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Pernicious azotaemia? A case series of subacute combined degeneration of the cord secondary to nitrous oxide abuse
Journal of Clinical Neuroscience xxx (xxxx) xxx
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical study
Pernicious azotaemia? A case series of subacute combined degeneration of the cord secondary to nitrous oxide abuse David John Tobias McArdle a,b,⇑, Frank Gaillard a,b a b
Department of Radiology, Royal Melbourne Hospital, Melbourne, Australia Faculty of Medicine, Dentistry, and Health Sciences at the University of Melbourne, Parkville, Australia
a r t i c l e
i n f o
Article history: Received 9 June 2019 Accepted 9 November 2019 Available online xxxx Keywords: Nitrous oxide Subacute combined degeneration of the cord B12 deficiency MRI Radiology
a b s t r a c t Nitrous oxide abuse is a rare cause of vitamin B12 deficiency and consequent subacute combined degeneration of the spinal cord. Worldwide and Australian statistics indicate that recreational use of nitrous oxide is increasing. We report four cases of females aged 18–24 years presenting with clinical symptoms of subacute combined degeneration of the spinal cord. MRI during admission demonstrated the classic findings of T2 hyperintensity, predominantly within the dorsal columns of the spinal cord, with variable involvement of the lateral corticospinal tracts. These cases highlight the ready availability of nitrous oxide and the fact that heavy prolonged recreational use is occurring in the community. It is important that clinicians in emergency and community settings are alerted to this unusual cause of subacute combined degeneration of the spinal cord because early aggressive vitamin B12 replacement together with behavioural change can reverse this disabling neurological syndrome. Ó 2019 Elsevier Ltd. All rights reserved.
1. Introduction Nitrous oxide is a colourless, sweet smelling gas, with low toxicity at low dose allowing it to be used both medicinally and as a propellant in food. Its medical use is as a dissociative analgesic and anaesthetic agent, properties first reported by British chemist Humphry Davy in 1800 [1]. It has been used recreationally for its euphoric effects as long as it has been in clinical use and was popularised at laughing-gas parties of the British upper class in the 19th century [2]. Inhalation results in euphoria, giggling, giddiness, sensory and perceptual disturbance that has a rapid onset (approximately 20 s) and brief duration (minutes) [3,4]. Today, recreational use of nitrous oxide is typically obtained from gas cartridges designed for whipped cream; either inhaled directly or first discharged into a balloon [4] (see Fig. 1). These cartridges are available in supermarkets or online (100 canisters sell for ~ $60 AUD) and are known colloquially as ‘laughing gas’, ‘bulbs’, ‘whippets’ or ‘nangs’ [3,5,6]. The Australian Trends in Ecstasy and Related Drug Markets 2016 survey found that 36% of their sample had used nitrous oxide within the six months preceding the survey, increased from 25% in the 2015 survey [7]. Recreational use had increased in all states ⇑ Corresponding author at: Royal Melbourne Hospital, Department of Radiology, 300 Grattan Street, Parkville, VIC 3050, Australia. E-mail address: [email protected] (D.J.T. McArdle).
and territories and the highest rates were found in Victoria (62%) [7]. This is in keeping with international trends, with the 2018 Global Drug Survey of more than 130,000 participants from over 40 countries, indicating that nitrous oxide was the seventh most commonly used recreational drug worldwide [8]. Pathophysiologically, nitrous oxide interferes with the vitamin B12 (cobalamin) metabolic pathway and can lead to manifestations of vitamin B12 deficiency either after heavy prolonged use or following a single exposure in those with a subclinical deficiency [9]. Vitamin B12 deficiency is well documented to cause subacute combined degeneration of the spinal cord [10]. This affects the posterior columns and lateral corticospinal tracts of the cervical and upper thoracic cord, producing a myelopathy, and has characteristic magnetic resonance imaging (MRI) findings [10]. Most biochemical and MRI proven cases of subacute combined degeneration of the cord secondary to recreational nitrous oxide reported in the literature have been described in single case reports [11–16], with only three published Australian examples to our knowledge [5,17,18]. A recent case series from the United Kingdom has reported ten patients with subacute combined degeneration of the cord secondary to nitrous oxide abuse presenting within a 6-month period, raising public health concerns [3]. Here, we present four patients that presented to an inner-city Australian tertiary centre within an 18-month period, further drawing attention to this emerging global public health issue.
