Skip to main content

Serum copper decrease and cerebellar atrophy in patients with nitrous oxide-induced subacute combined degeneration: two cases report

Abstract

Background

Subacute combined degeneration (SCD) is a neurological complication commonly associated with vitamin B12 deficiency. It can result from nitrous oxide (N2O) abuse and cause neuropsychiatric symptoms. However, there has been no literature regarding alterations of serum copper and cerebellum in SCD patients.

Case presentation

We reported two cases of young SCD patients with histories of N2O abuse. In these cases, elevated homocysteine, macrocytic anemia, spinal cord abnormalities, and peripheral nerve injuries were detected. In addition, decreased serum copper level and cerebellar atrophy were reported for the first time. The patients’ symptoms improved after withdrawal of N2O exposure and vitamin B12 supplements.

Conclusion

We reported two SCD cases with serum copper alteration and cerebellar atrophy after N2O abuse for the first time. These might be crucial complements to the diagnosis of SCD.

Peer Review reports

Background

Subacute combined degeneration (SCD) is a neurological disease usually induced by vitamin B12 deficiency [1,2,3,4]. Previous studies demonstrate that SCD can result from recreational nitrous oxide (N2O) abuse and cause various neuropsychiatric disorders [5,6,7,8,9]. However, no literature has been concerned about the serum copper and cerebellar changes through the diagnostic process. Here for the first time, we report two cases of SCD patients induced by N2O abuse with decreased cupric ion and cerebellar atrophy, intending to explore new clinical features of the disease.

Case presentation

Case 1

A 20-year-old woman complained of weakness and numbness in both lower limbs for 10 days. She had inhaled N2O gas for over a year before admission. Physical examination showed decreased muscle strength in both lower limbs (grade 4/5) and deep sensational disturbances in extremities. The muscle tension was normal, and the tendon reflex of the limbs was symmetrically active. The patient also had a “drunken” gait, “explosive speech”, nystagmus, and cerebellar ataxia (positive Romberg sign, abnormal finger-to-nose and heel-to-shin tests with eyes open or closed).

Laboratory examinations showed increased serum vitamin B12 (>1525 pg/mL, normal range 180–914 pg/mL) and decreased folic acid (3.54 ng/mL, normal range > 4.00 ng/mL) levels. The serum homocysteine (15.5 umol/L, normal range 6.0–14.0 umol/L) level was increased, and the methylene tetrahydrofolate reductase (MTHFR) genotype reveals normal metabolic capacity. The blood routine test presented macrocytic anemia. The detection of metal ions revealed declined serum copper level (10.5 umol/L, normal range 12.6–24.4 umol/L), and serum zinc level was within the normal range. The routine, biochemical, immunological, and etiological examination in cerebral spinal fluid appeared normal. Other laboratory examinations were within the normal range. The motor and sensitive nerve conduction velocities and electromyography showed decreased motor and sensitive nerve conduction velocities in extremities and sensorimotor polyneuropathy. Spinal MRI revealed abnormal signals in posterior and lateral columns of the spinal cords, presented as inverted “V”- shaped lesions (Fig. 1a, b). Brain MRI displayed slight cerebellar atrophy (Fig. 2a, b). Besides, she had poor cognitive behavior with a mini-mental state examination (MMSE) score of 18.

Fig. 1
figure 1

Spinal MRI findings of the two patients. In case 1, (a) sagittal T2-weighted imaging showed symmetrical hyperintensities from C2 to C5 segment in both posterior and lateral columns of the spinal cords, and (b) axial T2-weighted imaging revealed typical inverted “V”- shaped lesion. In case 2, (c) sagittal T2-weighted imaging showed symmetrical hyperintensities from C2 to T1 segment in both posterior and lateral columns of the spinal cords, and (d) axial T2-weighted imaging revealed typical inverted “V”- shaped lesion

Fig. 2
figure 2

Brain MRI findings of the two patients. Axial T2-weighted imaging and sagittal T1-weighted imaging showed enlarged cerebellar sulci in (a, b) case 1 and (c, d) case 2 relatively, indicating cerebellar atrophies

The patient was diagnosed with SCD and asked to stop N2O inhalation. Ten days after cobalamin, folate, and symptomatic treatment, the homocysteine level returned to normal. Four days later, the patient was discharged with reduced limb numbness and slightly increased muscle strength of both lower limbs than before.

The patient was asked to continue taking cobalamin and folate after discharge. At 2-week’s follow-up, her walking function and cognitive behavior improved (MMSE score = 22). Three months after discharge, the patient got recovered in the muscle strength and gait, but still felt numbness in toes. The patient completely recovered in the follow-up at 6 and 12 months after discharge respectively. The levels of serum vitamin B12, folate, copper, and hemoglobin were all in the normal range at 3, 6, and 12 months after discharge.

