Journal of Neurology (2018) 265:1089–1095 https://doi.org/10.1007/s00415-018-8801-3 ORIGINAL COMMUNICATION No laughing matter: subacute degeneration of the spinal cord due to nitrous oxide inhalation Stephen Keddie1,2 · Ashok Adams1 · Andrew R. C. Kelso1,4 · Benjamin Turner1 · Klaus Schmierer1,4 · Sharmilee Gnanapavan1,4 · Andrea Malaspina1,4 · Gavin Giovannoni1,4 · Ian Basnett1 · Alastair J. Noyce1,3,4,5 Received: 28 January 2018 / Revised: 13 February 2018 / Accepted: 14 February 2018 / Published online: 3 March 2018 © The Author(s) 2018. This article is an open access publication Abstract Background Whilst the dangers of ‘legal highs’ have been widely publicised in the media, very few cases of the neurological syndrome associated with the inhalation of nitrous oxide (N­ 2O) have been reported. Here we set out to raise awareness of subacute degeneration of the spinal cord arising from recreational ­N2O use so that formal surveillance programs and public health interventions can be designed. Methods Case series documenting the clinical and investigational features of ten consecutive cases of subacute degeneration of the spinal cord presenting to a hospital with a tertiary neurosciences service in East London. Results Sensory disturbance in the lower (± upper) limbs was the commonest presenting feature, along with gait abnormali- ties and sensory ataxia. MRI imaging of the spine showed the characteristic features of dorsal column hyperintensity on ­T2 weighted sequences. Serum ­B12 levels may be normal because subacute degeneration of the spinal cord in this situation is triggered by functional rather than absolute ­B12 defciency. Discussion A high index of suspicion is required to prompt appropriate investigation, make the diagnosis and commence treatment early. This is the largest reported series of patients with subacute degeneration of the spinal cord induced by recrea- tional use of N­ 2O. However, the number of patients admitted to hospital likely represents the ‘tip of the iceberg’, with many less severe presentations remaining undetected. After raising awareness, attention should focus on measuring the extent of the problem, the groups afected, and devising ways to prevent potentially long-term neurological damage. Keywords Subacute degeneration of the spinal cord · Myelopathy · Hydroxocobalamin · Vitamin ­B12 Introduction * Alastair J. Noyce [email protected] Nitrous oxide ­(N2O or laughing gas) has been used in clini- cal practice as a dissociative anaesthetic for over 170 years, 1 The Royal London Hospital, Emergency Care and Acute but its recreational use has become widespread, facilitated Medicine Clinical Academic Group, Neuroscience, Barts by legal over-the-counter availability. N­ O abuse is rapidly Health NHS Trust, London, UK 2 rising throughout the USA and UK, and has become the 2 National Hospital for Neurology and Neurosurgery seventh most commonly used recreational drug according and Department of Molecular Neuroscience, MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, to the Global Drug Survey 2016 [1]. Queen Square, London, UK Several case reports have documented the potential for 3 Department of Molecular Neuroscience, UCL Institute ­N2O to cause damage to the nervous system through interfer- of Neurology, Queen Square, London, UK ence with vitamin B­ 12 metabolism, leading to megaloblas- 4 Barts and The London School of Medicine, Neuroscience tic anaemia and subacute degeneration of the spinal cord and Trauma, Blizard Institute, Queen Mary University [2–5] which itself can be irreversible [6]. Here, we report of London, London, UK the largest series of patients with neurological complications 5 Barts and The London School of Medicine, Preventive from ­N2O abuse, in an efort to raise awareness and prompt Neurology Unit, Wolfson Institute of Preventive Medicine, appropriate surveillance, so that an adequate public health Queen Mary University of London, Charterhouse Square, response may be designed and implemented. London WC1N 1PJ, UK Vol.:(0123456789)1 3 1090 Journal of Neurology (2018) 265:1089–1095 Methods was well preserved in most patients. Additional clinical features were gait ataxia (n = 8), falls (n = 3), Romberg’s All adult patients presenting between 1st of November sign (n = 6), pseudoathetosis (n = 5), Lhermitte’s phenom- 2016 and 1st May 2017 to the Emergency Department of enon (n = 1), Uhtof’s phenomenon (n = 1), and segmental n the Royal London Hospital, with a history of N 2O use myoclonus ( = 1). and symptoms suggestive of subacute degeneration of the spinal cord were included. Two patients had a pre- Investigations existing diagnosis of subacute degeneration of the spinal cord and re-presented during this period (cases 8 and 10). Median haemoglobin level