Although several cases of SCD associated with vitamin B12 deficiency induced by N2O abuse have been described, the relationship between the evolution of dynamic neuroimaging and clinical manifestations has never been reported. To the best of our knowledge, this is the first report of 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+) ion, which is a product of the methylation of Hcy (to form methionine), commonly reacts with methyltetrahydrofolate to regenerate methylcobalamin4. Once the cobalt ion is oxidized by N2O, methylcobalamin, as a cofactor of methionine synthase in the transfer of Hcy to methionine, subsequently inhibits S-adenosylmethionine, which is essential for the methylation of myelin sheath phospholipids5. Thus, inactivation of vitamin B12 metabolism results in the demyelination of the spinal cord6.
Few patients with cobalamin deficiency have normal serum vitamin B12 levels. According to the metabolic pathway described above, a normal serum level of vitamin B12 is not indicative of the precise or timely cellular availability of vitamin B12. Instead, elevated serum levels of Hcy or methylmalonic acid are better biomarkers for the diagnosis of cellular vitamin B12 deficiency7. Although the serum levels of vitamin B12 and folic acid returned to normal in this patient, elevated Hcy levels showed greater value as an indicator of cellular vitamin B12 deficiency. Thus, demyelination of the cervical spinal cord may still exist in this patient even if the serum vitamin B12 and folic acid levels are normal.
Moreover, the lag in the conventional MRI findings compared to clinical manifestations was 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 the clinical-radiological dissociation observed in our case may be related to the neuropathological basis of intramedullary and interstitial edema, similar to that observed in CPM. 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 manifest as restricted diffusion, indicating an energy failure, which results in cytotoxic edema.
DWI provides quantitative and qualitative functional information on the microdiffusion of water molecules at the cellular level and has been widely used for the evaluation of 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 the early stages. Hence, we hypothesize that T2-weighted imaging is not sensitive enough to reflect the early intramedullary and interstitial cytotoxic edema caused by SCD, which may be another possible reason for the clinical-imaging dissociation in the present case.
In conclusion, we recommend that N2O abuse should be considered in patients presenting with SCD, especially if the patient is young and otherwise healthy. The inability of serum vitamin B12 to reflect cellular vitamin B12 levels and that of T2-weighted imaging in revealing cytotoxic edema in the early stages may have contributed to the clinical-imaging dissociation. Thus, clinicians should 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 for possible clinical-imaging dissociation.