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Within the last decade, antibodies targeting the node and paranode of myelinated peripheral nerves have been increasingly identified in patients with acquired immune-mediated neuropathies, commonly termed ‘nodo-paranodopathies’. Crucially, these patients often present with additional clinical features not usually seen with the most common immune-mediated neuropathies, Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy, and respond poorly to conventionally used immunomodulatory therapies. Emerging evidence that these are pathologically distinct diseases has further prompted the use of more targeted treatment, such as the B cell depleting monoclonal antibody rituximab, which has been reported to significantly improve functional outcomes in this subset of patients. We provide an overview of the emerging clinical and serological phenotypes in patients with specific nodal/paranodal antibodies, the practicalities of antibody testing and current evidence supporting the use of non-standard therapies.

Previous studies have described the clinical, serological and pathological features of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and antibodies directed against the paranodal proteins neurofascin-155, contactin-1 (CNTN1), contactin-associated protein-1 (Caspr1), or nodal forms of neurofascin. Such antibodies are useful for diagnosis and potentially treatment selection. However, antibodies targeting Caspr1 only or the Caspr1/CNTN1 complex have been reported in few patients with CIDP. Moreover, it is unclear if these patients belong to the same pathophysiological subgroup. Using cell-based assays in routine clinical testing, we identified sera from patients with CIDP showing strong membrane reactivity when both CNTN1 and Caspr1 were co-transfected (but not when CNTN1 was transfected alone). Fifteen patients (10 male; aged between 40 and 75) with antibodies targeting Caspr1/CNTN1 co-transfected cells were enrolled for characterization. The prevalence of anti-Caspr1/CNTN1 antibodies was 1.9% (1/52) in the Sant Pau CIDP cohort, and 4.3% (1/23) in a German cohort of acute-onset CIDP. All patients fulfilled European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) definite diagnostic criteria for CIDP. Seven (47%) were initially diagnosed with Guillain-Barré syndrome due to an acute-subacute onset. Six (40%) patients had cranial nerve involvement, eight (53%) reported neuropathic pain and 12 (80%) ataxia. Axonal involvement and acute denervation were frequent in electrophysiological studies. Complete response to intravenous immunoglobulin was not observed, while most (90%) responded well to rituximab. Enzyme-linked immunosorbent assay (ELISA) and teased nerve fibre immunohistochemistry confirmed reactivity against the paranodal Caspr1/CNTN1 complex. Weaker reactivity against Caspr1 transfected alone was also detected in 10/15 (67%). Sera from 13 of these patients were available for testing by ELISA. All 13 samples reacted against Caspr1 by ELISA and this reactivity was enhanced when CNTN1 was added to the Caspr1 ELISA. IgG subclasses were also investigated by ELISA. IgG4 was the predominant subclass in 10 patients, while IgG3 was predominant in other three patients. In conclusion, patients with antibodies to the Caspr1/CNTN1 complex display similar serological and clinical features and constitute a single subgroup within the CIDP syndrome. These antibodies likely target Caspr1 primarily and are detected with Caspr1-only ELISA, but reactivity is optimal when CNTN1 is added to Caspr1 in cell-based assays and ELISA.

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.

INTRODUCTION: This series characterises 9 patients with neurohistopathologically proven peripheral nerve neurolymphomatosis. METHODS: A search of the hospital neuropathology database from 2002-2019 identified biopsy proven cases. Clinical data, investigation modalities, treatments and outcomes were collated. RESULTS: Median age at neuropathy onset was 47 years, commonly as the initial disease manifestation. Most (8/9) presented with painful asymmetrical sensory disturbance, with additional cranial nerve involvement in three. Neurophysiology typically demonstrated multiple axonal mononeuropathies. Cerebrospinal fluid protein was often raised (6/8). Magnetic resonance imaging suggested peripheral nerve infiltration in 6/9 and positron emission tomography CT in 4/9. Bone marrow biopsy was abnormal in 6/8. Treatment involved systemic or intrathecal chemotherapy and radiotherapy. Median survival was 23 months. DISCUSSION: Neurolymphomatosis is a rare but important cause of neuropathy, particularly in those lacking systemic evidence of lymphoma as correct aggressive treatment can prolong survival. Nerve biopsy is essential to classify lymphoma type and rule out alternatives. Keywords [181] Peripheral neuropathy, [216] Nerve tumour, [283] All clinical neurophysiology, [58] Natural history studies, [150] Haematologic This article is protected by copyright. All rights reserved.

Arterial and venous thromboses occur in patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein level, and skin changes) syndrome at a previously reported rate of 20%. We reviewed the University College London Hospitals (UCLH) POEMS Registry to determine the rate of venous thromboembolism (VTE), arterial events, and risk factors. This registry, established in 1999 and comprising 103 patients at the time of this study, is the largest single-center cohort in Europe. Of the 83 assessable patients, median age at presentation was 52 years (range, 31-84). Twenty-five patients experienced clinically apparent arterial or venous events, and 2 had concurrent arterial and venous thromboses. Eleven patients had VTEs, including deep vein thrombosis (DVT; 3 of 11), pulmonary embolism (4 of 11), and peripherally inserted central catheter–associated DVT, which occurred during autologous stem cell transplantation (3 of 11). Sixteen patients experienced arterial events: stroke (7 of 16), peripheral arterial occlusion (5 of 16), myocardial infarction (3 of 16), and microvascular disease (1 of 16), with no discernible relationship with thrombocytosis or polycythemia. Thirty percent of POEMS patients have arterial and venous thromboses, higher than previously reported. There were more arterial than venous events, and most occurred during active disease, before the start of chemotherapy, indicating the need for a preemptive approach to thromboprophylaxis.