https://doi.org/10.1016/j.jocn.2019.11.003 0967-5868/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: D. J. T. McArdle and F. Gaillard, Pernicious azotaemia? A case series of subacute combined degeneration of the cord secondary to nitrous oxide abuse, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.11.003
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D.J.T. McArdle, F. Gaillard / Journal of Clinical Neuroscience xxx (xxxx) xxx
2.2. Case 2 A 19-year-old female Chinese international student presented to the emergency department with difficulty walking and confusion that had developed over several days. There was no significant medical history. On examination, she initially had increased spasticity, hyperreflexia of the left upper limb and a broad-based gait. This progressed to increasing weakness and diminished reflexes during admission. After initial work-up, further questioning identified regular use of nitrous oxide via ‘‘whippets” for a few weeks prior to presentation, but she did not quantify her use further. Blood tests revealed a normocytic anaemia, Hb 100 g/L and mean corpuscular volume (MCV) 97 fL (upper limit of normal 99 fL) and serum B12 was <92 pmol/ L (normal range 140-650 pmol/L). Nerve conduction studies revealed a moderate, symmetrical, length-dependent motor axonal neuropathy/neuronopathy. CSF studies and MRI brain were normal. MRI cervical spine showed subacute combined degeneration of the cord from C3 to C6 (Fig. 2). She was managed with intramuscular B12 injections and transferred to a hospital in China for ongoing rehabilitation. 2.3. Case 3
Fig. 1. Photograph showing multiple disposed used nitrous oxide canisters in the street outside student accommodation in inner city Melbourne.
2. Case series 2.1. Case 1 A 24-year-old Caucasian female presented to the emergency department with a 3-month history of peripheral sensory loss. Her symptoms began with foot numbness and paraesthesias; over one week, these symptoms ascended to a T4 sensory level, followed by hand paraesthesias. Thereafter, she reported fluctuation in these symptoms. There was no significant past medical history. On examination, she had a positive Romberg test and a sensory ataxic gait. Upper limb examination was significant for brisk reflexes and decreased pinprick and temperature sensation in the hands. Lower limb examination revealed symmetrical power deficits (3/5 ankle dorsiflexion and toe extension, 4/5 ankle eversion/ inversion), attenuated knee and ankle reflexes, attenuated vibration sensation to the ankles, and patchy sensory loss to light touch. Further history taking revealed regular nitrous oxide use, up to 200 times per day, over a nine-month period. Full blood count was within the normal range. Serum vitamin B12 was low at 116 pmol/L (normal range 140–650 pmol/L) and homocysteine was raised at 41 lmol/L (normal range <12 lmol/L). Other blood tests were unremarkable, including viral, peripheral neuropathy, vasculitic and demyelination screens. CSF testing was unremarkable. MRI brain was normal. MRI of the cervical and thoracic spine demonstrated bilateral increased T2 hyperintensity involving the dorsal columns of the cord from C1 to C5 in keeping with subacute combined degeneration (Fig. 2). The patient was managed with B12 replacement and discharged home. Nerve conduction studies performed two-weeks after discharge revealed a persistent moderate length dependent axonal sensorimotor neuropathy.
A 19-year-old female Chinese international student presented to the emergency department after being found on the floor of her home, malnourished with rambling speech. She had not communicated with her family for two weeks. Physical examination was significant for gait ataxia, truncal ataxia, hyperalgesia/dysaesthesia, and urinary retention. Collateral history eventually revealed that the patient had been taking drugs she described as ‘‘air” and the patient presented images of nitrous oxide cannisters to the treating physicians. Details on the quantity consumed were not recorded. Blood tests revealed a macrocytic anaemia and serum B12 was <92 pmol/L (normal range 140-650 pmol/L). MRI brain was normal. MRI of the spine showed typical findings for subacute combined degeneration of the cord, most prominent in the cervical spine but extending along the length of the cord (Fig. 2). Nerve conduction studies revealed reduced upper and lower limb motor amplitudes consistent with a motor neuropathy. She was treated with vitamin B12 replacement and transferred to a spinal rehabilitation facility in China. 2.4. Case 4 An 18-year-old female Chinese international student presented to the emergency department with a four-day history of difficulty walking and falls. She reported lower limb weakness and numbness starting peripherally and spreading to her whole body. Physical examination was significant for an ataxic gait, 3/5 power in ankle dorsiflexion and plantar flexion bilaterally, hyperreflexia in the upper and lower limbs, an absent ankle jerk reflex, and decreased sensation from a T4-T5 level. Two days into her admission, further history obtained with a Mandarin interpreter revealed regular nitrous oxide use over the past six months (300 canisters in the last month). Haemoglobin and MCV were normal. Vitamin B12 was low at 128 pmol/L (normal range 140–650 pmol/L). CSF studies and CT brain were normal. MRI of the spine showed subacute combined degeneration of the cord, with predominant involvement of the dorsal columns, throughout the entire cervical and the lower thoracic spinal cord (Fig. 2). Nerve conduction studies revealed a length dependent sensorimotor axonal polyneuropathy. She was treated with vitamin B12 replacement and discharged with plans for ongoing outpatient physical rehabilitation in China.
