Recreational use of nitrous oxide (N2O) has increased rapidly in recent years and is now the second most commonly used recreational drug among young people in the UK. There has been a corresponding rise in cases of nitrous oxide-induced subacute combined degeneration of the cord (N2O-SACD), a pattern of myeloneuropathy usually associated with severe vitamin B12deficiency. This can cause serious and permanent disability in young people but, if recognised early, may be effectively treated. All neurologists should be aware of N2O-SACD and its treatment; however, there are currently no agreed guidelines. Based on our experience in East London, an area of high N2O use, we provide practical advice on its recognition, investigation and treatment.

Introduction The incidence of Guillain Barre syndrome is 2/100,000/year- a common cause of acute neurological admission to a neurology ward. The incidence of neurological complications from Nitrous Oxide (NOS) abuse is unknown. Anecdotal evidence suggests it is becoming a more common cause of admission to our 37 bedded ward. We reviewed all admissions for the 3 year period before & after the COVID pandemic based on coding for Guillain Barre syndrome plus all ICD codes related to Nitrous Oxide (eg T41). Results 2017-19: 23 GBS admissions vs 2020-2022:27 admissions. 2017-19: No NOS-related admissions. Since July 2020, 13 NOS-related admissions- for 2022, 8 NOS & only 3 GBS admissions. Conclusions Over this period, GBS remains a more common cause for admission than NOS-related myeloneuropathy. There were no NOS admissions until July 2020, the majority were in latter part of 2022, suggesting a rapidly increasing public health issue. We hypothesize this is due to: 1) Decreasing NOS street price 2) Greater availability via illegal websites and franchises. 3) Poor legal enforcement (only 4 arrests under the Psychoactive Drugs Act (2016) in the W Midlands(per- sonal communication). There needs to be more research on NOS-related admissions and outcome. 8.7% of 16-24y olds have used NOS in the previous year, as well as greater education of NOS users on the risks. Data quality is a major issue- >120 patients were excluded after incorrect coding.

Recruitment of medical associate professionals should be paused to allow time for problems around regulation, scope of practice, and supervision to be resolved, writes David Nicholl