Membranous glomerulonephritis (MGN) is a common cause of nephrotic syndrome in adults, mediated by glomerular antibody deposition to an increasing number of newly recognised antigens. Previous case reports have suggested an association between patients with anti-contactin-1 (CNTN1)-mediated neuropathies and MGN. In an observational study we investigated the pathobiology and extent of this potential cause of MGN by examining the association of antibodies against CNTN1 with the clinical features of a cohort of 468 patients with suspected immune-mediated neuropathies, 295 with idiopathic MGN, and 256 controls. Neuronal and glomerular binding of patient IgG, serum CNTN1 antibody and protein levels, as well as immune-complex deposition were determined. We identified 15 patients with immune-mediated neuropathy and concurrent nephrotic syndrome (biopsy proven MGN in 12/12), and 4 patients with isolated MGN from an idiopathic MGN cohort, all seropositive for IgG4 CNTN1 antibodies. CNTN1-containing immune complexes were found in the renal glomeruli of patients with CNTN1 antibodies, but not in control kidneys. CNTN1 peptides were identified in glomeruli by mass spectroscopy. CNTN1 seropositive patients were largely resistant to first-line neuropathy treatments but achieved a good outcome with escalation therapies. Neurological and renal function improved in parallel with suppressed antibody titres. The reason for isolated MGN without clinical neuropathy is unclear. We show that CNTN1, found in peripheral nerves and kidney glomeruli, is a common target for autoantibody-mediated pathology and may account for between 1 and 2% of idiopathic MGN cases. Greater awareness of this cross-system syndrome should facilitate earlier diagnosis and more timely use of effective 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.

Polyneuropathy Organomegaly, Endocrinopathy, Monoclonal protein and Skin changes syndrome is a rare multisystem condition with a range of manifestations which are often overlooked as trivial comorbidities, until their whole triggers the possibility of the diagnosis. The diagnosis is typically delayed by 12-16 months, by which time patients can be severely disabled. There are no established consensus guidelines. We provide clinicians a comprehensive blueprint for managing POEMS from diagnostic suspicion through the work-up, selection of therapy, follow-up, and treatment of relapse based on published evidence and our large single-center experience. A multidisciplinary approach is essential including expert hematologists, neurologists, histopathologists, radiologists, and neurophysiologists. The aim of treatment is to eradicate the underlying plasma cell dyscrasia, but there are limited trial data to guide treatment decisions. Supportive care considerations include management of endocrinopathy, neuropathy, thrombosis, and infection. Response assessment is centered on clinical, neuropathy, hematological, vascular endothelial growth factor, and radiological criteria. Future clinical trials are welcomed in this setting where evidence is limited.

Background: A high prevalence of antiphospholipid antibodies has been reported in case series of patients with neurological manifestations and COVID-19; however, the pathogenicity of antiphospholipid antibodies in COVID-19 neurology remains unclear. Methods: This single-centre cross-sectional study included 106 adult patients: 30 hospitalised COVID-neurological cases, 47 non-neurological COVID-hospitalised controls, and 29 COVID-non-hospitalised controls, recruited between March and July 2020. We evaluated nine antiphospholipid antibodies: anticardiolipin antibodies [aCL] IgA, IgM, IgG; anti-beta-2 glycoprotein-1 [aβ2GPI] IgA, IgM, IgG; anti-phosphatidylserine/prothrombin [aPS/PT] IgM, IgG; and anti-domain I β2GPI (aD1β2GPI) IgG. Findings: There was a high prevalence of antiphospholipid antibodies in the COVID-neurological (73.3%) and non-neurological COVID-hospitalised controls (76.6%) in contrast to the COVID-non-hospitalised controls (48.2%). aPS/PT IgG titres were significantly higher in the COVID-neurological group compared to both control groups (p

IgM paraprotein-associated peripheral neuropathy (PN) in patients without overt evidence of lymphoma is a recognised clinical entity of unknown aetiology. Interrogating the bone marrow B-cell or plasma cell clones underlying paraproteinemic neuropathies may improve our understanding of both pathogenesis and treatment options. This retrospective observational analysis of IgM paraprotein-associated PN identified five patients with small pathological MYD88 L265P and CD20-positive B-cell clones in their bone marrow using multi-parametric flow cytometry, who have shown durable neurological response to rituximab. We posit that multi-parametric flow cytometry may be instrumental in identifying the cellular source of the paraprotein in IgM paraprotein-associated PN, and thus directing appropriate immunomodulatory therapy. Further understanding of these small pathological B-cell clones may also provide additional insight into mechanisms of monoclonal gammopathy of clinical significance overall.

Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) syndrome is a rare multisystem disease associated with a plasma-cell dyscrasia. Although pachymeningeal involvement has occasionally been described, MRI of the central nervous system (CNS) has not yet been extensively investigated. We retrospectively evaluated CNS MRI in Europe’s largest single-center cohort of POEMS syndrome. Of 77 patients who have been formally diagnosed with POEMS, 41 had MRI brain and 29 had MRI spine. A control group of 33 patients with chronic inflammatory demyelinating polyneuropathy (CIDP) was used as this is the major differential diagnosis. Of these CIDP patients, 12 underwent both MRI brain and spine, 7 had solely MRI brain and 14 had MRI spine. In 41 POEMS patients with MRI brain, we identified frequent smooth, diffuse meningeal thickening of the cerebral convexities and falx (n = 29, 71%), of which 4 had meningeal collections. 17 (41%) had vascular abnormalities including white-matter disease, of which 4 had established infarcts. Of 29 patients with MRI spine, 17 (59%) had thickening of the brachial and lumbosacral plexus. Conversely in 19 CIDP patients with MRI brain, none had meningeal thickening (p

SARS-CoV-2 is associated with new-onset neurological and psychiatric conditions. Detailed clinical data, including factors associated with recovery, are lacking, hampering prediction modelling and targeted therapeutic interventions. In a UK-wide cross-sectional surveillance study of adult hospitalized patients during the first COVID-19 wave, with multi-professional input from general and sub-specialty neurologists, psychiatrists, stroke physicians, and intensivists, we captured detailed data on demographics, risk factors, pre-COVID-19 Rockwood frailty score, comorbidities, neurological presentation and outcome. A priori clinical case definitions were used, with cross-specialty independent adjudication for discrepant cases. Multivariable logistic regression was performed using demographic and clinical variables, to determine the factors associated with outcome. A total of 267 cases were included. Cerebrovascular events were most frequently reported (131, 49%), followed by other central disorders (95, 36%) including delirium (28, 11%), central inflammatory (25, 9%), psychiatric (25, 9%), and other encephalopathies (17, 7%), including a severe encephalopathy (n = 13) not meeting delirium criteria; and peripheral nerve disorders (41, 15%). Those with the severe encephalopathy, in comparison to delirium, were younger, had higher rates of admission to intensive care and a longer duration of ventilation. Compared to normative data during the equivalent time period prior to the pandemic, cases of stroke in association with COVID-19 were younger and had a greater number of conventional, modifiable cerebrovascular risk factors. Twenty-seven per cent of strokes occurred in patients 60 years old, the younger stroke patients presented with delayed onset from respiratory symptoms, higher rates of multi-vessel occlusion (31%) and systemic thrombotic events. Clinical outcomes varied between disease groups, with cerebrovascular disease conferring the worst prognosis, but this effect was less marked than the pre-morbid factors of older age and a higher pre-COVID-19 frailty score, and a high admission white cell count, which were independently associated with a poor outcome. In summary, this study describes the spectrum of neurological and psychiatric conditions associated with COVID-19. In addition, we identify a severe COVID-19 encephalopathy atypical for delirium, and a phenotype of COVID-19 associated stroke in younger adults with a tendency for multiple infarcts and systemic thromboses. These clinical data will be useful to inform mechanistic studies and stratification of patients in clinical trials., Ross Russell et al. report novel details of COVID-19 neurological complications: multiple overlapping diagnoses in the same patients, a severe encephalopathy atypical for delirium, and a lowered threshold for stroke in younger adults. Higher age, pre-morbid frailty score and white cell count predicted clinical outcome., Graphical Abstract Graphical Abstract

Background and Aims Recently a number of antigens have been identified as pathogenic antibody targets in cases of primary membranous glomerulonephritis(MGN), including phospholipase A2 receptor (PLA2R), thrombospondin type 1 domain containing 7A(THSD7A), and NELL-1, while exostosin is found in secondary (lupus associated) MGN. However, other as yet undiscovered antigens are thought to exist. Although rare, there is a recognised association between chronic inflammatory demyelinating polyneuriopathy (CIDP) and nephrotic syndrome. Method We investigated the link between CICP and MGN and the associations with Contactin-1(CNTN1), a node of Ranvier neuronal protein, as a potential common autoantigen, by immunohistochemistry, RT-PCR and proteomic analysis of isolated glomeruli. We tested sera from 468 patients with suspected immune-mediated neuropathies, 295 with idiopathic MGN, and 210 disease controls, for CNTN1 antibodies. Results We describe a series of 16 patients, all presenting with CIDP, nephrotic syndrome due to MGN, and with circulating and deposited anti-contactin-1 (CNTN1) antibodies (IgG4 predominant in those tested) in the kidney. The onset and resolution of both disorders had a close temporal relationship, and the majority of cases were resistant to first-line therapies typically employed for inflammatory neuropathies, but achieved a good outcome with non-standard treatment. Importantly, four (1.4%) further patients with isolated MGN identified from a serum bank of 295 idiopathic MGN patients with no CIDP were also positive for anti-CNTN1 antibodies. CNTN1 protein was detected by mass spectroscopy within glomeruli from patients with CNTN1 antibodies, but not in healthy kidney or anti-PLA2R associated MGN. CNTN1 mRNA was found in renal cortical tissue. Conclusion These data provide evidence that CNTN1 antibodies precipitate both autoimmune neuropathy and MGN. The temporal correlation of these disorders, as well as the presence of CNTN1 protein and antibodies in both peripheral nerve and diseased glomeruli, supports a common antibody-mediated pathological process, and defines a new antigenic target in MGN. CNTN1 antibodies have diagnostic and therapeutic relevance, and may additionally serve as a means of monitoring disease activity in both conditions. Other factors may explain presentation with isolated neurological disease or MGN.

