Epidemiology

Most patients developing N₂O-SACD are young (16–30 years). Around 75% are male,9 13 16 but women may be more susceptible to N₂O-SACD at higher doses of N₂O (>20 canisters per session).9 In different geographical regions, members of different communities are more likely to use N₂O and hence to develop N₂O-SACD. In East London, most patients presenting to the hospital with N₂O-SACD are of Bangladeshi descent13; in the Netherlands, Moroccan–Dutch men appear to be more affected17; and in Australia, harmful use is highest among university students.18

The risk of developing SACD symptoms increases with greater N₂O use: those using one canister per session have around a 1.9% risk of experiencing distal paraesthesia compared with 8.5% in people who use over 100 canisters per session.9 In general, people presenting to the hospital with N₂O-SACD report heavy recreational use over months to years.16 19–21 In our clinical practice over the past 5 years, patients have reported using an average of 580 canisters per week (IQR 147.5–1012.5), which is in keeping with other reports.20 However, those with pre-existing subclinical B12 deficiency are much more susceptible at lower doses of N₂O.6 22–24 In this scenario, one-off use in anaesthesia can cause N₂O-SACD,6 and anecdotally some of our patients who have come to harm through recreational use reported using only 5–10 canisters on one occasion.

Clinical features

The clinical features of N₂O-SACD closely resemble those of classical SACD. Symptoms can present over a varying time course, from several days to 6 months.16 25 Where there has been only a single exposure to N₂O, the time delay to symptoms is 2–6 weeks.5 The initial presenting complaint is often distal paraesthesia involving the lower and/or upper limbs. If the patient ignores this or if N₂O-SACD is not diagnosed at presentation, patients may then develop gait ataxia (worse in low lighting), falls or inability to walk independently.1 13 Figure 1 shows features to prompt consideration of an alternative diagnosis.

On direct questioning, a large majority of patients have distal paraesthesia, mainly in the feet but often also the hands.13 16 Many report unsteadiness on walking.24 Less common symptoms are weakness,16 19 Lhermitte’s phenomenon,1 bladder or bowel urgency or incontinence,1 19 20 impotence or other sexual dysfunction,1 segmental myoclonus1 13 or psychiatric complaints.16 Some patients have urinary retention on presentation, and clinicians should consider arranging a bladder scan.20 Note there may also be symptoms suggesting pulmonary embolism or deep vein thrombosis, as N₂O-induced hyperhomocysteinaemia can cause a hypercoagulable state.26 Additionally, clinicians should ask patients about risk factors for low serum B₁₂ levels, which would increase their vulnerability to N₂O-SACD. These include dietary preferences, previous gastric or small bowel resections, or chronic intestinal conditions such as Crohn’s disease or coeliac disease. Several common drugs can also decrease serum B₁₂ concentrations, including gastric acid suppressants, metformin, potassium supplements and the contraceptive pill.

On examination, the physical findings are generally symmetrical. Common signs are distal loss of vibration and joint-position sense,1 16 27 and a positive Romberg’s sign or ataxic gait.1 13 16 21 Pseudoathetosis may occur through loss of joint-position sense.11 There may be hyporeflexia or (less commonly) hyper-reflexia at the knee or ankle, and this pattern may reflect the relative contributions of myelopathy and neuropathy to the clinical picture.1 16 19 In more severe cases, the plantar responses may be extensor.19 21 25 Muscle weakness is usually relatively mild but can become severe in advanced cases.1 21

Quantification of N₂O use

Patients often do not spontaneously report N₂O use. They may also not connect N₂O use with their neurological symptoms, although those living in areas where use is common do increasingly recognise its possibility of harm.28 It is important to enquire specifically and to record the quantity, duration, pattern and type of N₂O container used. Most patients in our experience purchase N₂O online, where it is readily available to the general public and is marketed for use in whipping cream. Commonly, patients use 8 g canisters (known as ‘whippits’ or ‘chargers’ in the UK and ‘nangs’ in Australia), but cylinder use—which make it easier to consume large amounts of N₂O—is becoming more common. Occasionally, patients report using medical-grade N₂O, which is not available for sale to the general public but may have been stolen from healthcare facilities and sold.29 We recommend quantifying N₂O use in ‘canister equivalents’, with one cylinder approximately equal to 75 canisters (table 1). In general, N₂O abusers use containers of the gas to inflate balloons, which are then inhaled. Using a mask or releasing N₂O into enclosed spaces is less common and particularly dangerous, as there is a risk of death by asphyxiation without preceding dyspnoea.30