GCH1 encodes GTP cyclohydrolase 1 (GCH1), the rate-limiting enzyme in tetrahydrobiopterin (BH4) synthesis [[1]Werner E.R. Blau N. Thöny B. Tetrahydrobiopterin: biochemistry and pathophysiology.Biochem. J. 2011; 438: 397-414Crossref PubMed Scopus (282) Google Scholar]. BH4 is a cofactor for tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. GCH1 mutations cause DOPA-responsive dystonia (DRD), a non-neurodegenerative condition resulting from dopamine deficiency. However, GCH1 mutations and GCH1 locus variants are also an important risk factor for developing Parkinson's disease (PD) [[2]Mencacci N.E. Isaias I.U. Reich M.M. Ganos C. Plagnol V. Polke J.M. et al.Parkinson's disease in GTP cyclohydrolase 1 mutation carriers.Brain. 2014; 137: 2480-2492Crossref PubMed Scopus (124) Google Scholar,[3]Nalls M.A. Blauwendraat C. Vallerga C.L. Heilbron K. Bandres-Ciga S. Chang D. et al.System Genomics of Parkinson's Disease Consortium; International Parkinson's Disease Genomics Consortium, Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies.Lancet Neurol. 2019; 18: 1091-1102Abstract Full Text Full Text PDF PubMed Scopus (421) Google Scholar]. The mechanism by which GCH1 mutations predispose to dopaminergic neurodegeneration, is unknown. It has been speculated that chronic dopamine depletion might jeopardize nigrostriatal neuronal health [[2]Mencacci N.E. Isaias I.U. Reich M.M. Ganos C. Plagnol V. Polke J.M. et al.Parkinson's disease in GTP cyclohydrolase 1 mutation carriers.Brain. 2014; 137: 2480-2492Crossref PubMed Scopus (124) Google Scholar]. Alternatively, toxicity could be independent of dopamine deficiency, as BH4 acts as an antioxidant through direct scavenging of superoxide (O2−) [[4]Nakamura K. Bindokas V.P. Kowlessur D. Elas M. Milstien S. Marks J.D. et al.Tetrahydrobiopterin scavenges superoxide in dopaminergic neurons.J. Biol. Chem. 2001; 276: 34402-34407Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar]. Moreover, BH4 is an essential cofactor for the nitric oxide synthase (NOS) enzymes [[1]Werner E.R. Blau N. Thöny B. Tetrahydrobiopterin: biochemistry and pathophysiology.Biochem. J. 2011; 438: 397-414Crossref PubMed Scopus (282) Google Scholar]. Reduced BH4 availability impairs the ability of NOS to produce NO and instead promotes NOS-mediated O2− production, a phenomenon known as NOS uncoupling [[1]Werner E.R. Blau N. Thöny B. Tetrahydrobiopterin: biochemistry and pathophysiology.Biochem. J. 2011; 438: 397-414Crossref PubMed Scopus (282) Google Scholar]. Thus, nigrostriatal neuronal vulnerability in GCH1 mutation carriers could also be due to oxidative stress, independently of the dopamine synthesis defect. Fibroblasts do not express tyrosine hydroxylase and do not produce dopamine. Here, to explore potential dopamine-independent toxicity mechanisms of GCH1 mutations, we analyzed apoptosis and O2− production in skin fibroblasts from 4 patients carrying 3 different known pathogenic GCH1 mutations and 4 age-matched healthy controls (Supplementary Table 1; Supplementary Materials and Methods). Two patients (PAT1 and PAT4) showed dopaminergic neurodegeneration on dopamine transporter (DAT) imaging, while PAT2 and PAT3 had DRD with normal DAT scan (Supplementary Table 1). In skin fibroblasts, GCH1 expression is known to be very low in basal conditions but to be strongly induced by treatment with interferon-γ (IFN-γ) (Supplementary Materials and Methods). Indeed, GCH1 was almost undetectable in patient and control cells in basal conditions, but was strongly upregulated after 24 h treatment with IFN-γ (Supplementary Fig. 1). GCH1 abundance after IFN-γ treatment was significantly lower in mutant than control fibroblasts (Supplementary Fig. 1): relative to respective age-matched controls, GCH1 level was 49.0 ± 13.2% in PAT1 (P < 0.05; N = 3), 52.0 ± 5.5% in PAT2 (P < 0.001; N = 3), 57.4 ± 18.1% in PAT3 (P < 0.05; N = 7) and 40.5 ± 15.7% in PAT4 (P < 0.01; N = 4). We exposed IFN-γ-treated fibroblasts to the classic apoptosis-inducing agent staurosporine and assessed apoptosis using western for cleaved PARP (Supplementary Figs. 2A–D). Staurosporine induced dose-dependent apoptosis both in patient and control cells (Supplementary Figs. 2A–D). Interestingly, staurosporine induced significantly more apoptosis in fibroblasts from PAT1, PAT3 and PAT4 than in controls (Supplementary Figs. 2A,C,D). By contrast, PAT2, a DRD patient with normal DAT scan at the age of 60, did not show increased apoptosis compared with control cells (Supplementary Fig. 2B). TUNEL staining confirmed that IFN-γ-treated fibroblasts from PAT1, PAT3 and PAT4, but not PAT2, were more susceptible to staurosporine-induced apoptosis than controls (Supplementary Fig. 3). In the absence of IFN-γ treatment, there were no significant differences in staurosporine-induced apoptosis between mutant and control cells (Supplementary Fig. 4). If the increased fibroblast apoptosis of some GCH1 mutation carriers is caused by BH4 deficiency, it should be mitigated by supplementation with exogenous BH4. However, uptake of extracellular BH4 into cultured cells is very inefficient [[5]Sawabe K. Yamamoto K. Harada Y. Ohashi A. Sugawara Y. Matsuoka H. et al.Cellular uptake of sepiapterin and push-pull accumulation of tetrahydrobiopterin.Mol. Genet. Metabol. 2008; 94: 410-416Crossref PubMed Scopus (27) Google Scholar]. By contrast, the BH4 precursor sepiapterin is taken up efficiently and converted intracellularly to BH4 via the salvage pathway, which does not require GCH1 (Supplementary Fig. 5) [[4]Nakamura K. Bindokas V.P. Kowlessur D. Elas M. Milstien S. Marks J.D. et al.Tetrahydrobiopterin scavenges superoxide in dopaminergic neurons.J. Biol. Chem. 2001; 276: 34402-34407Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar,[5]Sawabe K. Yamamoto K. Harada Y. Ohashi A. Sugawara Y. Matsuoka H. et al.Cellular uptake of sepiapterin and push-pull accumulation of tetrahydrobiopterin.Mol. Genet. Metabol. 2008; 94: 410-416Crossref PubMed Scopus (27) Google Scholar]. Indeed, sepiapterin significantly diminished staurosporine-induced apoptosis in PAT1 fibroblasts (Supplementary Fig. 2E). We then measured O2− levels using dihydroethidium. Importantly, IFN-γ-treated fibroblasts from all 4 GCH1 mutation carriers had significantly higher O2− levels than controls, both with and without staurosporine treatment (Fig. 1A–D). Without IFN-γ treatment, there were no significant differences in O2− levels between mutant and control cells (Supplementary Fig. 6). The higher O2− levels in IFN-γ-treated GCH1 mutant fibroblasts compared with IFN-γ-treated control cells could result from loss of the direct O2− scavenging effect of BH4 [[4]Nakamura K. Bindokas V.P. Kowlessur D. Elas M. Milstien S. Marks J.D. et al.Tetrahydrobiopterin scavenges superoxide in dopaminergic neurons.J. Biol. Chem. 2001; 276: 34402-34407Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar]. Alternatively, BH4 deficiency could increase O2− production via NOS uncoupling [[1]Werner E.R. Blau N. Thöny B. Tetrahydrobiopterin: biochemistry and pathophysiology.Biochem. J. 2011; 438: 397-414Crossref PubMed Scopus (282) Google Scholar]. To distinguish between these 2 mechanisms, we used the NOS inhibitor l-NAME. l-NAME abolished the increased O2− levels in IFN-γ-treated mutant fibroblasts, both with and without staurosporine treatment (Fig. 1E), indicating that NOS mediated enhanced O2− production in the mutant cells. Moreover, l-NAME also mitigated staurosporine-induced apoptosis in GCH1 mutant fibroblasts (Fig. 1F and G). In conclusion, IFN-γ-treated fibroblasts from 4 GCH1 mutation carriers all displayed increased O2−, and fibroblasts from 3 of the 4 carriers showed increased staurosporine-induced apoptosis. NOS inhibition mitigated O2− production and apoptosis in GCH1 mutant fibroblasts, suggesting that O2− production by uncoupled NOS may be a dopamine-independent mechanism contributing to toxicity of GCH1 mutations. Although all 4 mutation carriers showed increased O2− levels, only 3 also showed increased apoptosis. This difference in apoptosis in the face of elevated O2− could be due to (epi)genetically determined interindividual differences in anti-oxidant defence mechanisms. It will be interesting to investigate this also in iPSC-derived GCH1 mutant neurons. GCH1 mutant and control fibroblasts in our study were carefully matched for donor age, because donor age can affect the response of cultured human skin fibroblasts to oxidative stress [[6]Matsuo M. Ikeda H. Sugihara T. Horiike S. Okano Y. Masaki H. Resistance of cultured human skin fibroblasts from old and young donors to oxidative stress and their glutathione peroxidase activity.Gerontology. 2004; 50: 193-199Crossref PubMed Scopus (12) Google Scholar]. A limitation of our study was that donors of mutant and control fibroblasts were not entirely gender-matched. However, there is no evidence, to our knowledge, that apoptosis or oxidative stress in cultured human skin fibroblasts are affected by donor gender. We found some correlation between the fibroblast and clinical phenotypes. The 2 carriers with dopaminergic neurodegeneration (PAT1 and PAT4) both had increased apoptosis in fibroblasts, whereas there was no increased apoptosis in the 60-year-old carrier with normal DAT scan (PAT2). However, this correlation was not perfect, as the 25-year-old carrier with normal DAT scan (PAT3) nevertheless had increased apoptosis in fibroblasts. Follow-up will tell whether PAT3 will develop neurodegeneration later in life. This study was supported by a grant from Research Foundation – Flanders (FWO) . Joanne Terbeek, Dorien Imberechts and Inge Kinnart are PhD Fellows of the FWO. Wim Vandenberghe is a Senior Clinical Investigator of the FWO.

