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Radiol Case Rep
Radiol Case Rep
Radiology Case Reports
1930-0433
Elsevier

S1930-0433(24)00816-1
10.1016/j.radcr.2024.08.031
Case Report
Subacute combined degeneration from nitrous oxide abuse
Singh Harjinder MD harjinderps10@gmail.com
a⁎
Beriwal Nitya MD b
Minhas Jasdeep Singh BS c
Robinson Ciji MD a
a Department of Internal Medicine, Henry Ford Allegiance Health, Jackson, MI, USA
b Department of Neurology, The University of Chicago Medical Center, Chicago, IL, USA
c Department of Internal Medicine, St. George's University School of Medicine, University Centre Grenada, West Indies, Grenada
⁎ Corresponding author. harjinderps10@gmail.com
07 9 2024
12 2024
07 9 2024
19 12 56005604
29 4 2024
5 8 2024
7 8 2024
© 2024 The Authors. Published by Elsevier Inc. on behalf of University of Washington.
2024

https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Nitrous oxide is an anesthetic medication which can also be recreationally abused in the form of whippet canisters. Its prolonged abuse can interfere with Vitamin B12 metabolism and lead to its functional deficiency. We report a case of a 30-year-old male who presented with generalized weakness and was found to have subacute combined degeneration (SCD) of the spinal cord. His laboratory workup showed low Vitamin B12 with elevated homocysteine and methylmalonic Co-A levels, and further questioning revealed prolonged nitrous oxide abuse. Nitrous oxide causes functional inactivation of methylcobalamin by rendering it unable to function as a coenzyme for methionine synthase enzyme. This leads to the decreased production of methionine and subsequent production of myelin. This case describes nitrous oxide abuse as an important etiology to be considered in patients presenting with weakness and myeloneuropathy and describes important imaging findings.

Keywords

Nitrous oxide
Subacute combined degeneration
Paralysis
Drug abuse
Vitamin B12
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pmcIntroduction

Nitrous oxide is an anesthetic drug which can be misused for recreational purposes in the form of whippet canisters. It interferes with Vitamin B12 metabolism and causes its interference with methylation, leading to reduced formation of methylcobalamin. Methylcobalamin is an apoenzyme required for the conversion of homocysteine to methionine and the further formation of myelin. Myelin is a continuously regenerating tissue and continuous supply of methylcobalamin is essential for it [1]. Nitrous oxide's availability as a recreational agent is unregulated but has the ability to cause complications such as subacute combined degeneration (SCD) and potentially irreversible neurologic consequences. This case aims to shed light on the unregulated use of nitrous oxide, and the investigations needed to diagnose SCD.

Case presentation

A 30-year-old male presented with a 2-week history of bilateral limb paraesthesias, generalized weakness, and inability to walk. His prior medical history constituted bipolar disorder and schizoaffective disorder, for which he was taking fluphenazine and lamotrigine. The patient was somnolent but alert and oriented to time, place, and person. His neurological examination revealed absent fine touch sensations in all distal extremities and decreased proprioception at the lower extremity joint movements bilaterally. He had motor strength of 5/5 in bilateral upper and lower extremities and an unremarkable cranial nerve examination. He had 1+ deep tendon reflexes in bilateral lower extremities, with extensor plantar reflexes bilaterally. There were no signs of meningismus, ataxia or dysmetria. The complete blood count was unremarkable, with hemoglobin of 14.6 g/dL (normal range 13.5-17.0 g/dL) and mean corpuscular volume (MCV) of 93.2 fL (normal range 80-100 fL). Magnetic Resonance Imaging (MRI) showed increased signal on short tau inversion recovery (STIR) and T2-weighted images involving the dorsal cord from C2 to C7 disc level, extending to upper thoracic discs consistent with subacute combined degeneration (Fig. 1). The vertebral bodies and intervertebral discs were maintained in height and signal throughout. Cross-sectional imaging at the cervical spine level showed an “inverted V sign” or “rabbit ear sign” highlighted by the increased signal intensity in the areas of demyelination of dorsal columns (Fig. 2).Fig. 1 Mid sagittal plane view of T2-MRI sequence showing increased T2 signal intensity (arrows) in dorsal columns suggesting subacute combined degeneration.