Please cite this article as: D. J. T. McArdle and F. Gaillard, Pernicious azotaemia? A case series of subacute combined degeneration of the cord secondary to nitrous oxide abuse, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.11.003
D.J.T. McArdle, F. Gaillard / Journal of Clinical Neuroscience xxx (xxxx) xxx
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Fig. 2. Selected T2-weighted axial and sagittal MRI images from case 1 (A, B), 2 (C, D), 3 (E, F) and 4 (G, H). Sagittal images (A, C, E, F) demonstrate T2 hyperintensity of the posterior cord extending over multiple vertebral levels (arrows). On axial images (B, D, F, H), the characteristic inverted ‘‘V” pattern of hyperintensity of the dorsal columns is seen (arrows), with lateral corticospinal tract involvement also demonstrated in case 3 (F).
3. Discussion These four cases of subacute combined degeneration of the cord secondary to nitrous oxide inhalation highlight the ready availability of nitrous oxide and the fact that prolonged and heavy recreational use is occurring in the community. It is significant that four similar, unrelated cases, presented to our facility (one of multiple large tertiary metropolitan hospitals) within a short timeperiod. Prolonged use of nitrous oxide leads to sustained interference with the vitamin B12 metabolic pathway, resulting in haematological and neurological dysfunction. Nitrous oxide irreversibly oxidises the cobalt ions of vitamin B12, rendering it inactive [6]. It is therefore not available as a coenzyme to convert homocysteine to methionine (methylcobalamin), or methyl-malonyl CoA to succinyl CoA (adenosyl cobalamin), leading to increased serum homocysteine and methyl-malonic acid (MMA) [6,19]. This sequence interrupts methylation of myelin proteins, resulting in unstable myelin sheaths and demyelination involving both the central and peripheral nervous systems [3]. In the presence of clinical manifestations of deficiency but normal serum vitamin B12, raised MMA and homocysteine is indicative of a functional deficiency [3,19– 21]. Vitamin B12 deficiency, regardless of aetiology, is well known to produce subacute combined degeneration of the spinal cord and polyneuropathy [5]. In cases arising secondary to nitrous oxide abuse, the condition tends to manifest following heavy use of 10 to >250 bulbs per day, over a period of weeks to months. Clinically, subacute combined degeneration of the cord begins with insidious subacute paraesthesias in the hands and feet, progressing to sensory loss, ataxia and weakness [10,22]. The clinical diagnosis is confirmed with low serum B12 or raised MMA and homocysteine (which should be measured in suspected cases with normal serum B12), and supported by typical MRI findings and/or abnormal nerve conduction studies [17,22]. The characteristic MRI findings are symmetrical T2 hyperintensity within the posterior columns, with variable involvement of the
lateral corticospinal tracts [10]. This produces the classic ‘‘inverted V sign” on axial T2-weighted sequences [23]. The affected region appears normal on T1 weighted imaging and there is no contrast enhancement [24]. These findings are usually contiguous over many vertebral bodies, which helps distinguish it from demyelination from other aetiologies radiologically [10]. At a microscopic level, the high T2 signal on MRI corresponds to degeneration and spongy vacuolation of the myelin sheaths, which is followed by axonal degeneration and astrocytic gliosis as the disease progresses [25]. Variable resolution of MRI changes and clinical recovery is seen depending on the severity of symptoms at presentation and the timeliness of treatment [10,22]. With early B12 replacement and cessation of nitrous oxide use, complete recovery is possible [11]. While it may be coincidental, it is noteworthy that three of the four young female patients presented here were Chinese international students. Of note, in the UK sample reported by Keddie et al. two thirds of patients were of Bangladeshi descent [3]. This raises several points worthy of consideration. Firstly, use of inhalants such as nitrous oxide may not be uniform across cultural groups and awareness of these patterns within the community may be helpful for identification of problematic use and harm minimisation interventions. Secondly, although it is likely that this represents differences in usage pattern among different groups, it is possible that there may be ethnicity-related genetic, metabolic or nutritional predispositions to developing subacute combined degeneration of the cord in this context [3]. To our knowledge this has not be reported. Finally, these cases serve as a reminder that cultural assumptions and language barriers must not deter clinicians from obtaining a thorough drug history in community and emergency settings. 