catheter was inserted.

The clinical examination suggested an upper motor neuron pattern of weakness and numbness involving the lower limb, with possible differentials being myelopathy such as degenerative cervical myelopathy, neurodegenerative disease such as amyotrophic lateral sclerosis, demyelinating disease such as multiple sclerosis, vascular accidents such as ischemia or hemorrhage, and space occupying lesion involving the spinal cord. Blood tests were performed including complete blood count, renal panel with extended electrolytes, liver panel and thyroid function test – the only abnormalities were a hemoglobin of 13.2 g/dL (normocyctic and normochromic) and the white cell count of 2.83 x 10⁹/L. X-ray of the lumbar spine showed normal alignment with vertebral body heights and intervertebral disc spaces which were maintained. Magnetic Resonance Imaging (MRI) scan of the lumbosacral spine showed L4-5 disc desiccation with central disc protrusion causing mild indentation of the thecal sac with no evidence of spinal canal, lateral recess and foraminal stenosis. He was admitted to the inpatient unit for further evaluation.

The following morning, repeat physical examination found worsening weakness which progressed to involve C5-C8 myotomes over both upper limbs, impaired proprioception and vibration sensation of bilateral L4-S1 dermatomes, sustained ankle clonus bilaterally, as well as new anal tone laxity without saddle anesthesia. Further history from the patient revealed that his symptoms occurred after inhalation of nitrous oxide gas for recreational purpose. This raised suspicion of nitrous oxide-induced subacute combined degeneration of the spinal cord due to vitamin B12 deficiency. Further laboratory investigations revealed a low serum vitamin B12 level of 89 pg/ml (reference range: 245–890 pg/ml). MRI scan of the cervical spine (Figure 1) and thoracic spine (Figure 2) was performed. In the MRI cervical spine, there was abnormal long segment T2-weighted (T2w) hyperintensity seen in the cervical spinal cord that extended from C2 to C6 level which predominantly affects the dorsal columns in an ‘inverted V-shaped’ configuration. MRI thoracic spine also showed an abnormal short-segment T2-weighted hyperintensity in the distal thoracic spinal cord at T11 level, again affecting the dorsal columns with an ‘inverted V-shaped’ configuration. There were no enhancing extradural, intradural or intramedullary mass like lesions, abnormal T2-weighted signal abnormalities, and spinal cord compression.

Figure 1.

(a) to (d). In the sagittal T2w (a) and Short Tau Inversion Recovery (STIR) sequences (b), there is abnormal long segment T2w hyperintensity seen extending from C2 level up to C6 level, most prominent at C3 to C4 level (arrows). In axial T2w sequences ((c) and (d)) at C3 level, the T2w signal abnormality is seen along the dorsal columns of the cervical spinal cord and typically exhibits an ‘inverted V-shaped’ configuration (long thin arrows; (c)), with slight asymmetric prominence on right side (short thick arrow; (d)).

Figure 2.

(a) to (e). In the distal thoracic spinal cord at T11 level (arrow), there is another abnormal short segment T2w hyperintensity seen on both sagittal T2w (a) and sagittal STIR sequences (b). It shows subtle post-contrast enhancement of T1w post-gadolinium contrast sequences as well (c). In axial T2w sequences at T11 level, the abnormal T2w hyperintensity is seen along the dorsal column of the thoracic spinal cord, and shows typical ‘inverted V-shaped’ morphology (long thin arrows; (d)), with asymmetric prominence on right side (short thick arrow; (e)).

The patient was eventually diagnosed with posterolateral cord syndrome secondary to nitrous oxide-induced subacute combined degeneration of the spinal cord due to vitamin B12 deficiency. ⁵ He was started on intramuscular cyanocobalamin (1 mg) with documented improvement in his neurological deficits within hours. The patient was admitted for a total of 11 days, during which he was referred to rehabilitation medicine service for inpatient rehabilitation, which the patient declined. Subsequently, the patient requested for an against medical advice discharge for further treatment abroad. It was uncertain if the patient achieved full neurological recovery as he was lost to follow up.

Discussion

Approaching acute motor weakness

It is not uncommon for patients to present to the Emergency Department with complaints of limb weakness. Through thorough history and physical examination, emergency physicians can elicit specific characteristics with regards to the pattern of weakness, the onset and course of weakness, as well as the presence of associated symptoms to localize the likely site of the underlying pathology and subsequently direct investigations to a diagnosis.^6,7

When assessing a patient presenting with weakness, an upper motor neuron pattern of weakness with increased tone, hyperreflexia and positive Babinski sign suggests pathology of upper motor neuron which originates in the cerebral cortex and descends to the brainstem or spinal cord, whereas a lower motor neuron pattern of weakness with decreased tone, hypo- or areflexia and absent Babinski sign suggests pathology of the lower motor neuron which originates in the brainstem or spinal cord and innervates skeletal muscles. ⁸ Possible anatomical sites of upper motor neuron disease include cerebral lesions of the parasagittal region due to the somatotopic arrangement of motor fibers or pontine lesions, or spinal cord lesions with corticospinal tract involvement. On the other hand, anatomical sites of lower motor neuron disease are at the level of or distal to the anterior horn cells including peripheral nerve (neuropathy), neuromuscular junction, or muscle (myopathy). ⁹

Another consideration is the ascending, descending or diffuse pattern of weakness.^6,7 In those presenting with an ascending pattern of weakness, important differential diagnoses include transverse myelitis, tick paralysis and Guillain-Barre syndrome. In contrast, in patients presenting with a descending pattern of weakness with ocular or bulbar involvement preceding limb weakness, one should consider causes such as myasthenia gravis or Lambert-Eaton myasthenic syndrome, botulism or diphtheria. Where diffuse weakness is present, a broad list of differentials including periodic paralysis due to electrolyte abnormalities or thyrotoxicosis, toxicological causes such as organophosphate poisoning and myositis should be considered.