Preliminary pathological and biomarker data suggest that SARS-CoV-2 infection can damage the nervous system. To understand what, where and how damage occurs, we collected serum and CSF from patients with COVID-19 and characterised neurological syndromes involving the peripheral and central nervous system (n = 34). We measured biomarkers of neuronal damage and neuroinflammation, and compared these with non-neurological control groups, which included patients with (n = 94) and without (n = 24) COVID-19. We detected increased concentrations of neurofilament light, a dynamic biomarker of neuronal damage, in the CSF of those with central nervous system inflammation (encephalitis and acute disseminated encephalomyelitis) (14800pg/mL [400, 32400]), compared to those with encephalopathy (1410pg/mL [756, 1446], peripheral syndromes (GBS) (740pg/mL [507, 881]) and controls (872pg/mL [654,1200]). Serum neurofilament light levels were elevated across patients hospitalised with COVID-19, irrespective of neurological manifestations. There was not the usual close correlation between CSF and serum neurofilament light, suggesting serum neurofilament light elevation in the non-neurological patients may reflect peripheral nerve damage in response to severe illness. We did not find significantly elevated levels of serum neurofilament light in community cases of COVID-19 arguing against significant neurological damage. Glial fibrillary acidic protein, a marker of astrocytic activation, was not elevated in the CSF or serum of any group, suggesting astrocytic activation is not a major mediator of neuronal damage in COVID-19., Graphical Abstract Graphical Abstract

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

Background: There is an established association between acquired inflammatory demyelinating neuropathies and nephrotic syndrome, but a common immunopathological mechanism has yet to be determined. Antibodies to known glomerular podocyte antigens occur in up to 90% of patients with nephrotic syndrome due to idiopathic membranous glomerulonephritis (MGN), the majority targeting the phospholipase A2 receptor (PLA2R). In patients with immune-mediated neuropathies, antibodies targeting molecules of the node of Ranvier, such as contactin-1 (CNTN1), are increasingly recognised. Methods: In this study, sera from 468 patients with suspected immune-mediated neuropathies, 295 with idiopathic MGN, and 210 disease controls, were tested for CNTN1 antibodies. Topographical binding patterns were determined using teased nerve fibres and live myelinated nerve co-cultures. CNTN1 expression in human kidney was characterised by immunohistochemistry, western blotting and PCR. Findings: A total of 16 patients with an immune-mediated neuropathy and MGN were seropositive for IgG4 anti-CNTN1 antibodies. The onset and resolution of both disorders had a close temporal relationship. The majority of cases were resistant to first-line therapies typically employed for inflammatory neuropathies, but achieved a good outcome with non-standard treatment. Four further patients with isolated MGN were also positive for the same antibodies at lower titres. CNTN1 protein was detected within glomerular deposits in biopsies from patients with CNTN1 antibodies, but not in healthy kidney or anti-PLA2R associated MGN. Interpretation: These data provide evidence that CNTN1 antibodies precipitate both autoimmune neuropathy and MGN. The temporal correlation of these disorders, as well as the presence of CNTN1 protein and antibodies in both peripheral nerve and diseased glomeruli, supports a common antibody-mediated pathological process, and defines a new antigenic target in MGN. CNTN1 antibodies have diagnostic and therapeutic relevance, and may additionally serve as a means of monitoring disease activity in both conditions. Funding Statement: Medical Research Council (MRC), GBS/CIDP Foundation International, MRC and Kidney Research UK. Declaration of Interests: SR runs a not-for-profit diagnostic testing service for nodal/paranodal antibodies. He has received a speaker’s honorarium and/or travel expenses from Fresenius Medical Care, Excemed, Alnylam and argenx. AR has received honoraria from Sarepta, Roche and Sanofi Aventis, is a member of MND Association Clinical Advisory Board, and was a member of NICE MND Guideline Development Group. ASC receives funding from NIHR University College London Hospitals Biomedical research centre. AM is a clinical fellow with grant reference number MR/P001777/1. SPi is was funded by a grant from the Karolinska Institutet during the course of the study. All other authors have nothing to declare. Ethics Approval Statement: Research Ethics Committee approval number 14/SC/0280

Context POEMS syndrome is a rare multisystem disorder characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma-proliferative disorder, and skin changes, among other features. Objective To describe the prevalence and course of endocrine dysfunction in POEMS. Design Cohort study with systematic review of the endocrinopathy in POEMS. Setting Seventy-five patients with POEMS were evaluated by the multidisciplinary team at our tertiary specialist center. Patients Endocrine data were available for 59 patients who attended the clinic from June 1999 to May 2018. Interventions All patients had regular endocrine screening, including testing for diabetes, pituitary and thyroid dysfunction and assessment of bone metabolism. Main outcome measure Prevalence and survival time to develop endocrinopathy in POEMS. Results Thirty-four (63%) patients presented with an endocrinopathy at POEMS diagnosis and 54 (92%) had at least one endocrine abnormality at follow-up. The median follow-up was 4.4 (interquartile range, 1.5, 7.9) years. The most common endocrine abnormality was hypogonadism in 68%, followed by hyperprolactinemia (56%), hypothyroidism (54%), abnormal glucose metabolism (24%), adrenal insufficiency (17%), and high IGF-1 levels (15%). Spontaneous resolution of endocrine abnormalities at the end of follow-up was observed: 14% of patients with hypogonadism; 42%, hyperprolactinemia; 34%, hypothyroidism; and 38%, high IGF-1 levels. Conclusions Endocrinopathy was found in 63% of patients at diagnosis and in 92% of patients during follow-up in our cohort. Therefore, patients with POEMS should be systematically assessed for endocrinopathy. The most common deficiencies were hypogonadism and hypothyroidism; however, but endocrinopathy can normalize, so ongoing treatment should remain under review.