4. Conclusion Nitrous oxide is readily available in Australia and worldwide, with evidence that recreational use is steadily increasing. Consequently, severe neurological sequalae of abuse such as subacute
Please cite this article as: D. J. T. McArdle and F. Gaillard, Pernicious azotaemia? A case series of subacute combined degeneration of the cord secondary to nitrous oxide abuse, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.11.003
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D.J.T. McArdle, F. Gaillard / Journal of Clinical Neuroscience xxx (xxxx) xxx
combined degeneration of the spinal cord and peripheral polyneuropathy are becoming a more common presentation. It is thus important that clinicians are alerted to this unusual cause of subacute combined degeneration of the spinal cord and peripheral demyelinating neuropathy because early aggressive vitamin B12 replacement and behavioural change can reverse this disabling neurological syndrome. Funding There is no grant/funding information or conflicts of interest to disclose. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jocn.2019.11.003. References [1] Davy H. Researches, chemical and philosophical – chiefly concerning nitrous oxide or and dephlogisticated nitrous air and its respiration. Bristol: Biggs & Cottle; 1800. [2] Moon JS, Kuza CM, Desai MS, James William. Nitrous oxide, and the anaesthetic revelation. J Anesthesia History 2018;4(1):1–6. [3] Keddie S, Adams A, Kelso ARC, et al. No laughing matter: subacute degeneration of the spinal cord due to nitrous oxide inhalation. J Neurol 2018;265(5):1089–95. [4] van Amsterdam J, Nabben T, van den Brink W. Recreational nitrous oxide use: Prevalence and risks. Regulatory Toxicol Pharmacol: RTP 2015;73(3):790–6. [5] Cartner M, Sinnott M, Silburn P. Paralysis caused by ‘‘nagging”. Med J Australia 2007;187(6):366–7. [6] Garakani A, Jaffe RJ, Savla D, et al. Neurologic, psychiatric, and other medical manifestations of nitrous oxide abuse: a systematic review of the case literature. Am J Addictions 2016;25(5):358–69. [7] Stafford JB, Breen C. Australian Trends in Ecstasy and related Drug Markets 2016. Findings from the Ecstasy and Related Drugs Reporting System (EDRS). Australian Drug Trends Series No. 172. 2017. Sydney, National Drug and Alcohol Research Centre, UNSW Australia.
[8] Winstock AR Barratt MJ, Maier LJ, Ferris JA. Global Drug Survey (GDS) 2018. Key Findings Report. 2018. London, UK. [9] Patel KK, Mejia Munne JC, Gunness VRN, 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. [10] Ravina B, Loevner LA, Bank W. MR findings in subacute combined degeneration of the spinal cord: a case of reversible cervical myelopathy. AJR Am J Roentgenol 2000;174(3):863–5. [11] Jalbert ER, Fahmi A, Li C, Goshtasbi M, Zaman M. Subacute combined degeneration of the dorsal columns in a patient with nitrous oxide induced B12 inactivation: a case report. J Neurol Neurosci 2016;6(3). [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. [13] Waters MF, Kang GA, Mazziotta JC, DeGiorgio CM. Nitrous oxide inhalation as a cause of cervical myelopathy. Acta Neurol Scand 2005;112(4):270–2. [14] Ng J, Frith R. Nanging. Lancet 2002;360(9330):384. [15] Antonucci MU. Subacute combined degeneration from recreational nitrous oxide inhalation. J Emerg Med 2018;54(5):e105–7. [16] Tatum WO, Bui DD, Grant EG, Murtagh R. Pseudo-guillain-barre syndrome due to ‘‘whippet”-induced myeloneuropathy. J Neuroimaging: Official J Am Soc Neuroimaging 2010;20(4):400–1. [17] Cheng HM, Park JH, Hernstadt D. Subacute combined degeneration of the spinal cord following recreational nitrous oxide use. BMJ Case Reports 2013. 