Case 2

A 19-year-old woman complained of speech disorders, weakness, and numbness of her lower limbs for 2 weeks. She had inhaled N2O gas for nearly one year and the dose was largely increased in the recent two months. Half a year after inhalation, she began to take vitamin B complex irregularly. The patient hummed and talked discontinuously, and also presented intermittent hallucinations during the conversation on admission. Physical examination showed decreased muscle strength of lower limbs (grade 4/5), declined muscle tension, hypoesthesia, and deep sensational disturbances in extremities. The patient also had a “drunken” gait, “explosive speech”, nystagmus, and cerebellar ataxia (positive Romberg sign, abnormal finger-to-nose and heel-to-shin tests with eyes open or closed).

Laboratory examinations showed increased serum vitamin B12 (>1515 pg/mL, normal range 180–914 pg/mL) level and macrocytic anemia. The serum homocysteine (22.6 umol/L, normal range 6.0–14.0 umol/L) level was increased, and the methylene tetrahydrofolate reductase (MTHFR) genotype revealed normal metabolic capacity. We were also concerned about the copper metabolism and found decreased serum copper (10.1 umol/L, reference range 12.6–24.4 umol/L) and ceruloplasmin (0.194 g/L, reference range 0.22–0.58 g/L) levels. The serum zinc level was within the normal range. The routine, biochemical, immunological, and etiological examination in cerebral spinal fluid appeared normal. Other laboratory examinations were within the normal range. The motor and sensitive nerve conduction velocities and electromyography showed decreased motor and sensitive nerve conduction velocities in extremities and sensorimotor polyneuropathy. Spinal MRI revealed abnormal signals in posterior and lateral columns of the spinal cords, presented as inverted “V”- shaped lesions (Fig. 1c, d). Brain MRI indicated slight cerebellar atrophy (Fig. 2c, d). She had poor cognitive behavior with an MMSE score of 14 on admission.

The patient was diagnosed with SCD and asked to stop N2O inhalation. After cobalamin, folate, and symptomatic treatment for 9 days, the homocysteine level returned to normal. She was discharged 2 days later with better cognitive performances (MMSE score increased to 28) and sensational function.

The patient was asked to continue taking cobalamin and folate after discharge. At 2-week’s follow-up, she had much fewer hallucinations with the MMSE score of 30, but still walked unsteadily. Three months after discharge, the patient got recovered in the muscle strength and superficial sensation, but still had slight ataxia. The patient completely recovered in the follow-up at 6 and 12 months after discharge respectively. The levels of serum vitamin B12, folate, copper, and hemoglobin were all in the normal range at 3, 6, and 12 months after discharge.

Discussion and conclusions

In recent years, N2O has gained increasing popularity worldwide especially among young people due to its euphoric effects [10, 11]. According to previous studies, it is not unusual that N2O can cause cobalamin deficiency and SCD [5, 7, 11,12,13]. Although serum vitamin B12 is a most convenient and accessible laboratory approach to evaluate cobalamin deficiency, it is to note that quite a few SCD patients are detected with normal or elevated serum vitamin B12 [14,15,16,17]. In fact, a growing number of N2O addicts are beginning to take vitamin B12 irregularly before admission. Even if patients do not take the supplements after inhaling N2O, serum vitamin B12 levels may also be in the normal range [18]. A meta-analysis manifests that about a third of SCD patients are detected with no-low serum vitamin B12 levels [19]. In a systematic review, Garakani et al. indicate that only less than half of adolescents with N2O abuse disclosed low levels of serum vitamin B12 [18].

These bring about challenges to traditional diagnostic thought that the total serum vitamin B12 is the most preferential indicator to diagnose SCD. Literature suggests that a SCD patient with a normal or elevated level of serum vitamin B12 may still have a vitamin B12 shortage in the body, which is also described as functional vitamin B12 deficiency [20]. It has been gradually realized that serum vitamin B12 does not reflect genuine “active” vitamin B12 level. Compared with serum vitamin B12, there are more sensitive markers to reveal cobalamin deficiency at the tissue level, such as methylmalonic acid and homocysteine [21, 22]. Therefore, it is reasonable to use combined serological indicators for assessing vitamin B12 deficiency. As is shown in our cases, the declined level of serum vitamin B12 is not a compulsory element for SCD diagnosis, while an elevated level of homocysteine is helpful for the evaluation of functional vitamin B12 deficiency.