Fig 1:

Fig. 2 Cross-sectional plane view of T2-MRI sequence showing increased T2 signal intensity (arrows) in the region of dorsal columns resembling rabbit ears demonstrating “rabbit ear sign”.

Fig 2:

Further blood work revealed undetectable Vitamin B12 levels of <150 pg/mL (normal 232-1245 pg/mL) and a workup for the underlying cause of Vitamin B12 deficiency was pursued to determine the inciting factor. He had a negative intrinsic factor antibody, elevated homocysteine level of >44 µmol/L (normal 3-14 µmol/L), and an elevated methylmalonic acid level of 1.22 µmol/L (normal <0.40 µmol/L). He did not have any history suggesting small bowel diseases such as Crohn's disease or celiac disease to account for a possible malabsorptive syndrome. On further review of possible causes of Vitamin B12 deficiency, the patient reported using around 10 nitrous oxide cartridges (whippets) a day for the last 6 months for recreational purposes.

Over the next few days in the hospital, he was found to have persistent urinary retention and constipation which was attributed to SCD associated autonomic disturbances. Cerebrospinal fluid testing (Table 1) was reassuring with mildly elevated protein to 64.8 mg/dL, and no evidence of pleocytosis. Given no pleocytosis, and no hyper intensities on MRI brain (Fig. 3) there were no concerns for demyelinating etiology or autoimmune encephalitis. Also, there was low evidence of bacterial or viral infection due to no pleocytosis.Table 1 Cerebrospinal fluid analysis from the lumbar puncture.

Table 1:Component, CSF	Ref Range and Units	Value	
Color	Colorless	Colorless	
Red Blood Cells	0 /cu mm	20	
Total Nucleated Cell Count	0-5 /cu mm	1	
Glucose	40-80 mg/dL	67	
Protein	15-55 mg/dL	64.82	
Lactic acid	1.2-2.4 mmol/L	1.8	
HSV 1 DNA	Not detected	Not detected	
HSV 2 DNA	Not detected	Not detected	
B. burgdorferi Abs (EIA)	<0.99 LIV	0.08	
West Nile IgG Abs	<1.30 IV	<1.30	
West Nile IgM Abs	<0.90 IV	<0.90	
VDRL, CSF	Nonreactive	Nonreactive	
CMV, DNA, PCR	Not detected	Not detected	
EBV DNA	Not detected	Not detected	
IgG	0.8-6.1 mg/dL	6.5	
Albumin	<35 mg/dL	46.3	
IgG, serum	610.3-1616 mg/dL	777	
Albumin, serum	3500–5200 mg/dL	4,399	
IgG Index/CSF	0.3-0.7 Ratio	0.8	
Toxoplasma gondii DNA (PCR)	Not detected	Not detected	
CMV, Cytomegalovirus; CSF, Cerebrospinal fluid; DNA, Deoxyribose nucleic acid; EBV, Ebstein Barr Virus; EIA, Enzyme immunoassay; HSV, Herpes Simplex Virus; IgG, Immunoglobulin G, IgM: Immunoglobulin M; PCR, Polymerase chain reaction; VDRL, Venereal Disease Research Laboratory.

Fig. 3 MRI Brain T2 (A, B) showing and T2 FLAIR (C, D) cross-sectional plane views show no evidence of acute infarct, hemorrhage, or hyper intense lesions. The arrows in A and C, and B and D show no signal abnormality in the cerebral cortex and cerebellum respectively to indicate any pathology.

Fig 3:

The patient was started on daily intramuscular Vitamin B12 injections (1000 µg) for 1 week and then transitioned to weekly injections for 2 months. He was noted to have urinary retention for which foley catheter was placed. It was presumed to be from the interruption in the neural pathways from the extensive degeneration. Over the course of 10 days in the hospital, he did not have much improvement in his neurologic deficits and was discharged to an inpatient rehabilitation facility for regular physical therapy. A follow-up appointment with Neurology was arranged and the patient was counselled to abstain from further nitrous oxide use.

