Though several cases of SCD associated with vitamin B12 deficiency induced by N2O abuse have been described, the relationship between the dynamic neuroimaging evolution and clinical manifestations of a patient with N2O-induced SCD has never been reported. To the best of our knowledge, this is the first report of a clinical-neuroimaging dissociation in a patient with N2O-induced SCD.
N2O induces SCD by irreversibly oxidizing the cobalt ion of vitamin B12 (cobalamin). The highly nucleophilic cobalamin (1+), created upon the methylation of Hcy to form methionine, commonly reacts with methyltetrahydrofolate to regenerate methylcobalamin4. Once the cobalt ion is oxidized by N2O, the methylcobalamin, as a cofactor of methionine synthase in transferring Hcy to methionine, subsequently inhibits S-adenosylmethionine, which is essential for the methylation of myelin sheath phospholipids5. Thus, inactivating vitamin B12 metabolism results in the demyelination of the spinal cord6.
Few cobalamin-deficient patients have normal serum vitamin B12 levels. According to the metabolic pathway described above, a normal level of serum vitamin B12 is not indicative of the precise or timely cellular availability of vitamin B12. Instead, elevated serum levels of Hcy or methylmalonic acid serve as better biomarkers for the diagnosis of cellular vitamin B12 deficiency7. Although the serum levels of vitamin B12 and folic acid of this patient returned to normal, the elevated Hcy showed greater value as an indicator of cellular vitamin B12 deficiency. That is to say, demyelination of the cervical spinal cord may still exist.
In addition, the lag of the conventional MRI findings behind the clinical manifestations is similar to that seen in central pontine myelinolysis (CPM). In 1996, SCD was classified as a pure myelinolytic disease with no apparent loss of myelin or areas of partial neuropathological remyelination8. Hence, we surmise that – similar to what may be observed in cases of CPM – the clinical-radiological dissociation observed in our case may relate to the neuropathological basis of intramedullary and interstitial edema. Hyperintensity on spinal cord diffusion-weighted imaging (DWI) and a corresponding hypointensity on the apparent diffusion coefficient maps have been previously reported in patients with SCD9,10. These acute demyelinating lesions manifested as restricted diffusion, indicating an energy failure that caused cytotoxic edema.
DWI provides quantitative and qualitative functional information on the microdiffusion of water molecules at the cellular level, and has been widely applied to evaluate a variety of brain disorders, such as acute cerebral infarction11. Similarly, DWI is superior to T2-weighted imaging for the diagnosis of cytotoxic edema in its early stages. Hence, we hypothesize that the T2-weighted imaging was not sensitive enough to reflect the early intramedullary and interstitial cytotoxic edema due to SCD, and may be another possible reason for the clinical-imaging dissociation of the present case.
In conclusion, we recommend that N2O abuse should be considered when patients present with SCD – especially if the patient is young and otherwise healthy. The inability of serum vitamin B12 to reflect cellular vitamin B12 levels and T2-weighted imaging to reveal cytotoxic edema in the early stages may have contributed to the clinical-imaging dissociation. Clinicians should, therefore, comprehensively assess the condition of patients with N2O-induced SCD, avoid terminating treatment due to the resolution of clinical symptoms and serological findings, and carefully evaluate worsening imaging results as a possible clinical-imaging dissociation.