Copper is one of the trace elements which plays an important role as a component of enzymes in the nervous system [23]. As an essential element of methionine synthase in the methylation cycle, the lack of serum copper leads to dysfunction of methionine synthase, which can cause demyelination that resembles SCD [24, 25]. The pathological copper deficiency was usually caused by insufficient storage (preterm and infants), insufficient intakes or malabsorption (diet causes, chronic diarrhea, celiac disease, Crohn’s disease, long-time parenteral nutrition, intestinal surgery, and excessive zinc), increased demands (pregnancy, lactation and wound healing), increased losses (major burns and renal replacement therapy), or hereditary diseases (such as Menkes disease) [26, 27]. As our cases had clear histories of N2O abuse and none of the above causes were involved, we suspected a possible link between the copper deficiency and N2O abuse. So far as we know, this is the first report concerning the alteration of serum copper in SCD following N2O abuse. To our knowledge, there has been no statement why N2O abuse could cause copper deficiency in previous articles. We speculated the possible reasons are as follows: Copper is a cofactor for a variety of biological reactions and thought to be necessary for methionine synthase and S-adenosylhomocysteine hydrolase, which play vital roles within the methylation cycle [10]. N2O can oxidize the cobalt ion which attenuates the function of methylcobalamin, inhibits methionine synthase, and elevates the concentration of homocysteine [5]. This might be followed by a decrease in the activity of S-adenosylhomocysteine hydrolase and a consequent decline in copper concentration by feedback regulations. However, more studies are needed to uncover the possible mechanism.

SCD generally affects the spinal cord and peripheral nerves, but rarely impacts the brain [28, 29]. The essential brain pathological manifestation involves demyelination in the cerebral white matter [30]. However, there has been no report of cerebellar atrophy following SCD up to the present. To exclude cerebral atrophy induced by other diseases, the histories of our patients were asked repeatedly. Any symptoms in the nervous system, like speech disorder, weakness, clumsiness, abnormal sensation, unsteady gait, dizziness, etc., did not exist before N2O abuse. Through asking detailed histories, present causes for cerebral atrophy, like multiple system atrophy, intracranial infection, paraneoplastic syndrome, hereditary diseases (such as spinocerebellar degeneration, Friedreich ataxia, and dentatorubral-pallidoluysian atrophy), alcohol/drug abuse, traumatic brain injury, cerebrovascular disorders, etc. [31,32,33], were also excluded. As both of the young patients were with no medical or family histories before N2O inhalation, it was unlikely that the atrophies of our cases were caused by other reasons. We thus suspect that these changes resulted from N2O abuse. Our article is the first report involving cerebellar atrophy following N2O abuse, which diversifies brain changes in SCD patients. Previous literature argues that the cerebellum has a smaller requirement for vitamin B12, which may indicate smaller storage of vitamin B12 in the cerebellum. Therefore, the cerebellum may be more sensitive to chronic vitamin B12 deficiency. This is perhaps a potential cause of cerebellum ataxia under a long-course vitamin B12 deficiency [34, 35]. Although the mechanism is vague, it highlights the harmfulness of N2O abuse as a long-term recreational purpose from neuroimaging studies.

Our article provided potential importance to sophisticate the diagnosis of SCD. Here we reported two cases of young SCD patients after N2O abuse, who were both detected with elevated vitamin B12, declined serum copper, and cerebellar atrophy. It is supposed that the serum copper and cerebellar alteration could be auxiliary diagnostic indicators of SCD. These may be meaningful for comprehensive diagnoses of SCD patients.

Availability of data and materials

The data that support the findings of the current study are available form the corresponding author upon reasonable request.

Abbreviations

SCD:

Subacute combined degeneration

N2O:

nitrous oxide

MTHFR:

methylene tetrahydrofolate reductase

MMSE:

Mini-mental State Examination

References

  1. Lanska DJ. Chapter 30: historical aspects of the major neurological vitamin deficiency disorders: the water-soluble B vitamins. Handb Clin Neurol. 2010;95:445–76.

    Article  Google Scholar 

  2. Lever EG, Elwes RD, Williams A, Reynolds EH. Subacute combined degeneration of the cord due to folate deficiency: response to methyl folate treatment. J Neurol Neurosurg Psychiatry. 1986;49(10):1203–7.

    CAS  Article  Google Scholar 

  3. Briani C, Dalla Torre C, Citton V, Manara R, Pompanin S, Binotto G, et al. Cobalamin deficiency: clinical picture and radiological findings. Nutrients. 2013;5(11):4521–39.