We describe the details of a COVID-19 outbreak in a 25-bedded Birmingham neurology/stroke ward in the early phase of the pandemic (March to May 2020). Twenty-one of 133 admissions (16%) tested positive for COVID-19 and of those, 8 (6% of all admissions to the ward) were determined to be nosocomial. Thus 38% (8/21) of COVID-19 infections were hospital-acquired. Ten of the patients that contracted COVID-19 died; of these three were hospital-acquired cases. Five of the 21 patients had negative swabs prior to receiving a positive test result. This study highlights the importance of appropriate use of personal protective equipment (PPE) with high-risk patients (including those with stroke and complex brain injury with tracheostomies) and the difficulties of COVID-19 management in a high-risk patient population.

Consider α fetoprotein testing in later-onset ataxia as a screening marker as, if elevated, the differential diagnosis narrows considerably.

Human infection with the trematode Fasciola occurs with a worldwide prevalence of up to 17 million. Sheep and cattle are the normal host. Infection typically results in hepatobiliary disease, but extrahepatic manifestations are occasionally reported. Here, we present the case of a previously healthy 31-year-old Kurdish woman, admitted to hospital with a subarachnoid hemorrhage, eosinophilic meningitis, and lung and liver disease. A diagnosis of Fasciola infection was made based on strongly positive serology in blood and cerebrospinal fluid. The patient improved following treatment with triclabendazole and prednisolone.

Consider alpha fetoprotein testing in later-onset ataxia as a screening marker as, if elevated, the differential diagnosis narrows considerably.

![Graphic][1] Each year at its annual conference the ABN awards the ABN Medal to a distinguished neurologist who has made a major contribution to neurology and to the Association. Our 2019 medallist is Professor Dame Pamela Shaw and her citation, delivered by Prof Chris McDermott, may be viewed at http://www.theabn.org/what-we-do/awards,-fellowships-and-bursaries/abn-medal/ from Tuesday 21 May 2019. Following a recent election process, Tom Warner has been elected unopposed as ABN President Elect 2019-2021 and will follow David Burn as President 2021-2023. Biba Stanton and Sofia Eriksson have been elected as … [1]: /embed/inline-graphic-1.gif

Whistleblowing is established as an important aspect of safeguarding patients. Nevertheless, whistleblowers themselves have suffered as a result of their efforts to expose ‘wrongdoing’. In this paper, based on a presentation at the Royal Society of Medicine, in March 2019, the author considers what progress has been made since the Francis Inquiry report.