POEMS syndrome is a rare and disabling autoinflammatory condition characterised by a typical peripheral neuropathy and the presence of a monoclonal plasma cell disorder. The acronym ‘POEMS’ represents the complex and multisystem features of the disease, including polyneuropathy, organomegaly, endocrinopathy, a monoclonal plasma cell disorder and skin disease. The diagnosis of POEMS is a significant challenge because of the heterogeneity of clinical presentations and variation of POEMS features. Patients are often misdiagnosed with another cause of inflammatory neuropathy and receive one or more ineffective immunomodulatory medications, resulting in delayed diagnosis and further clinical deterioration before a diagnosis is made. University College London Hospitals sees one of the largest reported POEMS cohorts in Europe, and runs a multispecialist clinic to assist with diagnosis, treatment and ongoing support. This review draws upon our experience to present the typical features of POEMS syndrome and highlight diagnostic conundrums commonly experienced, supplemented with clinical cases. We provide an investigative guide for clinicians when considering POEMS as the diagnosis, and propose a treatment algorithm that centres on the site and degree of monoclonal cell proliferation.

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 (N2O) 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 abnormalities 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 deficiency. 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 recreational use of N2O. 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 affected, and devising ways to prevent potentially long-term neurological damage.

A 26-year-old man was referred with facial weakness, dysarthria, dysphagia, ophthalmoparesis and severely weak and wasted legs. His symptoms had begun when aged 20 with electric shock pains and paraesthesia in both feet progressing over 6 months to the lower calves. He then developed buttock numbness and occasional faecal incontinence. By age 22, he had diffuse lower limb weakness and wasting, with difficulty standing from a seated position and frequent tripping. He became wheelchair-dependent within 3 years. Over the same time period, he developed progressive facial weakness, bilateral ptosis, slurred speech, difficulty chewing and swallowing and lost 10 kg of weight. He reported hearing difficulty, and an audiogram showed high-frequency hearing loss. Important negatives included absence of upper limb symptoms, autonomic, cardiac, respiratory or cognitive dysfunction. He was from a non-consanguineous, Lithuanian background and the eldest of three siblings. He was born following a normal pregnancy and delivery, and motor development was normal. He had sustained a left corneal abrasion with visual impairment following an accidental chemical injury aged 14. During the initial investigation of his symptoms (age 23), he was found to have a choroid plexus lesion in the fourth ventricle. It was completely resected and histology confirmed benign choroid plexus papilloma WHO grade I. Postoperative neuro-oncology discussion deemed the lesion cured. He had bilateral ptosis, bilateral facial wasting and could not close his mouth against gravity (figure 1A). Visual acuity was reduced to perception of light on the left, 6/9 on the right. There was almost complete, complex ophthalmoplegia (figure 1B) without fatiguability. Trigeminal sensation was reduced. He could not achieve eyelid closure; frontalis, buccinator and orbicularis oris were symmetrically weak. His speech was dysarthric and his tongue was weak. His uvula was central with symmetrical palatal movement, but the gag reflex was reduced. Figure 1 Clinical examination at age 26. …

