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BackgroundNitrous oxide (N2O) is the second most common recreational drug used by 16- to 24-year-olds in the UK. Neurological symptoms can occur in some people that use N2O recreationally, but most information comes from small case series.MethodsWe describe 119 patients with N2O-myeloneuropathy seen at NHS teaching hospitals in three of the UK’s largest cities: London, Birmingham and Manchester. This work summarises the clinical and investigative findings in the largest case series to date.ResultsParaesthesia was the presenting complaint in 85% of cases, with the lower limbs more commonly affected than the upper limbs. Gait ataxia was common, and bladder and bowel disturbance were frequent additional symptoms. The mid-cervical region of the spinal cord (C3–C5) was most often affected on MRI T2-weighted imaging. The number of N2O canisters consumed per week correlated with methylmalonic acid levels in the blood as a measure of functional B12deficiency (rho (ρ)=0.44, p=0.04).ConclusionsPreventable neurological harm from N2O abuse is increasingly seen worldwide. Ease of access to canisters and larger cylinders of N2O has led to an apparent rise in cases of N2O-myeloneuropathy in several areas of the UK. Our results highlight the range of clinical manifestations in a large group of patients to improve awareness of risk, aid early recognition, and promote timely treatment.

BACKGROUND: Multifocal motor neuropathy (MMN) is a rare, probably immune‐mediated disorder characterised by slowly progressive, asymmetric, distal weakness of one or more limbs with no objective loss of sensation. It may cause prolonged periods of disability. Treatment options for MMN are few. People with MMN do not usually respond to steroids or plasma exchange. Uncontrolled studies have suggested a beneficial effect of intravenous immunoglobulin (IVIg). This is an update of a Cochrane Review first published in 2005, with an amendment in 2007. We updated the review to incorporate new evidence. OBJECTIVES: To assess the efficacy and safety of intravenous and subcutaneous immunoglobulin in people with MMN. SEARCH METHODS: We searched the following databases on 20 April 2021: the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and WHO ICTRP for randomised controlled trials (RCTs) and quasi‐RCTs, and checked the reference lists of included studies. SELECTION CRITERIA: We considered RCTs and quasi‐RCTs examining the effects of any dose of IVIg and subcutaneous immunoglobulin (SCIg) in people with definite or probable MMN for inclusion in the review. Eligible studies had to have measured at least one of the following outcomes: disability, muscle strength, or electrophysiological conduction block. We used studies that reported the frequency of adverse effects to assess safety. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed the literature searches to identify potentially relevant trials, assessed risk of bias of included studies, and extracted data. We followed standard Cochrane methodology. MAIN RESULTS: Six cross‐over RCTs including a total of 90 participants were suitable for inclusion in the review. Five RCTs compared IVIg to placebo, and one compared IVIg to SCIg. Four of the trials comparing IVIg versus placebo involved IVIg‐naive participants (induction treatment). In the other two trials, participants were known IVIg responders receiving maintencance IVIg at baseline and were then randomised to maintenance treatment with IVIg or placebo in one trial, and IVIg or SCIg in the other. Risk of bias was variable in the included studies, with three studies at high risk of bias in at least one risk of bias domain. IVIg versus placebo (induction treatment): three RCTs including IVIg‐naive participants reported a disability measure. Disability improved in seven out of 18 (39%) participants after IVIg treatment and in two out of 18 (11%) participants after placebo (risk ratio (RR) 3.00, 95% confidence interval (CI) 0.89 to 10.12; 3 RCTs, 18 participants; low‐certainty evidence). The proportion of participants with an improvement in disability at 12 months was not reported. Strength improved in 21 out of 27 (78%) IVIg‐naive participants treated with IVIg and one out of 27 (4%) participants who received placebo (RR 11.00, 95% CI 2.86 to 42.25; 3 RCTs, 27 participants; low‐certainty evidence). IVIg treatment may increase the proportion of people with resolution of at least one conduction block; however, the results were also consistent with no effect (RR 7.00, 95% CI 0.95 to 51.70; 4 RCTs, 28 participants; low‐certainty evidence). IVIg versus placebo (maintenance treatment): a trial that included participants on maintenance IVIg treatment reported an increase in disability in 17 out of 42 (40%) people switching to placebo and seven out of 42 (17%) remaining on IVIg (RR 2.43, 95% CI 1.13 to 5.24; 1 RCT, 42 participants; moderate‐certainty evidence) and a decrease in grip strength in 20 out of 42 (48%) participants after a switch to placebo treatment compared to four out of 42 (10%) remaining on IVIg (RR 0.20, 95% CI 0.07 to 0.54; 1 RCT, 42 participants; moderate‐certainty evidence). Adverse events, IVIg versus placebo (induction or maintenance): four trials comparing IVIg and placebo reported adverse events, of which data from two studies could be meta‐analysed. Transient side effects were reported in 71% of IVIg‐treated participants versus 4.8% of placebo‐treated participants in these studies. The pooled RR for the development of side effects was 10.33 (95% CI 2.15 to 49.77; 2 RCTs, 21 participants; very low‐certainty evidence). There was only one serious side effect (pulmonary embolism) during IVIg treatment. IVIg versus SCIg (maintenance treatment): the trial that compared continuation of IVIg maintenance versus SCIg maintenance did not measure disability. The evidence was very uncertain for muscle strength (standardised mean difference 0.08, 95% CI −0.84 to 1.00; 1 RCT, 9 participants; very low‐certainty evidence). The evidence was very uncertain for the number of people with side effects attributable to treatment (RR 0.50, 95% CI 0.18 to 1.40; 1 RCT, 9 participants; very low‐certainty evidence). AUTHORS' CONCLUSIONS: Low‐certainty evidence from three small RCTs shows that IVIg may improve muscle strength in people with MMN, and low‐certainty evidence indicates that it may improve disability; the estimate of the magnitude of improvement of disability has wide CIs and needs further studies to secure its significance. Based on moderate‐certainty evidence, it is probable that most IVIg responders deteriorate in disability and muscle strength after IVIg withdrawal. SCIg might be an alternative treatment to IVIg, but the evidence is very uncertain. More research is needed to identify people in whom IVIg withdrawal is possible and to confirm efficacy of SCIg as an alternative maintenance treatment.

Vaccination against viruses has rarely been associated with Guillain-Barré syndrome (GBS), and an association with the COVID-19 vaccine is unknown. We performed a population-based study of National Health Service data in England and a multicentre surveillance study from UK hospitals to investigate the relationship between COVID-19 vaccination and GBS. Firstly, case dates of GBS identified retrospectively in the National Immunoglobulin Database from 8 December 2021 to 8 July 2021 were linked to receipt dates of COVID-19 vaccines using data from the National Immunisation Management System in England. For the linked dataset, GBS cases temporally associated with vaccination within a 6-week risk window of any COVID-19 vaccine were identified. Secondly, we prospectively collected incident UK-wide (four nations) GBS cases from 1 January 2021 to 7 November 2021 in a separate UK multicentre surveillance database. For this multicentre UK-wide surveillance dataset, we explored phenotypes of reported GBS cases to identify features of COVID-19 vaccine-associated GBS. Nine hundred and ninety-six GBS cases were recorded in the National Immunoglobulin Database from January to October 2021. A spike of GBS cases above the 2016–2020 average occurred in March–April 2021. One hundred and ninety-eight GBS cases occurred within 6 weeks of the first-dose COVID-19 vaccination in England [0.618 cases per 100,000 vaccinations; 176 ChAdOx1 nCoV-19 (AstraZeneca), 21 tozinameran (Pfizer) and one mRNA-1273 (Moderna)]. The 6-week excess of GBS (compared to the baseline rate of GBS cases 6–12 weeks after vaccination) occurred with a peak at 24 days post-vaccination; first-doses of ChAdOx1 nCoV-19 accounted for the excess. No excess was seen for second-dose vaccination. The absolute number of excess GBS cases from January–July 2021 was between 98–140 cases for first-dose ChAdOx1 nCoV-19 vaccination. First-dose tozinameran and second-dose of any vaccination showed no excess GBS risk. Detailed clinical data from 121 GBS patients were reported in the separate multicentre surveillance dataset during this timeframe. No phenotypic or demographic differences identified between vaccine-associated and non-vaccinated GBS cases occurring in the same timeframe. Analysis of the linked NID/NIMS dataset suggested that first-dose ChAdOx1 nCoV-19 vaccination is associated with an excess GBS risk of 0.576 (95% confidence interval 0.481–0.691) cases per 100 000 doses. However, examination of a multicentre surveillance dataset suggested that no specific clinical features, including facial weakness, are associated with vaccination-related GBS compared to non-vaccinated cases. The pathogenic cause of the ChAdOx1 nCoV-19 specific first dose link warrants further study.