2013:bcr2012008509. [18] Shulman RM, Geraghty TJ, Tadros M. A case of unusual substance abuse causing myeloneuropathy. Spinal Cord 2007;45(4):314–7. [19] Thompson AG, Leite MI, Lunn MP, Bennett DL. Whippits, nitrous oxide and the dangers of legal highs. Practical Neurol 2015;15(3):207–9. [20] Lindenbaum J, Savage DG, Stabler SP, Allen RH. Diagnosis of cobalamin deficiency: II. Relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations. Am J Hematol 1990;34(2):99–107. [21] Turner MR, Talbot K. Functional vitamin B12 deficiency. Practical Neurol 2009;9(1):37–41. [22] Sun HY, Lee JW, Park KS, Wi JY, Kang HS. Spine MR imaging features of subacute combined degeneration patients. Eur Spine J 2014;23(5):1052–8. [23] Narra R, Mandapalli A, Jukuri N, Guddanti P. ‘‘Inverted V sign” in sub-acute combined degeneration of cord. J Clin Diagnostic Res: JCDR 2015;9(5). TJ01. [24] Zhang HN, Wang L, Sun L, Yang Y. Three-point sign in subacute combined degeneration of the spinal cord: a case report. Medicine 2018;97(31):e11620. [25] Ellison D, Love S, Harding BN, et al. Neuropathology: a reference text of CNS pathology. 3rd ed. Italy: Elsevier; 2013.
Please cite this article as: D. J. T. McArdle and F. Gaillard, Pernicious azotaemia? A case series of subacute combined degeneration of the cord secondary to nitrous oxide abuse, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.11.003
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical study
Pernicious azotaemia? A case series of subacute combined degeneration of the cord secondary to nitrous oxide abuse David John Tobias McArdle a,b,⇑, Frank Gaillard a,b a b
Department of Radiology, Royal Melbourne Hospital, Melbourne, Australia Faculty of Medicine, Dentistry, and Health Sciences at the University of Melbourne, Parkville, Australia
a r t i c l e
i n f o
Article history: Received 9 June 2019 Accepted 9 November 2019 Available online xxxx Keywords: Nitrous oxide Subacute combined degeneration of the cord B12 deficiency MRI Radiology
a b s t r a c t Nitrous oxide abuse is a rare cause of vitamin B12 deficiency and consequent subacute combined degeneration of the spinal cord. Worldwide and Australian statistics indicate that recreational use of nitrous oxide is increasing. We report four cases of females aged 18–24 years presenting with clinical symptoms of subacute combined degeneration of the spinal cord. MRI during admission demonstrated the classic findings of T2 hyperintensity, predominantly within the dorsal columns of the spinal cord, with variable involvement of the lateral corticospinal tracts. These cases highlight the ready availability of nitrous oxide and the fact that heavy prolonged recreational use is occurring in the community. It is important that clinicians in emergency and community settings are alerted to this unusual cause of subacute combined degeneration of the spinal cord because early aggressive vitamin B12 replacement together with behavioural change can reverse this disabling neurological syndrome. Ó 2019 Elsevier Ltd. All rights reserved.
1. Introduction Nitrous oxide is a colourless, sweet smelling gas, with low toxicity at low dose allowing it to be used both medicinally and as a propellant in food. Its medical use is as a dissociative analgesic and anaesthetic agent, properties first reported by British chemist Humphry Davy in 1800 [1]. It has been used recreationally for its euphoric effects as long as it has been in clinical use and was popularised at laughing-gas parties of the British upper class in the 19th century [2]. Inhalation results in euphoria, giggling, giddiness, sensory and perceptual disturbance that has a rapid onset (approximately 20 s) and brief duration (minutes) [3,4]. Today, recreational use of nitrous oxide is typically obtained from gas cartridges designed for whipped cream; either inhaled directly or first discharged into a balloon [4] (see Fig. 1). These cartridges are available in supermarkets or online (100 canisters sell for ~ $60 AUD) and are known colloquially as ‘laughing gas’, ‘bulbs’, ‘whippets’ or ‘nangs’ [3,5,6]. The Australian Trends in Ecstasy and Related Drug Markets 2016 survey found that 36% of their sample had used nitrous oxide within the six months preceding the survey, increased from 25% in the 2015 survey [7]. Recreational use had increased in all states ⇑ Corresponding author at: Royal Melbourne Hospital, Department of Radiology, 300 Grattan Street, Parkville, VIC 3050, Australia. E-mail address: [email protected] (D.J.T. McArdle).