    Article  Google Scholar 

  4. Morishita A, Tomita H, Takaishi Y, Nishihara M, Kohmura E. A case of subacute combined degeneration of the spinal cord diagnosed by characteristic findings of magnetic resonance imaging: case report and review of 22 cases. No Shinkei Geka. 2005;33(5):489–95.

    PubMed  Google Scholar 

  5. Jiang J, Shang X. Clinical-radiological dissociation in a patient with nitrous oxide-induced subacute combined degeneration: a case report. BMC Neurol. 2020;20(1):99.

    CAS  Article  Google Scholar 

  6. Samia AM, Nenow J, Price D. Subacute combined degeneration secondary to nitrous oxide abuse: quantification of use with patient follow-up. Cureus. 2020;12(10):e11041.

    PubMed  PubMed Central  Google Scholar 

  7. Zhao B, Zhao L, Li Z, Zhao R. Subacute combined degeneration induced by nitrous oxide inhalation: two case reports. Medicine (Baltimore). 2020;99(18):e19926.

    Article  Google Scholar 

  8. Chen HJ, Huang CS. Nitrous oxide-induced subacute combined degeneration presenting with dystonia and Pseudoathetosis: a case report. Acta Neurol Taiwanica. 2016;25(2):50–5.

    Google Scholar 

  9. Choi C, Kim T, Park KD, Lim OK, Lee JK. Subacute combined degeneration caused by nitrous oxide intoxication: a report of two cases. Ann Rehabil Med. 2019;43(4):530–4.

    Article  Google Scholar 

  10. Emmanouil DE, Quock RM. Advances in understanding the actions of nitrous oxide. Anesth Prog. 2007;54(1):9–18.

    Article  Google Scholar 

  11. Lan SY, Kuo CY, Chou CC, Kong SS, Hung PC, Tsai HY, et al. Recreational nitrous oxide abuse related subacute combined degeneration of the spinal cord in adolescents - a case series and literature review. Brain and Development. 2019;41(5):428–35.

    Article  Google Scholar 

  12. Yuan JL, Wang SK, Jiang T, Hu WL. Nitrous oxide induced subacute combined degeneration with longitudinally extensive myelopathy with inverted V-sign on spinal MRI: a case report and literature review. BMC Neurol. 2017;17(1):222.

    Article  Google Scholar 

  13. Patel KK, Mejia Munne JC, Gunness VRN, Hersey D, Alshafai N, Sciubba D, et al. Subacute combined degeneration of the spinal cord following nitrous oxide anesthesia: a systematic review of cases. Clin Neurol Neurosurg. 2018;173:163–8.

    Article  Google Scholar 

  14. Cao J, Su ZY, Xu SB, Liu CC. Subacute combined degeneration: a retrospective study of 68 cases with short-term follow-up. Eur Neurol. 2018;79(5–6):247–55.

    CAS  Article  Google Scholar 

  15. Divate PG, Patanwala R. Neurological manifestations of B(12) deficiency with emphasis on its aetiology. J Assoc Physicians India. 2014;62(5):400–5.

    PubMed  Google Scholar 

  16. Hemmer B, Glocker FX, Schumacher M, Deuschl G, Lücking CH. Subacute combined degeneration: clinical, electrophysiological, and magnetic resonance imaging findings. J Neurol Neurosurg Psychiatry. 1998;65(6):822–7.

    CAS  Article  Google Scholar 

  17. Li J, Ren M, Dong A, Wu Y, Han N, Deng B, et al. A retrospective study of 23 cases with subacute combined degeneration. Int J Neurosci. 2016;126(10):872–7.

    CAS  Article  Google Scholar 

  18. Garakani A, Jaffe RJ, Savla D, Welch AK, Protin CA, Bryson EO, et al. Neurologic, psychiatric, and other medical manifestations of nitrous oxide abuse: a systematic review of the case literature. Am J Addict. 2016;25(5):358–69.

    Article  Google Scholar 

  19. Cao J, Xu S, Liu C. Is serum vitamin B12 decrease a necessity for the diagnosis of subacute combined degeneration?: a meta-analysis. Medicine (Baltimore). 2020;99(14):e19700.

    CAS  Article  Google Scholar 

  20. Sobczyńska-Malefora A, Gorska R, Pelisser M, Ruwona P, Witchlow B, Harrington DJ. An audit of holotranscobalamin ("active" B12) and methylmalonic acid assays for the assessment of vitamin B12 status: application in a mixed patient population. Clin Biochem. 2014;47(1–2):82–6.

    Article  Google Scholar 

  21. Green R. Indicators for assessing folate and vitamin B-12 status and for monitoring the efficacy of intervention strategies. Am J Clin Nutr. 2011;94(2):666s–72s.