Background IgM paraprotein-associated peripheral neuropathies (PN) are a heterogenous group of disorders seen in patients with IgM MGUS and Waldenström's Macroglobulinaemia (WM). Anti-myelin associated glycoprotein (MAG) antibodies are causally identified in ~50% of such cases, but other neuropathies with other IgM-targets are described, along with AL amyloidosis and cryoglobulinaemic vasculitis amongst others. Presence of neuropathy alone is typically not an indication for treatment, but progressive disability is. Due to their relative rarity and heterogeneity, the true prevalence and optimal management of these neuropathies is currently unclear. Methods The Rory Morrison WMUK Registry, a national IgM-related disorders database incorporating 18 centres, was searched for all patients with PN and retrospective data clinical data extracted. Research ethics approval was obtained. Results IgM-related PN was identified 153 patients, of whom 99 (64.7%) had underlying WM and 54 (35.3%) had IgM MGUS. Anti-MAG neuropathy was present in 83 (54.6%) patients, anti-ganglioside in 3 (2%), AL amyloid in 7 (4.3%), cryoglobulinemia in 6 (3.7%), one (0.6%) case of CANOMAD syndrome, and a non-MAG IgM-neuropathy in 53 (34.5%%). PN was present at diagnosis in 143 (93.5%) whereas 10 (6.5%) were diagnosed during the course of their disease. Median age at diagnosis was 64 years (30-92) and 101/153 (66%) were male. Table 1 details results at diagnosis. κ-light chain was present in 80.3%, λ in 11.8% and 7.9% had multiple M-protein bands expressing both light chains. MYD88L265P was identified in 44/55 tested patients (80%) and in 23/30 (76.7%) cases of anti-MAG. In those with an IgM-related disorder, 13/20 (65%) had MYD88L265P, higher than in other IgM MGUS patients (7/14, 50%). CXCR4MUT were found in 3/22 (13.6%). Median bone marrow infiltration on trephine was 13% (range 0-85%), but 10 patients had no evidence of disease, 5 had disease on flow cytometry only, 2 an isolated finding of MYD88L265P and 1 isolated CXCR4MUT on PCR. IgM-related PN was seen in 99/719 (13.8%) of all registry patients with WM. At diagnosis, the bone marrow burden, M-protein and B2M were all significantly lower (p Therapy had been required in 81 (53.3%) patients, including at time of diagnosis in 23 (15%). Median time from diagnosis to treatment was long, at 6.7 years (95% CI 3.2-9.1 years). PN was the sole treatment indication in 64/81 (79%) cases. Time to treatment commencement did not appear to be affected by M-protein quantity or marrow burden, but patients with WM were more likely to have received treatment for their PN (59/108, 54.6%). Frontline treatment incorporated rituximab (R) in 66/81 (81.5%) patients, including R-monotherapy in 30, DRC 20, R-CHOP/R-CVP eight and BR in seven. A major biochemical response was seen in 19/34 (55.9%) patients. Clinical response was seen in 34 of 45 evaluable cases (75.6%), with improvement in 13 (28.9%) and stabilisation in 21 (46.7%). Clinical response or stabilisation was significantly more likely with R-containing therapy (82.1% vs 33.3%, p 0.04), non-amyloid related PN (82% vs 0%, p = 0.01) and attainment of ≥ partial response. All patients (n=12) with normal BMAT or isolated MYD88L265P responded to R-containing frontline therapy, another positive prognostic factor (p = 0.08). Progression of PN occurred after an initiation period of clinical response in 7/34 (20.5%), necessitating re-treatment at a median of 4.3 years after frontline therapy. Median time to 2nd line therapy was 6.7 years, longer than for other WM treatment indications (p = 0.04). Conclusions IgM-related PN is a cause of morbidity for a significant proportion of patients with WM, with a prevalence of 13.7%. However, a third of cases occur in those with IgM MGUS and even very small clonal populations seem capable of causing disease but appear responsive to rituximab therapy. Patients typically have comparatively low systemic disease burden and low rates of CXCR4MUT, perhaps representing a more indolent phenotype or a product of earlier diagnosis. PN is frequently the sole indication for treatment, reflecting this. Clinical improvement or stabilisation was seen in 75% of treated patients, and attainment of ≥50% reduction in IgM (PR) and treatment with rituximab is associated with a more favourable outcome, whereas AL amyloid neuropathy appears to be more treatment resistant. Disclosures Lindsay: Amgen: Other: Travel Expenses; Takeda: Honoraria, Other: Travel Expenses; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses. Carr:Lupin: Honoraria; CSL: Honoraria; Grifols: Other: Travel support. McCarthy:Janssen: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees. El-Sharkawi:Roche: Other: Conference fees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pratt:Binding Site Ltd: Other: Personal fees; Amgen: Other: Personal fees; Janssen: Other: Personal fees; Celgene: Other: Personal fees; Takeda: Other: Personal fees; Gilead: Other: Personal fees; Sanofi-Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. D'Sa:Janssen: Honoraria, Research Funding; Sanofi: Honoraria; BeiGene: Honoraria, Research Funding.

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) is a rare paraneoplastic phenomenon secondary to plasma cell dyscrasia. Treatment is aimed at the underlying plasma cell clone and its survival factors. Autologous stem cell transplantation (ASCT) is selected for patients who have multifocal skeletal disease and/or bone marrow involvement with adequate performance status (Dispenzieri, 2017). Because of the rarity of the disease, there are relatively few papers describing outcomes following ASCT. This analysis seeks to add further to the emerging evidence and elucidate prognostic factors.

Background and purpose The cryopyrin-associated periodic fever syndrome (CAPS) is an autosomal dominant autoinflammatory disorder caused by mutations in the NLRP3 gene and is typified by recurrent episodes of systemic inflammation resulting in fever, urticarial rash and arthralgia. In addition to these systemic aspects, CAPS has multiple neurological manifestations. The largest case series to date is presented focusing on the neurological features of this disorder. Methods The case histories of a cohort of 38 UK patients with genetically proven CAPS who were treated with interleukin 1β (IL-1β) inhibition as part of a national treatment programme and underwent detailed neurological assessment were reviewed. Results Across the entire disease course neurological manifestations were present in 95% of patients; 84% had some form of headache; 66% sensorineural hearing loss; 60% myalgia; 34% papilloedema and 26% optic atrophy. Patients with the T348M mutation tended to have a more severe neurological phenotype with an earlier age of onset. Four patients had cerebrospinal fluid examination, three of whom had evidence of aseptic meningitis. There was a marked response to IL-1β inhibition, which has revolutionized management of these patients (29/32 patients with headache responding). Conclusion Neurological symptoms are extremely common in CAPS and these results highlight the importance of increasing awareness amongst neurologists, particularly as highly effective therapies are available.