and territories and the highest rates were found in Victoria (62%) [7]. This is in keeping with international trends, with the 2018 Global Drug Survey of more than 130,000 participants from over 40 countries, indicating that nitrous oxide was the seventh most commonly used recreational drug worldwide [8]. Pathophysiologically, nitrous oxide interferes with the vitamin B12 (cobalamin) metabolic pathway and can lead to manifestations of vitamin B12 deficiency either after heavy prolonged use or following a single exposure in those with a subclinical deficiency [9]. Vitamin B12 deficiency is well documented to cause subacute combined degeneration of the spinal cord [10]. This affects the posterior columns and lateral corticospinal tracts of the cervical and upper thoracic cord, producing a myelopathy, and has characteristic magnetic resonance imaging (MRI) findings [10]. Most biochemical and MRI proven cases of subacute combined degeneration of the cord secondary to recreational nitrous oxide reported in the literature have been described in single case reports [11–16], with only three published Australian examples to our knowledge [5,17,18]. A recent case series from the United Kingdom has reported ten patients with subacute combined degeneration of the cord secondary to nitrous oxide abuse presenting within a 6-month period, raising public health concerns [3]. Here, we present four patients that presented to an inner-city Australian tertiary centre within an 18-month period, further drawing attention to this emerging global public health issue.
https://doi.org/10.1016/j.jocn.2019.11.003 0967-5868/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: D. J. T. McArdle and F. Gaillard, Pernicious azotaemia? A case series of subacute combined degeneration of the cord secondary to nitrous oxide abuse, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.11.003
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D.J.T. McArdle, F. Gaillard / Journal of Clinical Neuroscience xxx (xxxx) xxx
2.2. Case 2 A 19-year-old female Chinese international student presented to the emergency department with difficulty walking and confusion that had developed over several days. There was no significant medical history. On examination, she initially had increased spasticity, hyperreflexia of the left upper limb and a broad-based gait. This progressed to increasing weakness and diminished reflexes during admission. After initial work-up, further questioning identified regular use of nitrous oxide via ‘‘whippets” for a few weeks prior to presentation, but she did not quantify her use further. Blood tests revealed a normocytic anaemia, Hb 100 g/L and mean corpuscular volume (MCV) 97 fL (upper limit of normal 99 fL) and serum B12 was <92 pmol/ L (normal range 140-650 pmol/L). Nerve conduction studies revealed a moderate, symmetrical, length-dependent motor axonal neuropathy/neuronopathy. CSF studies and MRI brain were normal. MRI cervical spine showed subacute combined degeneration of the cord from C3 to C6 (Fig. 2). She was managed with intramuscular B12 injections and transferred to a hospital in China for ongoing rehabilitation. 2.3. Case 3
Fig. 1. Photograph showing multiple disposed used nitrous oxide canisters in the street outside student accommodation in inner city Melbourne.
2. Case series 2.1. Case 1 A 24-year-old Caucasian female presented to the emergency department with a 3-month history of peripheral sensory loss. Her symptoms began with foot numbness and paraesthesias; over one week, these symptoms ascended to a T4 sensory level, followed by hand paraesthesias. Thereafter, she reported fluctuation in these symptoms. There was no significant past medical history. On examination, she had a positive Romberg test and a sensory ataxic gait. Upper limb examination was significant for brisk reflexes and decreased pinprick and temperature sensation in the hands. Lower limb examination revealed symmetrical power deficits (3/5 ankle dorsiflexion and toe extension, 4/5 ankle eversion/ inversion), attenuated knee and ankle reflexes, attenuated vibration sensation to the ankles, and patchy sensory loss to light touch. Further history taking revealed regular nitrous oxide use, up to 200 times per day, over a nine-month period. Full blood count was within the normal range. Serum vitamin B12 was low at 116 pmol/L (normal range 140–650 pmol/L) and homocysteine was raised at 41 lmol/L (normal range <12 lmol/L). Other blood tests were unremarkable, including viral, peripheral neuropathy, vasculitic and demyelination screens. CSF testing was unremarkable. MRI brain was normal. MRI of the cervical and thoracic spine demonstrated bilateral increased T2 hyperintensity involving the dorsal columns of the cord from C1 to C5 in keeping with subacute combined degeneration (Fig. 2). The patient was managed with B12 replacement and discharged home. Nerve conduction studies performed two-weeks after discharge revealed a persistent moderate length dependent axonal sensorimotor neuropathy.
