Clinical-radiological dissociation of a patient with nitrous oxide-induced subacute combined degeneration: a case report

doi:10.21203/rs.2.494/v1

Download PDF

Case report

Clinical-radiological dissociation of a patient with nitrous oxide-induced subacute combined degeneration: a case report

https://doi.org/10.21203/rs.2.494/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 17 Mar, 2020

Read the published version in BMC Neurology →

You are reading this older preprint version

Read the latest preprint version →

Backgroud

Recently, a number of studies have reported subacute combined degeneration (SCD) induced by nitrous oxide (N2O) abuse. But there is no report about the relationship between the neuroimaging dynamic evolution and clinical manifestations in a patient with N2O-induced SCD.

Cases presentation

Herein we described a 24-year-old male who developed SCD with inverted V-sign on spinal column caused by massive N2O inhalation. The evolution of conventional MRI findings lagged behind clinical manifestations. It seemed to occur a clinical-radiological dissociation.

Conclusions

Both the inability of serum vitamin B12 to reflect cellular vitamin B12 in time and the low-sensitivity of T2-weighted images to reveal cytotoxic edema can account for the clinical-radiological dissociation.

Internal Medicine Specialties

subacute combined degeneration

nitrous oxide

vitamin B12 deficiency

magnetic resonance imaging

Subacute combined degeneration (SCD), a reversible and treatable neurological complication of vitamin B12 deficiency, is normally observed in patients suffered from malabsorption syndromes, inadequate intake in strict vegetarians and surgical procedures1. In recent years, several sporadic cases of the SCD induced by nitrous oxide (N2O) abuse have been described2. However, as far as we know, there is no report about the relationship between the neuroimaging dynamic evolution and clinical manifestation in a patient with N2O-induced SCD. Therefore, we reported a case of a young man diagnosed with SCD caused by massive N2O inhalation, which seemed to occur a clinical-radiological dissociation.

A 24-year-old man in a wheel-chair presented with numbness of all extremities and worsening lower-extremity weakness for approximately 20 days. He inhaled N2O about an average of 100-200 "whippit" cartridges per day, in order for recreation for at least three months. The patient demonstrated good dietary intake without alcohol use. There was neither a history of smoking nor illicit drug use. Neurologic examination showed clear consciousness, mild weakness in upper-limb and severe weakness in lower-limb, decreased sensation to vibration and pinprick, bilateral hyper-reflexia, sensory ataxia, positive Babinski sign, Romberg sign and Lhermitte's sign. Laboratory tests revealed decreased serum levels of red blood cell(RBC) (3.32×1012 /L, reference range 4.30-5.80×1012 /L) and hemoglobin(Hb) (118.4g/L, reference range 130-175g/L). Both the serum vitamin B12 (98.2 pmol/L, reference range 145-637 pmol/L) and folic acid (8.38 nmol/L, reference range 8.83-60.80 nmol/L) were decreased. Serum homocysteine(Hcy) was strongly elevated (>50μmol/L, reference range 5.46-16.20 μmol/L), indicating a functional vitamin B12 deficiency at the cellular level. The result of cerebrospinal ﬂuid(CSF) was normal, and findings on inflammatory, infectious and immune biomarkers of both CSF and serum were also unremarkable. The spinal magnetic resonance imaging(MRI) showed hyperintensities involving the posterior columns from C2 to C5 on T2-weighted imaging(T2WI) (Fig. 1a), with inverted V sign on the axial transverse image (Fig. 1c). The brain and thoracic MRI confirmed normal findings.

The patient was diagnosed with SCD of the spinal cord induced by N2O consumption. Treatment with a high dose of supplementary of intramuscular vitamin B12 injections (1.5 mg per day), oral folic acid (15mg per day), and abstinence of N2O simultaneously led to gradual improvement of symptoms. One month later, the symptoms of weakness and paresthesia resolved evidently. He was able to walk unsupported with remaining gait impairment. The serum levels of RBC, Hb and folic acid improved to normal. The concentration of serum vitamin B12 increased to more than 1476pmol/L (the maximum measurable value), but the serum Hcy still elevated (19.02μmol/L). At the same time, an interesting phemonenon was found. Both the clinical symptoms and laboratory values improved significantly, while the hyperintensities on T2WI extended horizontally and longitudinally from C1 to T1(Fig. 1 b), looked like “ball” at axial transverse image (Fig 1. d). It seemed to occur a clinical-radiological dissociation. It was worth noting that there was neither hormone used nor N2O exposure, and the patient was discharged with vitamin B12 supplementation regularly.

Though there are several cases concerning SCD associated with vitamin B12 deficiency induced by N2O abuse, the relationship between the neuroimaging dynamic evolution and clinical manifestation in patients with N2O-induced SCD has never been reported before. To our knowledge, to date, this is the first report about clinical-neuroimaging dissociation in the patient with N2O-induced SCD. N2O induces SCD by irreversibly oxidising the cobalt ion of vitamin B12 (cobalamin). The highly nucleophilic +1 cobalamin, created on methylation of Hcy to form methionine, commonly reacts with methyltetrahydrofolate to regenerate the methylcobalamin3. Once the cobalt ion is oxidated by N2O, the methylcobalamin as a cofactor of methionine synthase in the production of methionine and subsequently S-adenosylmethionine could be inhibited, which is essential for methylation of myelin sheath phospholipids4. Thus, inactivating of the vitamin B12 metabolism results in demyelination of the spinal cord5.