The patient was followed for one year as he received rehabilitation services at the inpatient facility and outpatient services. Despite aggressive physical and occupational therapy, the patient had little to no improvement in his neurological deficits. For urinary retention, the patient underwent a suprapubic catheterization procedure and undergoes close follow-up with Urology.

Discussion

Nitrous oxide was first discovered by Joseph Priestly in the late 1700s. Its ability to produce euphoria and render the user less sensitive to pain stimuli when inhaled was reported by Humphrey Davy in 1800 [2]. The recreational use of inhaled nitrous oxide gas is becoming increasingly popular as suggested by the 2014 Global Drug Survey. The findings showed 38.6% and 29.4% lifetime prevalence of N2O use in the UK and the US respectively. It is generally consumed via gas-filled balloons at festivals and clubs where the use of other recreational substances is common [3]. Its chronic use interferes with Vitamin B12 metabolism leading to neurological sequelae such as SCD which if not recognized or treated early can lead to long term permanent neurological deficits.

Vitamin B12 is a bound coenzyme of methionine synthase. The molecular structure of Vitamin B12 has a tetrapyrrole ring with a monovalent cobalt ion at the center which functions as a methyl carrier for the transmethylation reaction to convert homocysteine to methionine [1]. Nitrous oxide causes conversion of the cobalt ion contained in the structure of Vitamin B12 from monovalent to the bivalent form which can no longer function as a methyl carrier [4]. Decreased formation of methionine leads to decreased amounts of S-adenosyl methionine which is essential in the production of DNA, RNA, and myelin [1]. This dysregulation of myelin production within the spinal cord eventually results in demyelination of the spinocerebellar tracts, lateral corticospinal tracts, and dorsal columns, eventually leading to various neurologic manifestations.

Initial clinical features of chronic nitrous oxide abuse are due to the degeneration of dorsal column, a heavily myelinated tract and manifests as gait disturbance due to diminished proprioception and vibration sensation. This is usually followed by motor weakness due to the degeneration of lateral corticospinal tract which leads to spasticity, extensor plantar responses, and hyperreflexia [5]. Autonomic disturbances, dementia and psychosis have also been reported which is likely due to antagonism at the level of N-methyl D-aspartate receptors [6].

Nitrous oxide abuse is known to lead to functional Vitamin B12 deficiency which can be assessed by measuring levels of methylmalonic acid and homocysteine. These are the substrates of reactions catalyzed by Vitamin B12 and are crucial clues for early diagnosis. Mean serum B12 concentrations in such cases have shown a cumulative normal Vitamin B12 result with abnormal serum homocysteine and methylmalonic acid, which serve as a marker of functional B12 deficiency. Macrocytosis and anemia are not prominent features in this cohort of patients [7]. Magnetic resonance imaging (MRI) imaging of the spine shows a characteristic feature of dorsal column hyperintensity on T2 weighted images. MRI findings include demyelination in the dorsal columns with a high proportion of cases showing cervical spinal cord involvement. Lower limb mixed axonal and demyelinating patterns are also noted. No change on MRI brain is reported in literature [8].

Withdrawal of exposure and prompt vitamin B 12 supplementation is recommended for effective treatment. The usual recommended dose is 1000 to 2000 µg daily [9]. After the diagnosis, close follow-up remains essential due to high risks of relapse. Multidisciplinary measures with involvement of addiction medicine, psychotherapy and physical therapy are needed to help with recovery [9]. Earlier age of presentation (less than 50 years), short duration of symptoms, absence of sensory deficits, absence of Romberg's sign, absence of Babinski sign, involvement of ≤ 7 spinal segments on MRI, presence of spinal cord edema, and contrast enhancement of the spine and absence of spinal cord atrophy are associated with better short term neurological outcomes [10,11]. Our patient had sensory symptoms, positive Babinski bilaterally, and involvement of >7 spinal segments on MRI spine, which is suggestive of slower recovery with prolonged neurological manifestations.