A 19-year-old female Chinese international student presented to the emergency department after being found on the floor of her home, malnourished with rambling speech. She had not communicated with her family for two weeks. Physical examination was significant for gait ataxia, truncal ataxia, hyperalgesia/dysaesthesia, and urinary retention. Collateral history eventually revealed that the patient had been taking drugs she described as ‘‘air” and the patient presented images of nitrous oxide cannisters to the treating physicians. Details on the quantity consumed were not recorded. Blood tests revealed a macrocytic anaemia and serum B12 was <92 pmol/L (normal range 140-650 pmol/L). MRI brain was normal. MRI of the spine showed typical findings for subacute combined degeneration of the cord, most prominent in the cervical spine but extending along the length of the cord (Fig. 2). Nerve conduction studies revealed reduced upper and lower limb motor amplitudes consistent with a motor neuropathy. She was treated with vitamin B12 replacement and transferred to a spinal rehabilitation facility in China. 2.4. Case 4 An 18-year-old female Chinese international student presented to the emergency department with a four-day history of difficulty walking and falls. She reported lower limb weakness and numbness starting peripherally and spreading to her whole body. Physical examination was significant for an ataxic gait, 3/5 power in ankle dorsiflexion and plantar flexion bilaterally, hyperreflexia in the upper and lower limbs, an absent ankle jerk reflex, and decreased sensation from a T4-T5 level. Two days into her admission, further history obtained with a Mandarin interpreter revealed regular nitrous oxide use over the past six months (300 canisters in the last month). Haemoglobin and MCV were normal. Vitamin B12 was low at 128 pmol/L (normal range 140–650 pmol/L). CSF studies and CT brain were normal. MRI of the spine showed subacute combined degeneration of the cord, with predominant involvement of the dorsal columns, throughout the entire cervical and the lower thoracic spinal cord (Fig. 2). Nerve conduction studies revealed a length dependent sensorimotor axonal polyneuropathy. She was treated with vitamin B12 replacement and discharged with plans for ongoing outpatient physical rehabilitation in China.
Please cite this article as: D. J. T. McArdle and F. Gaillard, Pernicious azotaemia? A case series of subacute combined degeneration of the cord secondary to nitrous oxide abuse, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.11.003
D.J.T. McArdle, F. Gaillard / Journal of Clinical Neuroscience xxx (xxxx) xxx
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Fig. 2. Selected T2-weighted axial and sagittal MRI images from case 1 (A, B), 2 (C, D), 3 (E, F) and 4 (G, H). Sagittal images (A, C, E, F) demonstrate T2 hyperintensity of the posterior cord extending over multiple vertebral levels (arrows). On axial images (B, D, F, H), the characteristic inverted ‘‘V” pattern of hyperintensity of the dorsal columns is seen (arrows), with lateral corticospinal tract involvement also demonstrated in case 3 (F).
3. Discussion These four cases of subacute combined degeneration of the cord secondary to nitrous oxide inhalation highlight the ready availability of nitrous oxide and the fact that prolonged and heavy recreational use is occurring in the community. It is significant that four similar, unrelated cases, presented to our facility (one of multiple large tertiary metropolitan hospitals) within a short timeperiod. Prolonged use of nitrous oxide leads to sustained interference with the vitamin B12 metabolic pathway, resulting in haematological and neurological dysfunction. Nitrous oxide irreversibly oxidises the cobalt ions of vitamin B12, rendering it inactive [6]. It is therefore not available as a coenzyme to convert homocysteine to methionine (methylcobalamin), or methyl-malonyl CoA to succinyl CoA (adenosyl cobalamin), leading to increased serum homocysteine and methyl-malonic acid (MMA) [6,19]. This sequence interrupts methylation of myelin proteins, resulting in unstable myelin sheaths and demyelination involving both the central and peripheral nervous systems [3]. In the presence of clinical manifestations of deficiency but normal serum vitamin B12, raised MMA and homocysteine is indicative of a functional deficiency [3,19– 21]. Vitamin B12 deficiency, regardless of aetiology, is well known to produce subacute combined degeneration of the spinal cord and polyneuropathy [5]. In cases arising secondary to nitrous oxide abuse, the condition tends to manifest following heavy use of 10 to >250 bulbs per day, over a period of weeks to months. Clinically, subacute combined degeneration of the cord begins with insidious subacute paraesthesias in the hands and feet, progressing to sensory loss, ataxia and weakness [10,22]. The clinical diagnosis is confirmed with low serum B12 or raised MMA and homocysteine (which should be measured in suspected cases with normal serum B12), and supported by typical MRI findings and/or abnormal nerve conduction studies [17,22]. The characteristic MRI findings are symmetrical T2 hyperintensity within the posterior columns, with variable involvement of the