The timing of weakness can range from sudden onset which suggests a vascular cause such as cerebral or spinal infarct due to ischemia, dissection or bleeding; to gradual progression over hours which suggests metabolic or toxicologic cause; and over days to months which suggests neurologic condition due to neuropathy, neuromuscular disease or myopathy, as well as etiologies such as electrolyte abnormality, endocrinopathy and space occupying lesion.^6,7 Fluctuating course of weakness may be related to conditions like multiple sclerosis, while transient weakness may be due to conditions like hemiplegic migraine. Weakness which is fatigable on repeated testing is suggestive of a neuromuscular junction disease like myasthenia gravis.

Other associated symptoms and signs can also clue the emergency physician in to the likely site of disease. The presence of symptoms or signs such as neglect or extinction, dysphasia or aphasia, agraphia or acalculia, agnosia, hemianopia or gaze preference suggests a cerebral cortical lesion, and subcortical brainstem lesions may present with diplopia, nystagmus, dysphagia, dysarthria, or incoordination. ¹⁰ Bladder dysfunction with incontinence or urinary retention, in the context of motor weakness, should raise suspicion for spinal cord lesion. The presence of sensory symptoms or signs renders myopathies or neuromuscular junction pathologies unlikely, while the presence of fasciculations can suggest pathology originating from anterior horn cells. ⁹ For the emergency physician, it is important to evaluate for high risk respiratory or bulbar symptoms or signs, such as tachypnea, dysphonia, dysphagia, poor secretion management. These features are in keeping with lower motor neuron lesions involving cranial nerves IX to XII, cervical spinal cord lesions especially those involving C3-5 myotomes which innervate the diaphragm, neuropathies involving T2-6 that supply the intercostal muscles or neuromuscular junction diseases and myopathies involving chest wall muscles. In these patients, weakness of active neck flexion, forced vital capacity <20 mL/kg or negative inspiratory force <30 cm H₂O should prompt early intubation. ¹¹

Depending on the differential diagnoses, initial investigations may include blood glucose levels, serum electrolytes, thyroid function tests, creatine kinase, as well as targeted imaging investigations such as computer tomography scan of the brain, or x-ray and MRI of the spine. Early lumbar puncture for analysis of cerebrospinal fluid can also be considered to evaluate for infectious or immunological etiologies.

Nitrous oxide related neurotoxicity

Nitrous oxide binds and irreversibly inactivates vitamin B12, which functions as a co-factor for methionine synthetase, a crucial enzyme in one-carbon metabolism required for the formation of methionine and tetrahydrofolate (THF). ¹² Methionine is required for methylation of myelin sheath phospholipids while THF is needed for thymidine and DNA production.^2,12

Acute nitrous oxide use is associated with generally mild, self-limiting side effects such as nausea, hypoxia, disorientation and diminished motor coordination leading to falls. ¹ Steep temperature drop that occurs when pressurized nitrous oxide expands as it is released from containers on inhalation can cause cold burns or frostbite. Users may also sustain barotrauma in the form of pneumothorax or pneumomediastinum from inhaling pressurized gas.

Chronic nitrous oxide use can lead to more serious side effects such as megaloblastic anemia, bone marrow suppression, depression and dependence, as well as subacute combined degeneration of the spinal cord dorsal columns caused by vitamin B12 deficiency.^4,5,13 Patients with subacute combined degeneration of the spinal cord dorsal columns can present with reduced proprioception and vibration sensation, sensory ataxia, hyperreflexia, spasticity, weakness and bladder dysfunction. Laboratory tests may reveal normal or low-normal vitamin B12 levels, elevated homocysteine and methylmalonic acid levels.^1,4 Classically, the inverted ‘V’ sign will be seen on MRI of the spinal cord, with bilateral T2-weighted signal hyperintensity and edema involving the dorsal columns. ⁵ Treatment of nitrous oxide neurotoxicity involves cessation of use, vitamin B12 administration even if serum levels are normal, and methionine administration.^4,12 Additional folinic acid supplementation should be considered in the presence of bone marrow supplementation. Patients with recreational use of nitrous oxide should be referred to drug service if they exhibit symptoms of depression and dependence.^4,13

Conclusion

The differential diagnoses of a patient presenting with motor weakness is broad and requires a systematic approach when evaluating its underlying cause. While nitrous oxide neurotoxicity is uncommon, it is important to consider it as a possible differential in patients with preceding exposure, as treatment is readily available.