Glucocorticoid treatment of myeloneuropathy induced by nitrous oxide toxicity
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.237029
Source of Support: None, Conflict of Interest: None
Nitrous oxide (N2O) is clinically employed as an anesthetic, but its recreational use has increased in recent years. Irreversible oxidation of cobalt by N2O renders methylcobalamin inactive, which is required for methionine biosynthesis. This can cause neurological complications, including myeloneuropathy.
A 19-year old Chinese student studying in the US presented with numbness and weakness in her extremities that had developed over the previous 16 days. She stated that her symptoms had worsened over the previous 6 days and that she was beginning to experience difficulty in walking caused by a lack of balance and the sensation that she had “lost” her legs. She also felt that her hands were becoming “clumsy” and she evidenced flexion contractures of the fingers. She also suffered from a psychological condition. She denied experiencing blurred vision, nausea, vomiting, headache, back pain, abdominal pain, constipation, or urinary retention. She had no significant medical history. Her family history was unremarkable, and she had no history of tobacco use or significant alcohol consumption. She was not regularly taking any medication.
Upon further questioning, her social history was remarkable in that she engaged in recreational N2O inhalation. Bulbs containing N2O (“Whippets”) are sold in supermarkets and are intended to be used to make whipped cream. Approximately 10 months prior to presentation, our patient was first exposed to N2O at a party with friends. Her use of the gas gradually increased and she regularly used N2O approximately five or six times weekly with about 100 bulbs per se ssion for nearly 9 months.
On physical examination, manual muscle tests (MMTs) revealed weakness (scores 4/5) in both upper limbs and the proximal and distal regions of both lower limbs (scores − 4/5). Signs of knee hyperreflexia and ankle hyporeflexia were noted. Light touch sensations were impaired below the sixth cervical vertebra, and impaired vibratory sensations were noted in both lower limbs. Proprioception was diminished in both the toes and feet. The Romberg sign was positive, but the Lhermitte sign was negative. The Babinski sign was bilaterally positive. Cardiac, lung, and abdominal examinations were unremarkable.
Initial laboratory tests revealed normal electrolyte levels and renal function. No anemia was evident, but a standard blood workup revealed a mean corpuscular volume (MCV) of 101.9 fL (normal, 82.6–99.1 fL). The initial serum vitamin B12 level was in the low-to-normal range at 249 pg/mL (normal, 179–1,162 pg/mL), and the serum folate level was also normal at 8.0 ng/mL (normal, 2.7–34 ng/mL). Serum homocysteine level was elevated to 38.8 μmol/L (normal, <15 μmol/L). The blood sugar level, thyroid function tests and copper and ceruloplasmin levels were normal. No antibodies against syphilis, cytomegalovirus, human immunodeficiency virus (HIV), or hepatitis C virus (HCV) were detected. She was negative for autoantibodies against intrinsic factor and parietal cells, as well as for anti-nuclear factor, lupus anticoagulant, anti-cardiolipin antibodies, p-anti-neutrophil cytoplasmic antibody (ANCA), and c-ANCA. Cerebrospinal fluid parameters were within the normal range.
The initial spinal cord T2-weighted magnetic resonance imaging (MRI) revealed symmetrical hyperintense signal changes in the posterior columns at levels C2–C6 [Figure 1]. On T1-weighted imaging, the cervical spinal cord was slightly expanded [Figure 1]. Brain MRI revealed no abnormality. On electromyography, bilateral tibial and peroneal nerves exhibited reduced motor conduction velocities. Bilateral sural nerves exhibited reduced sensory conduction velocities. The F-wave amplitudes of bilateral tibial nerves were reduced. The somatosensory evoked potentials clearly indicated that the deep sensation pathways were impaired.
In differential diagnosis, we considered autoimmune conditions (autoimmune myelopathy, Guillain–Barré syndrome), infection (human immunodeficiency virus [HIV]-1 associated myelopathy, and neurosyphilis), a nutritional ailment (vitamin B12 or copper deficiency), demyelination (multiple sclerosis), and a neoplastic disorder (paraneoplastic syndrome). In addition, we considered methylmalonic acidemia.
During hospitalization, vitamin B12 0.5 mg was given intramuscularly twice daily. Spinal cord MRI [Figure 2] performed after 20 days of vitamin B12 replacement therapy showed that the lesions had not improved; indeed, the cervical spinal cord had expanded further. To reduce the spinal cord edema, methylprednisolone 80 mg was given via an intravenous drip once daily for 5 days and was then decreased gradually. Her neurological deficits gradually improved. On physical examination at discharge, the myodynamia had improved, and the manual muscle testing (MMT) scores of all limbs were almost normal (5-/5). Knee reflexia was normal, but ankle hyporeflexia remained. The light touch sensation impairment was evident below the T4 level. Proprioception was normal. The left Babinski sign was negative, but the right Babinski sign was suspiciously positive. At the 1-month follow-up, spinal cord MRI [Figure 3] revealed that the neurological deficits had almost completely resolved, except for weakness of hallux dorsiflexion. Complete recovery was evident at the 1-year follow-up.