To provide an overview of polyneuropathy organomegaly endocrinopathy M-protein and skin changes (POEMS) syndrome, detailing new insights into pathogenesis, prognostic factors, treatments, and outcome scores.With the development of large multicentre national cohorts of patients, POEMS syndrome is evolving into a well characterized multisystem hematoneurological syndrome. Without early diagnosis significant disability results from the neuropathy. Vascular endothelial growth factor (VEGF) is a useful and accurate biomarker supporting diagnosis and following disease activity. The past decade has seen a number of therapeutics become available to patients with POEMS, repurposed from myeloma treatment. Simple treatment algorithms are based on the extent of monoclonal proliferation and the performance status of patients. Risk factors, prognostic scores, and their impact on outcome measures have been developed from deeply phenotyped patient cohorts to predict response rate, progression-free survival and overall survival.Understanding links between the monoclonal lambda plasma cell disorder and resulting proinflammatory cytokine milieu is fundamental to determining POEMS syndrome pathophysiology. Similarities to chronic inflammatory demyelinating polyradiculoneuropathy and some other monoclonal proliferative diseases makes POEMS misdiagnosis common. A range of treatments are available, and more work to identify pathogenic mechanisms and treatment targets and prognostic scores will further enable treatment stratification for optimum outcomes.

Background and purpose The aim was to assess the therapeutic potential of bortezomib in the treatment of refractory N-methyl-d-aspartate receptor (NMDAR) antibody encephalitis and its potential in other immune-mediated, B-cell-driven neurological diseases. Methods Two cases of severe NMDAR antibody encephalitis, resistant to first and second line therapy with steroids, intravenous immunoglobulins, plasma exchange, cyclophosphamide and rituximab, were treated with four and five cycles of 1.3 mg/m2 bortezomib at 350 and 330 days following initial presentation. Results Both patients showed significant clinical improvement with reductions of NMDAR antibody titres following bortezomib treatment. This is the first case in the literature where the NMDAR antibody level was undetectable following treatment with bortezomib. Conclusion Bortezomib's unique ability to target long-lived autoreactive plasma cells appears to be a useful adjunct to standard second line immunosuppressive therapy in treatment-refractory NMDAR antibody encephalitis. The drug's pharmacodynamics, cell targeting and mechanism of action are reviewed, and it is postulated that bortezomib may be useful in a host of B-cell-driven neuroimmunological diseases.

Introduction Arterial and venous events are known to occur in patients with POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, Skin changes) syndrome which may also include myeloproliferation, with a reported rate in the literature of around 20%. This is higher than in the myeloma cohort where the VTE rate from the UK Myeloma XI study was reported as 11.8%. The approach to optimum management of thrombosis in POEMS patients remains undefined. Method The UCLH POEMS Registry is a comprehensive tertiary centre-based UK data repository including patients from 1999 to the present. Data were collated from patients referred in for diagnosis or after treatment and included blood results, neurological and general performance status, previous and active venous thromboembolism (VTE) and arterial events and their management. Results Of the 103 patients in the UCLH POEMS Registry, 20 were excluded due to missing data. Of the 83 patients included, median age was 52 years (31-84) and 54 (65%) were male. Mean haemoglobin at diagnosis was 143 g/L (89-190), platelet count 443 x10^9 (194-741), vascular endothelial growth factor (VEGF) 3536 pg/mL (388-15422), creatinine 75 μmol/L (32-168) and albumin 40 g/L (31-50). Performance status was ≥ 3 in 15 patients. Radiotherapy was used as a treatment modality in 21/83 (25%) and 48/83 (52%) patients received autografts. There were 51 outpatient-based chemotherapy regimens prescribed. Lenalidomide and dexamethasone (LD) was the most common prescription 30/51 (59%), followed by cyclophosphamide and dexamethasone in 10/51 (20%), LD plus cyclophosphamide in 3/51 (6%), melphalan and steroids 3/51 (6%), cyclophosphamide, dexamethasone and thalidomide 2/51 (4%), LD plus ixazomib 1/51 (2%), velcade, thalidomide and dexamethasone 1/51 (2%) and carfilzomib with dexamethasone 1/51 (2%). Of these 51 outpatient-based chemotherapy scripts, 30 received documented thromboprophylaxis (TP). Prophylactic low molecular weight heparin (pLMWH) was prescribed most frequently (17/30) with 16 of these patients receiving an immunomodulatory based chemotherapy regimen. Other TP agents used include: aspirin (6/30), treatment dose LMWH (tLMWH) (2/30), rivaroxaban (2/30), warfarin (2/30) and clopidogrel (1/30). Twenty-five patients experienced a total of 35 clinically apparent arterial or venous events. Seven had more than 1 thrombotic event, 2 of which developed both arterial and venous thromboses. Three patients had a prior history of VTE;1 with historic DVT developed pulmonary emboli, and 2 had arterial events after historic VTE. Eleven patients had 14 VTEs including DVT (6/14), PE (4/14) and 4 PICC-associated DVT occurring during melphalan-based autograft. Most VTEs occurred during active disease with median VEGF 2731 (444-5000). Five venous events occurred on chemotherapy, including 4 during a melphalan-based autograft, and 1 on LD. VTE occurred despite prophylactic LMWH in 3 patients (2 unknown). Treatment comprised LMWH (4), warfarin (4), or the direct oral anticoagulants, rivaroxaban (1) and apixaban (1). One patient did not receive treatment for a PICC-associated DVT. Sixteen patients experienced 21 arterial events including stroke (7/21), peripheral vascular disease (6/21), MI (4/21) and microvascular disease (2/21). Most events occurred during active disease with median VEGF 3155 (637-10640). Three occurred on anti-POEMS therapy: one patient (VEGF 4555) developed a second stroke on LD and LMWH prophylaxis; one patient on LD (VEGF 10640) and prophylactic rivaroxaban 10mg developed PVD, and another on melphalan and prednisolone (VEGF 2000-4000) and warfarin for atrial fibrillation (target INR 2.0-3.0) developed PVD. Conclusion The venous and arterial event rate in this cohort at 35/83 (42%) is over double that previously reported. There were more arterial events than venous, and most occurred in a state of active disease and off anti-POEMS therapy (26/35), suggesting that treatment-related risk factors are less of a driver for thrombosis than the disease itself. There was no discernible relationship with thrombocytosis. Thromboprophylaxis is commonly used in POEMS patients receiving outpatient-based chemotherapy with the most common agent being prophylactic LMWH. With the high incidence of arterial events in the presence of active disease, the role for anti-platelet agents or indeed DOACs remains undefined in this patient group. Disclosures Thomas: Sanofi: Membership on an entity's Board of Directors or advisory committees. D'Sa:Janssen: Honoraria, Research Funding.