BackgroundPOEMS syndrome is a rare cause of neuropathy misdiagnosed as Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) in 60% of cases. Ineffective CIDP directed therapy is expensive, introduces risk of complications, and often results in disease progression. Vascular endothelial growth factor (VEGF) is a sensitive and specific biomarker in the diagnosis of POEMS syndrome costing approximately £50. Introducing early directed screening with VEGF more accurately distinguishes POEMS syndrome from CIDP than the current standard of care (SOC).Methods100 cases from the UCLH POEMS database were selected. We grouped patients according to diagnostic pathway and compared health outcomes. We conducted a model-based cost-effectiveness analysis to compare diagnostic outcomes and costs of the current SOC with intervention pathways using VEGF screening. We used a study cohort of 1,250 patients with polyneuropathy (UK incidence) and conducted costing from a health-services perspective.ResultsTreatments associated with POEMS misdiagnosis led to a total healthcare expenditure in our cohort of £808,550-£1,111,756 over 20 years, with an average cost-per-POEMS-syndrome-patient misdiagnosed of£14,701-£20,214. Our intervention pathway which introduces VEGF screening into the current SOC results in 4 additional early POEMS diagnoses per year and a cost-saving of almost £40,000 through avoidance of non-POEMS directed therapy and related hospital costs.ConclusionVEGF testing should be routine for patients presenting with an acquired demyelinating neu- ropathy. This will improve early diagnosis of POEMS syndrome, enable effective therapy and reduce cos8ts5.stephen.keddie@nhs.net

BackgroundArterial and venous thrombotic events occur in patients with POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, Skin changes) syndrome with a previously reported rate of 20%. We reviewed the UK POEMS Registry to describe the rate of venous thromboembolism (VTE), arterial events and risk factors.MethodsThe UK POEMS Registry is the largest single-centre cohort in Europe and comprises 100 patients. Data were collected on arterial and venous thrombotic events from 1999 to present day.ResultsOf the 83 assessable patients, median age at presentation was 52 years. Twenty-five patients expe- rienced 35 clinically apparent arterial or venous events. Eleven patients had 14 VTEs including deep vein thrombosis (DVT, 4/14), pulmonary embolism (4/14) and peripherally inserted central catheter-associated DVT occurring during autologous stem cell transplant (4/14). Sixteen patients experienced 21 arterial events: stroke (7/21), peripheral arterial occlusion (6/21), myocardial infarction (4/21) and microvascular disease (2/21), with no discernible relationship with thrombocytosis or polycythaemia. The combined venous and arterial event rate was 42%, over double that previously reported. There were more arterial than venous events, and most occurred during active pre-treated disease indicating a need for a pre- emptive approach to thromboprophylaxis.ConclusionArterial and venous thromboses are more common in POEMS syndrome than previously reported and appear associated with disease pathology and activity. We propose a management strategy for appropriate thromboprophylaxis in POEMS patients throughout the course of disease.stephen.keddie@nhs.net