    Article  Google Scholar 

  22. Ulrich A, Müller D, Linnebank M, Tarnutzer AA. Pitfalls in the diagnostic evaluation of subacute combined degeneration. BMJ Case Rep. 2015;2015:bcr2014208622.

  23. van Dijkman SC, de Jager NCB, Rauwé WM, Danhof M, Della PO. Effect of age-related factors on the pharmacokinetics of Lamotrigine and potential implications for maintenance dose optimisation in future clinical trials. Clin Pharmacokinet. 2018;57(8):1039–53.

    Article  Google Scholar 

  24. Winston GP, Jaiser SR. Copper deficiency myelopathy and subacute combined degeneration of the cord - why is the phenotype so similar? Med Hypotheses. 2008;71(2):229–36.

    CAS  Article  Google Scholar 

  25. Nakamura T, Nishi M, Rikitake M, Koga D, Eto J, Tajima D, et al. A case of subacute combined degeneration of the spinal cord due to folic acid and copper deficiency. Brain and Development. 2019;41(1):111–5.

    Article  Google Scholar 

  26. Altarelli M, Ben-Hamouda N, Schneider A, Berger MM. Copper deficiency: causes, manifestations, and treatment. Nutr Clin Pract. 2019;34(4):504–13.

    CAS  Article  Google Scholar 

  27. King D, Siau K, Senthil L, Kane KF, Cooper SC. Copper deficiency myelopathy after upper gastrointestinal surgery. Nutr Clin Pract. 2018;33(4):515–9.

    PubMed  Google Scholar 

  28. Chen H, Li H, Li Y, Jing J, Raza HK, Zhang Z, et al. Clinical and imaging characteristics of subacute combined degeneration complicated with white matter lesions in the brain: a report of five cases. Somatosens Mot Res. 2018;35(2):119–23.

    Article  Google Scholar 

  29. Minn YK, Kim SM, Kim SH, Kwon KH, Sunwoo IN. Sequential involvement of the nervous system in subacute combined degeneration. Yonsei Med J. 2012;53(2):276–8.

    CAS  Article  Google Scholar 

  30. Surtees R. Biochemical pathogenesis of subacute combined degeneration of the spinal cord and brain. J Inherit Metab Dis. 1993;16(4):762–70.

    CAS  Article  Google Scholar 

  31. Gellersen HM, Guo CC, O'Callaghan C, Tan RH, Sami S, Hornberger M. Cerebellar atrophy in neurodegeneration-a meta-analysis. J Neurol Neurosurg Psychiatry. 2017;88(9):780–8.

    Article  Google Scholar 

  32. Karakaya M, Paketci C, Altmueller J, Thiele H, Hoelker I, Yis U, et al. Biallelic variant in AGTPBP1 causes infantile lower motor neuron degeneration and cerebellar atrophy. Am J Med Genet A. 2019;179(8):1580–4.

    CAS  PubMed  Google Scholar 

  33. Mavroudis I. Cerebellar pathology in Alzheimer's disease. Hell J Nucl Med. 2019;22(Suppl):174–9.

    PubMed  Google Scholar 

  34. Morita S, Miwa H, Kihira T, Kondo T. Cerebellar ataxia and leukoencephalopathy associated with cobalamin deficiency. J Neurol Sci. 2003;216(1):183–4.

    Article  Google Scholar 

  35. Chakrabarty B, Dubey R, Gulati S, Yoganathan S, Kumar A, Kumar A. Isolated cerebellar involvement in vitamin B12 deficiency: a case report. J Child Neurol. 2014;29(11):Np161–3.

    Article  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

No funding was obtained for this article.

Author information

Authors and Affiliations

Authors

Contributions

JC and LR collected the case information and drafted the manuscript. CL revised the manuscript. ZL discovered the case and revised the manuscript for intellectual content. All authors have read and approved the final version of the manuscript.

Corresponding author

Correspondence to Zhijun Li.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written informed consent was obtained from both patients and the patients’ legal guardians for publication of the cases and any accompanying data. This report does not contain any personal information that could lead to the identification of the patient.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Cao, J., Ran, L., Liu, C. et al. Serum copper decrease and cerebellar atrophy in patients with nitrous oxide-induced subacute combined degeneration: two cases report. BMC Neurol 21, 471 (2021). https://doi.org/10.1186/s12883-021-02496-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12883-021-02496-y

Keywords

  • Nitrous oxide
  • Subacute combined degeneration
  • Serum copper
  • Cerebellar atrophy
  • Cognitive decline