Blood testing

Active vitamin B12 is essential for the enzymatic conversion of homocysteine to methionine and of methylmalonic co-enzyme A to succinyl co-enzyme A. Thus, vitamin B12 deficiency or B12 inactivation tends to increase plasma homocysteine and methylmalonic acid (MMA). Tests for assessing B12 status include serum B12, homocysteine, MMA and holotranscobalamin (table 2).

On first suspecting N₂O-SACD, we take blood for serum B₁₂ and MMA. The laboratory processes the serum B₁₂ concentration routinely; the MMA is processed in all patients except those in whom the B₁₂ concentration is below the reference range, where it would not change the diagnosis or management. Homocysteine is an alternative to MMA, but it must be transported to the laboratory on ice, which in practice places a barrier to its use. Serum B₁₂ has relatively low sensitivity (~20% to 50%) for SACD, but MMA and homocysteine are both significantly raised in over 80% of reported cases.13 19 21 31 However, both homocysteine and MMA normalise with B₁₂ treatment and with abstinence from N₂O, and it is likely that MMA and homocysteine testing may be normal if delayed, although the exact time frame is unclear.32 Ideally therefore, all blood samples for biochemical tests should be drawn before starting treatment with B₁₂ injections, but treatment should not be delayed for testing to occur.

In addition to these diagnostic blood tests, we test full blood count, urea and electrolytes, liver function tests and thyroid function tests in all patients as part of the routine medical workup (figure 1). In N₂O-SACD, the mean corpuscular volume and haemoglobin are usually normal,13 16 21 in contrast to traditional SACD.33 Folate should be measured in all patients to identify codeficiencies. We offer HIV and syphilis testing to all patients, as both can cause treatable myelopathy that can present similarly to N₂O-SACD. In addition, serum copper and zinc concentrations can be tested if the history of N₂O use is not classical or if copper deficiency myeloneuropathy is a possibility; some patients anecdotally have multiple deficiencies simultaneously.23 In addition to the above tests, clinicians should consider the possibility of coexisting B₁₂ malabsorption, which may have been unmasked by N₂O use. This is particularly pertinent in those patients with an initial B₁₂ concentration below the reference range or N₂O-SACD after only modest N₂O use. In these cases, clinicians should test serum anti-intrinsic factor and antigastric parietal cell antibodies to investigate for pernicious anaemia, and consider testing for coeliac disease and markers of generalised malabsorption (eg, ferritin and vitamin D).34

MRI

MR scans of the cervical and thoracic cord may both confirm the diagnosis and exclude alternative causes. In 50%–100% of patients with N₂O-SACD, MRI shows dorsal column T2 hyperintensity in the cervical spinal cord with C3–C5 most commonly affected (figure 2B).13 16 21 Axial slices are particularly useful to see the classical ‘inverted V’ or ‘rabbit ears’ sign (figure 2A).35

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Figure 2

Classical MRI findings in nitrous oxide-induced subacute combined degeneration of the cord. The T2 axial image (A) shows hyperintense signal in the dorsal columns of the cervical spinal cord, creating an ‘inverted V’ sign. The sagittal image (B) shows the commonly found pattern of hyperintensity extending longitudinally over several cervical spinal segments.