In a retrospective analysis of 57 patients with SCD, only 8 patients achieved complete clinical and neurological resolution as a response to B12 therapy [10]. Patients of SCD require prolonged duration of at least 3-12 months to recover [12]. This indicates low potential for prompt recovery after Vitamin B12 supplementation as myelin formation takes time. CNS myelination in rodents was found to have a rate of 5 × 103 – 5 × 104 µm2/cell/day [13]. Early diagnosis and prompt treatment with a multidisciplinary approach is essential to prevent irreversible spinal cord damage and chronic neurological sequelae such as paraplegia and quadriplegia [14].

Conclusion

Nitrous oxide is an unregulated substance with increasing prevalence. Its users and clinicians need to be aware of it causing functional vitamin B12 deficiency and future consequences such as subacute combined degeneration. In suspected cases, absence of anemia and macrocytosis should not prevent the clinicians from ordering further diagnostic tests. At the time of diagnosis, treatment with Vitamin B12 is recommended along with removal of exposure to nitrous oxide. The clinical recovery of the published cases remains poor which implies the importance of preventive management.

Patient consent

A written, informed consent was obtained from the patient's legal guardian (mother) regarding the publication of this case.

Ethics approval

Our institution does not require ethical approval for reporting individual cases or case series.

Prior presentation of abstract statement

No previous presentations.

Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments: Not applicable.
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References

1 Nunn JF Clinical aspects of the interaction between nitrous oxide and vitamin b12 Br J Anaesth 59 1 1987 3 13 3548788
2 Weimann J Toxicity of nitrous oxide Best Pract Res Clin Anaesthesiol 17 1 2003 47 61 12751548
3 Kaar SJ Ferris J Waldron J Devaney M Ramsey J Winstock AR Up: the rise of nitrous oxide abuse. An international survey of contemporary nitrous oxide use J Psychopharmacol 30 4 2016 395 401 26912510
4 Banks RGS, Henderson RJ, Pratt JM. Reactions of gases in solution. Part III. Some reactions of nitrous oxide with transition-metal complexes. 1968. 10.1039/J19680002886.
5 Garakani A Jaffe RJ Savla D Welch AK Protin CA Bryson EO Neurologic, psychiatric, and other medical manifestations of nitrous oxide abuse: a systematic review of the case literature Am J Addict 25 5 2016 358 369 27037733
6 Savage S Ma D The neurotoxicity of nitrous oxide: the facts and “putative” mechanisms Brain Sci 4 1 2014 73 90 24961701
7 Marsden P Sharma AA Rotella JA Review article: clinical manifestations and outcomes of chronic nitrous oxide misuse: a systematic review Emerg Med Australas 34 4 2022 492 503 35695047
8 Xiao CP Ren CP Cheng JL Zhang Y Li Y Li BB Conventional MRI for diagnosis of subacute combined degeneration (SCD) of the spinal cord due to vitamin B-12 deficiency Asia Pac J Clin Nutr 25 1 2016 34 38 26965759
9 Langan RC Goodbred AJ Vitamin B12 deficiency: recognition and management 2017 American Family Physician https://www.aafp.org/pubs/afp/issues/2017/0915/p384.html Accessed March 14, 2024
10 Vasconcelos OM Poehm EH McCarter RJ Campbell WW Quezado ZM Potential outcome factors in subacute combined degeneration: review of observational studies J Gen Intern Med 21 10 2006 1063 1068 16970556
11 Cao J Su ZY Xu SB Liu CC Subacute combined degeneration: a retrospective study of 68 cases with short-term follow-up Eur Neurol 79 5–6 2018 247 255 29698962
12 Stabler SP. Clinical practice. Vitamin B12 deficiency N Engl J Med 368 2 2013 149 160 23301732
13 Poitelon Y Kopec AM Belin S Myelin fat facts: an overview of lipids and fatty acid metabolism Cells 9 4 2020 812 32230947
14 Qudsiya Z De Jesus O Subacute combined degeneration of the spinal cord (Archive) StatPearls [Internet] 2024 StatPearls Publishing Treasure Island (FL)