lateral corticospinal tracts [10]. This produces the classic ‘‘inverted V sign” on axial T2-weighted sequences [23]. The affected region appears normal on T1 weighted imaging and there is no contrast enhancement [24]. These findings are usually contiguous over many vertebral bodies, which helps distinguish it from demyelination from other aetiologies radiologically [10]. At a microscopic level, the high T2 signal on MRI corresponds to degeneration and spongy vacuolation of the myelin sheaths, which is followed by axonal degeneration and astrocytic gliosis as the disease progresses [25]. Variable resolution of MRI changes and clinical recovery is seen depending on the severity of symptoms at presentation and the timeliness of treatment [10,22]. With early B12 replacement and cessation of nitrous oxide use, complete recovery is possible [11]. While it may be coincidental, it is noteworthy that three of the four young female patients presented here were Chinese international students. Of note, in the UK sample reported by Keddie et al. two thirds of patients were of Bangladeshi descent [3]. This raises several points worthy of consideration. Firstly, use of inhalants such as nitrous oxide may not be uniform across cultural groups and awareness of these patterns within the community may be helpful for identification of problematic use and harm minimisation interventions. Secondly, although it is likely that this represents differences in usage pattern among different groups, it is possible that there may be ethnicity-related genetic, metabolic or nutritional predispositions to developing subacute combined degeneration of the cord in this context [3]. To our knowledge this has not be reported. Finally, these cases serve as a reminder that cultural assumptions and language barriers must not deter clinicians from obtaining a thorough drug history in community and emergency settings. 4. Conclusion Nitrous oxide is readily available in Australia and worldwide, with evidence that recreational use is steadily increasing. Consequently, severe neurological sequalae of abuse such as subacute
Please cite this article as: D. J. T. McArdle and F. Gaillard, Pernicious azotaemia? A case series of subacute combined degeneration of the cord secondary to nitrous oxide abuse, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.11.003
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combined degeneration of the spinal cord and peripheral polyneuropathy are becoming a more common presentation. It is thus important that clinicians are alerted to this unusual cause of subacute combined degeneration of the spinal cord and peripheral demyelinating neuropathy because early aggressive vitamin B12 replacement and behavioural change can reverse this disabling neurological syndrome. Funding There is no grant/funding information or conflicts of interest to disclose. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jocn.2019.11.003. References [1] Davy H. Researches, chemical and philosophical – chiefly concerning nitrous oxide or and dephlogisticated nitrous air and its respiration. Bristol: Biggs & Cottle; 1800. [2] Moon JS, Kuza CM, Desai MS, James William. Nitrous oxide, and the anaesthetic revelation. J Anesthesia History 2018;4(1):1–6. [3] Keddie S, Adams A, Kelso ARC, et al. No laughing matter: subacute degeneration of the spinal cord due to nitrous oxide inhalation. J Neurol 2018;265(5):1089–95. [4] van Amsterdam J, Nabben T, van den Brink W. Recreational nitrous oxide use: Prevalence and risks. Regulatory Toxicol Pharmacol: RTP 2015;73(3):790–6. [5] Cartner M, Sinnott M, Silburn P. Paralysis caused by ‘‘nagging”. Med J Australia 2007;187(6):366–7. [6] Garakani A, Jaffe RJ, Savla D, et al. Neurologic, psychiatric, and other medical manifestations of nitrous oxide abuse: a systematic review of the case literature. Am J Addictions 2016;25(5):358–69. [7] Stafford JB, Breen C. Australian Trends in Ecstasy and related Drug Markets 2016. Findings from the Ecstasy and Related Drugs Reporting System (EDRS). Australian Drug Trends Series No. 172. 2017. Sydney, National Drug and Alcohol Research Centre, UNSW Australia.
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Please cite this article as: D. J. T. McArdle and F. Gaillard, Pernicious azotaemia? A case series of subacute combined degeneration of the cord secondary to nitrous oxide abuse, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.11.003