Given the currently high prevalence of N₂O use, clinicians should be aware that N₂O users may have an alternative cause for a spinal cord syndrome, including inflammatory processes, cervical cord compression and hereditary syndromes. MRI is particularly useful to look for these other causes, since each has a distinct MRI appearance (described elsewhere).36 However, N₂O-SACD cannot be distinguished solely by imaging, as several other conditions exactly share its MRI findings; these include myelopathy caused by HIV infection, copper deficiency, vitamin E deficiency and methotrexate toxicity.37 MRI also cannot differentiate traditional SACD from N₂O-SACD, although N₂O-SACD may have less involvement of the thoracic cord, wider lesions on sagittal MRI, fewer spinal segments with lesions and a higher rate of the inverted V sign.19

We request MRI of the cervical cord on most patients with suspected N₂O-SACD. The exception is for patients with a very clear history of recently heavy N₂O use and mild symptoms that resolve with B₁₂ therapy and who have stopped N₂O; for such cases, imaging may not be necessary. We do not recommend routine brain MRI, unless suspecting an alternative disease process. Brain imaging in case series has either been universally normal,16 or it has shown T2/fluid attenuated inversion recovery (FLAIR) hyperintense white matter lesions in the frontal, periventricular and centrum semiovale regions.21

Further investigations

In general, patients with N₂O-SACD do not need further investigation. In patients undergoing peripheral neurophysiology studies, the most common finding is a mixed axonal and demyelinating sensorimotor neuropathy, with the axonal component being more common than the demyelinating.16 21 38

Patient education and support

Patient education is the most important aspect of N₂O-SACD management. All patients should be warned that N₂O has caused their symptoms and that treatment with B₁₂ will not work if they continue to use N₂O, since this would inactivate the B₁₂ supplements. However, relapse following return to N₂O use is relatively common,19 and so we encourage all patients to contact their local drug and alcohol service to support their abstinence.

Standard treatment regimen

As soon as N₂O-SACD is suspected in the emergency department, patients should start alternate daily intramuscular injections of 1 mg hydroxocobalamin without delay, continued for at least 2 weeks.39 40 This treatment regimen is derived from the standard B₁₂ course for traditional SACD.39 In practice, we give the first injection in the emergency department, and subsequent injections as an outpatient on Mondays, Wednesdays and Fridays (figure 1). It is often difficult to organise vitamin B₁₂ injections in primary care, especially at short notice, with real risk of treatment delay or incomplete treatment. In rare cases where a patient needs admission due to loss of functional independence, alternate day injections can start as an inpatient and switch to outpatient after discharge.

When to stop injections

It is often difficult to decide when to stop injections. Standard practice in traditional SACD is to continue alternate day injections until there is no further neurological improvement. We base N₂O-SACD treatment similarly on clinical progress. We therefore perform a standardised neurological examination at baseline and at 2 weeks, to track clinical improvement accurately (figure 1). Ideally, this includes an objective measure such as a 10 m walk test.

If the patient’s condition has improved and then plateaued, we consider stopping the acute course of injections. However, if there is ongoing improvement at 2 weeks, we continue for a further 2 weeks (six more injections) and re-review each fortnight with the same standardised neurological examination until improvement has plateaued, at which point we stop the acute course of injections. In patients where N₂O is probably the sole cause of SACD and the serum B₁₂ concentration was normal at first presentation, we do not continue B₁₂ supplementation every 3 months long-term. Where coexisting B₁₂ deficiency has probably contributed to a patient’s vulnerability to N₂O-SACD, they should continue long-term supplementation with either B₁₂ injections every 3–6 months or oral supplementation, depending on whether the deficiency is dietary or non-dietary.34

If there is no clinical improvement at all at 2 weeks, we rediscuss the diagnosis and scrutinise the patient’s reported abstinence from N₂O. This is relatively rare, but it is reasonable to continue the injections for up to 8 weeks, as occasionally there is a delayed clinical improvement. Serum folate should be checked and replaced if low. Methionine or folic acid may also be possible treatment adjuncts41 42; however, there is no clinical evidence to support their routine use, and we do not do this in practice.

Consideration of oral supplementation

Intramuscular B₁₂ supplementation is strongly preferable to oral supplements. However, a small minority of patients find injections unacceptable (eg, severe needle phobia). A potential alternative—but only in preference to no supplementation—is oral cyanocobalamin 1000–2000 mcg once a day.43