was 148 (range 117–170 g/L). Blood tests were performed to rule out alternative causes All patients had normal mean cell volume (median 92.4; of myelopathy in most patients, including virology, anti- range 89.8–94.8 fL). Four patients had low vitamin B12 lev- nuclear antibodies, anti-neutrophil cytoplasmic antibod- els (median 191; range 109–2000 ng/L). MMA was meas- ies, anti-cardiolipin antibodies, aquaporin 4 antibodies ured in eight patients (median 2.9; range 0.16–110 μmol/L) and paraneoplastic antibodies. Nutritional defciencies of and was not taken in patients whose B12 level was below copper and folate were also routinely tested. Cerebrospi- normal or elevated as a result of replacement. MMA was nal fuid examination was performed in four patients. All elevated in seven of the eight patients. Four of these could patients were seen and examined by an attending consult- be deemed clinically relevant/revealing, with an associated ant neurologist and imaging reported by a consultant neu- normal B12 level. Three were ‘complimentary’, with an asso- roradiologist. Where serum vitamin B 12 level was normal, ciated low B12 level. The MMA level was normal in one serum methylmalonic acid (MMA) was also measured. patient whose vitamin B 12 level was low (case 7), but it tran- Where possible, patients were followed up in the outpa- spired that they had been aware of the risks of myelopathy tient department. Due to difculties contacting patients and had been concurrently taking oral B12 1000 μg once a (change of address, GP or phone number), not all patients day as prophylaxis. Despite this they had nonetheless devel- were available to provide consent, and therefore all cases oped subacute degeneration of the spinal cord. have been fully anonymised. A CSF examination was performed in four patients. White cell counts were < 1 in all cases. Protein was raised in two patients at 0.5 and 0.7 g/L (normal ≤ 0.4 g/L). Glu- cose was within normal limits in all. Unmatched oligoclonal Results bands were demonstrated in one patient, the signifcance of which is unclear but would suggest a degree of intrathecal Demographics immunological response. MRI of the spinal cord was performed in nine patients There were approximately 150,000 attendances to the and showed T2 signal change afecting the dorsal columns Emergency Department over the 6-month study period. of the cervical spine, consistent with subacute degeneration Table 1 summarises the clinical features of the ten study of the spinal cord (see Fig. 1). In one patient, pathological cases included in this report. The median age of patients enhancement was detected initially. Follow-up MRI was per- was 22 years (range 17–26), three were women and seven formed in four patients after an average of 14 months (range were men. Seven patients were of Bangladeshi descent, 5–27 months) from presentation. In two patients the signal one Asian, one mixed White-Caribbean and one was change persisted and in the other two it had resolved. In the White. Eight were current smokers, six drank alcohol cases where MRI signal change had resolved (cases 7 and more than twice per week, and three used other drugs 10), both received treatment for a minimum of 4 months. recreationally (two used cocaine and one marijuana). On Case 7 had abstained from N20, had been taking oral B12 average, patients used N 2O around two-three times per prior to presenting, and was asymptomatic following treat- week, and the number of N2O canisters consumed ranged ment. Case 10 continued to use N20 once a fortnight and between 75 and 2000 per week. experienced persistent paraesthesia in the feet. The patient also had poor diabetic control, and nerve conduction stud- ies demonstrated mixed axonal and demyelinating features Clinical features consistent with diabetic neuropathy. Altered sensation in the limbs was the predominant pre- Management senting feature (seven had symptoms in the upper limbs and all ten had symptoms in the lower limbs). Strength All patients received hydroxocobalamin injections, 1 mg intramuscularly on alternate days, for a median of 2 weeks. 1 3 Journal of Neurology (2018)265:1089–1095 Journal ofNeurology Table 1 Clinical and investigational fndings in 10 patients with N2O-induced subacute degeneration of the spinal cord Case Number of UL sen- LL sensory UL distal LL distal UL refexes LL refexes Gait ataxia Bladder/ Other Vitamin MMA MRI at Follow-up reported sory motor motor bowel B12 level level presenta- MRI* N2O can- power power (ng/L) (μmol/L) tion isters per week 1 100 PP/JPS/LT Vib loss IV IV + +++ C Y Nil Myoclonic 138 0.7 C2–7 Persistent loss jerks, dorsal dorsal Uhtof’s column column hyperin- hyperin- tensity tensity, and enhance- enhance- ment ment resolved 2 1000 JPS/Vib Vib loss V V ++