Nevertheless, clinically, among cobalamin-deficient patients, a few have normol level of serum vitamin B12. According to the metabolic pathway aboved, a normal level of serum vitamin B12 is not reflective of the precise or timely availability of vitamin B12 in cell. Instead, the evelated serum levels of methylmalonic acid(MMA) and Hcy are better biomarkers for diagnosis of cellular vitamin B12 deficiency6. In our patient, although the serum levels of vitamin B12 and folic acid return to normal values, the elevated Hcy is a more valuable marker of cobalamin deficiency in cell. That is to say, the demyelination of the cervical spinal cord may still exist.

In addition, the phenomenon of conventional MRI findings lagging behind clinical manifestations brings us to central pontine myelinolysis(CPM). In 1996, SCD has been classified as a pure myelinolytic disease with no apparent loss of myelin or areas of partial remyelination neuropathologically7. Hence, we suppose that the feature of clinical-radiological dissociation in our case may be related to the neuropathological basis of intramedullary and interstitial oedema, just like CPM. Hyperintense signal on spinal cord diffusion-weighted imaging(DWI) and a corresponding hypointensity on the apparent diffusion coefficient(ADC) map in a patient with SCD can be seen in several sporadic cases nowadays8,9. These acute demyelinating lesions manifested as restricted diffusion indicate an energy failure leading to cytotoxic edema.

DWI provides quantitative and qualitative functional information on the microdiffusion of water molecules at the cellular level, which has been widely applied to evaluate a variety of brain disorders, like acute cerebral infarction10. Similarly, DWI is more sensitive to diagnose the cytotoxic edema than T2WI in the early time. Consequently, we hypothesized that the inability of T2WI to reflect intramedullary and interstitial cytotoxic edema timely of SCD was another possible reason for the clinical-imaging dissociation.

In conclusion, this case suggests that clinicians should take into account the possibility of N2O abusing in patients with SCD, especially healthy young ones. The inability of serum vitamin B12 to reflect cellular vitamin B12 in time and the low-sensitivity of T2WI to reveal cytotoxic edema can account for the clinical-radiological dissociation.

SCD: subacute combined degeneration

N2O: nitrous oxide

RBC: red blood cell

Hb: hemoglobin

MCV: mean corpuscular volume

MCH: mean corpuscular hemoglobin

Hcy: homocysteine

CSF: cerebrospinal ﬂuid

MRI: magnetic resonance imaging

T2WI: T2-weighted imaging

MMA: methylmalonic acid

CPM: central pontine myelinolysis

DWI: diffusion-weighted imaging

ADC: apparent diffusion coeffcient

Ethics approval and consent to participate

Not applicable

Consent for publication

Written informed consents were obtained from the patients themselves. A copy of the written consent is available for review by the editor if you want. We clarify the consent covered the publication of the information included in the case reports, as well as any associated images.

Availability of data and matarials

Not applicable. For protecting patient privacy.

Competing interests

The authors declare that they have no competing interests.

Funding

This study was supported by the National Natural Science Foundation of China [81502181 and 81100243].

The funding body supplied this manuscript with money and researchers in the study and collection, analysis, and interpretation of data and in writing the manuscript.

Authors’ contributions

JJ: concept and design of study, interpretation of data, drafting and revising the manuscript.

XS: critical revision of the manuscript for important intellectual content, study supervision.

all authors have read and approved the manuscript.

Acknowledgments

The authors would like to thank the patients themselves and their families for participation and help.

1. Green R, Allen LH, Bjørke-Monsen AL, Brito A, Guéant JL, Miller JW, Molloy AM, Nexo E, Stabler S, Toh BH, Ueland PM, Yajnik C. Vitamin B12 deficiency. Nat Rev Dis Primers. 2017; 3:17040.

2. Patel KK, Mejia Munne JC, Gunness VRN, Hersey D, Alshafai N, Sciubba D, Nasser R, Gimbel D, Cheng J, Nouri A. Subacute combined degeneration of the spinal cord following nitrous oxide anesthesia: A systematic review of cases. Clin Neurol Neurosurg. 2018; 173:163-168.

3. Jordan JT, Weiser J, Van Ness PC. Unrecognized cobalamin deficiency, nitrous oxide, and reversible subacute combined degeneration. Neurol Clin Pract. 2014;4(4):358-361.

4. Hathout L, El-Saden S. Nitrous oxide-induced B12 deficiency myelopathy: Perspectives on the clinical biochemistry of vitamin B12. J Neurol Sci. 2011;301(1-2):1-8.

5. Hunt A, Harrington D, Robinson S. Vitamin B12 deficiency. BMJ. 2014;349: g5226.

6. Briani C, Dalla Torre C, Citton V, Manara R, Pompanin S, Binotto G, Adami F. Cobalamin deficiency: clinical picture and radiological findings. Nutrients. 2013;5(11):4521-4539.

7. Powers J. Pathology of myelin. Mol. Chem. Neuropathol. 1996; 27:31-38.

8. Tian C. Hyperintense signal on spinal cord diffusion-weighted imaging in a patient with subacute combined degeneration. Neurol India.2011;59(3):429-431.

9. Kim EY, Lee SY, Cha SH, Yi KS, Cho BS, Kang MH. Subacute combined degeneration revealed by diffusion-weighted imaging: a case study. Clin Neuroradiol. 2013;23(2):157-159.

10. Simonsen CZ, Madsen MH, Schmitz ML, Mikkelsen IK, Fisher M, Andersen G. Sensitivity of diffusion- and perfusion-weighted imaging for diagnosing acute ischemic stroke is 97.5%. Stroke. 2015; 46(1):98-101.