On presentation, the MCV was 101.9 fL (normal, 82.6–99.1 fL) and posterior spinal column changes were evident on MRI. Electromyography revealed impairment of the peripheral nerves with loss of proprioception and progressive weakness. These findings, combined with other data, indicated that myeloneurolopathy was most likely in play. The medical history and blood tests excluded pernicious anemia, acquired malabsorption, and malnutrition. Unfortunately, we did not measure the organic acid levels of blood or urine and we did not schedule relevant genetic testing. However, the medical history and therapeutic response indicated that methylmalonic acidemia could be excluded. Our final diagnosis was N2O-induced myeloneurolopathy with peripheral neuropathy.
N2O irreversibly oxidizes the cobalt ion from the 1+ to the 3+ valence state, rendering methylcobalamin inactive. Normally, transfer of a methyl group from methylcobalamin is a step in the pathway of conversion of homocysteine to methionine. Methyltetrahydrofolate is the methyl group donor; the methyl group acceptor is homocysteine. Thus, tetrahydrofolate (THF) is regenerated and methionine is synthesized. When methylcobalamin is unavailable, the synthesis of both methionine and tetrahydrofolate is reduced. Methionine is required for methylation of phospholipids of the myelin sheath. Inadequate synthesis of methionine can trigger demyelination of the nervous system (including the spinal cord), peripheral neuropathy, and optic atrophy. Inadequate levels of tetrahydrofolate (THF) impair deoxyribose nucleic acid (DNA) synthesis, causing megaloblastic anemia, diarrhea, glossitis, and other bowel disturbances.
The literature describes neurological deficits caused by the use of N2O as an anesthetic ,,,, or for recreational purposes.,,,, Neurological complications caused by N2O may develop after either short-term inhalation (usually as an anesthetic) or long-term inhalation (for recreational purposes). The symptom onset in patients who undergo short-term N2O inhalation ranges from days to months. These patients usually have subclinical vitamin B12 deficiencies prior to the administration of anesthesia,,, and may thus be particularly susceptible to short-term N2O exposure. Patients who chronically abuse N2O usually lack subclinical vitamin B12 deficiencies; indeed, the serum B12 level may be normal even when neurological deficits are evident., In patients with short-term inhalation of N2O, inhibition of vitamin B12 metabolism is the principal cause of neurological complications. Upon vitamin B12 replacement, the prognosis is good. However, vitamin B12 replacement is not useful in some patients who chronically abuse N2O (usually at high doses); the symptoms may progress  and new neurological deficits may arise. This indicates that the neurological complications caused by N2O may be caused not only by inhibition of vitamin B12 metabolism but also by N2O toxicity per se (including a direct toxic effect and the toxicity caused by methylmalonic acid). In N2O-abusing patients, N2O toxicity per se may be the principal trigger of neurological deficits. We prescribed a high-dose vitamin B12 supplementation for our patient, but her symptoms did not improve. Repeat MRI of the cervical spine even showed that the expansion of cervical spinal cord had progressed. Methylprednisolone was added, following which neurological deficits gradually improved. This suggests that N2O toxicity per se might be the principal cause of neurological symptoms in chronic N2O abusers. No dose–effect curve for N2O is as yet available. Also, the meaning of “high-dose” N2O is unclear.
To the best of our knowledge, no prior report has described a patient with N2O-induced myeloneurolopathy whose symptoms did not markedly improve until glucocorticoid therapy was commenced after it became clear that B12 replacement therapy was not working. Our case highlights the fact that N2O toxicity per se is the principal cause of symptoms in patients chronically exposed to high-dose N2O. Spinal cord T2-weighted MRI revealed symmetrical hyperintense signal changes in the posterior columns, but gadolinium enhancement was not evident. However, Ernst et al., found that MRI of patients with N2O-induced myeloneuropathy featured a prominent and extensive enhancement.
Treatment of N2O-induced myeloneuropathy includes removal of the offending agent and a high-dose vitamin B12 replacement. Other supplements, including oral methionine, have been suggested. To the best of our knowledge, there have been no reports of cases receiving glucocorticoid therapy. As vitamin B12 replacement did not work and as MRI imaging revealed marked edema suggestive of N2O toxicity, we added a glucocorticoid, and the symptoms and physical signs improved.
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The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that name and initial will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
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[Figure 1], [Figure 2], [Figure 3]