A 51-year-old right-handed man developed a sensory neuropathy with the sensation of walking on pebbles, and tight cramping pains in the calves requiring amitriptyline. Two months later, he became unsteady with difficulty walking downstairs necessitating a stick, with associated fatigue and weight loss of half a stone. He had a history of haemophilia type A and liver cirrhosis from hepatitis C, contracted through the transfusion of blood products in the 1980s. On examination, there was evidence of a distal symmetrical sensorimotor polyneuropathy with Medical Research Council (MRC) power grade 4+/5 in the intrinsic hand muscles and 0/5 in ankle plantar and dorsiflexion. Supinator, knee and ankle deep tendon reflexes were all absent, with mute plantar responses. He had a loss of pinprick sensation to the knees, vibration loss to the costal margins and temperature perception was altered to the mid-thighs. There was dusky pigmentation of the skin and peripheral oedema in the lower limbs. His history and examination findings are typical of a distal symmetrical neuropathy (see box 1 for the differential diagnosis of a painful large fibre neuropathy). Serological workup for a neuropathy should include full blood count, B12, folate, erythrocyte sedimentation rate (ESR), glucose, thyroid function, a serum protein electrophoresis and immunofixation, and possibly an antinuclear antibody. Note that it is typical for hospital laboratories only to perform serum immunofixation if the serum protein electrophoresis is abnormal. The greater sensitivity of immunofixation may find low-level paraproteins that would be otherwise undetectable, and which may be highly relevant in the context of neuropathy. He also has a history of hepatitis C which is associated with cryoglobulinaemia and cryoglobulinaemic peripheral nerve vasculitis, and therefore an important differential. Constitutional symptoms, including weight loss, are uncommon in isolated peripheral neuropathy, and therefore systemic causes should be considered, including vasculitis, malignancies, metabolic (diabetes), …

Objective To examine patient knowledge about sudden unexpected death in epilepsy (SUDEP) compared to other risks in epilepsy. To explore patients’ experiences surrounding SUDEP disclosure and opinions on how information should be delivered. Design A cross-sectional questionnaire. Setting Royal Free Hospital, London outpatient epilepsy clinics. Participants New and follow-up patients attending epilepsy clinics at a London teaching hospital over six months. Patients identified as being at risk of suffering negative emotional or psychological consequences of SUDEP discussions were excluded. Main outcome measures Patient knowledge about epilepsy risks; patient opinion regarding source, timing and delivery of SUDEP information; impact on health seeking behaviour. Results Ninety-eight per cent of patients were aware of medication adherence, 84% of factors influencing seizure frequency, 78% of driving regulations, 50% of SUDEP and 38% of status epilepticus; 72% of patients felt that SUDEP information should be given to all patients. Preferences for timing of SUDEP discussions varied between those wanting information at diagnosis (40%) and those preferring to receive it after three clinic appointments (18%) to avoid information overload at the first consultation. Emotional responses (48% positive, 38% negative) predominated over measurable behavioural change following SUDEP discussions. Conclusions Less than half the patients knew about SUDEP and status epilepticus. Although the majority of patients with epilepsy wish to be informed about SUDEP early on in their diagnosis, information must be delivered in a way that promotes patient knowledge and empowerment.

Summary Background Teaching communication skills using role-play addresses an important learning need for medical students, with the debriefing process being central to the learning that occurs. In this work we examine the feasibility of using actor-reported ‘anger scores’, during a challenging communication scenario, as a tool to stimulate debriefing. Methods This teaching session was delivered to 10 groups of final-year MBBS (Bachelor of Medicine and Bachelor of Surgery) students at Newcastle University. One student from each group took on the role of the foundation year 1 (F1) doctor and had 10 minutes to talk to an angry relative (actor), who was unhappy with the care her mother had received. During the scenario the actor recorded her level of anger on a 10–point Likert scale (1, ‘no anger’; 10, ‘extreme anger’) at 1–minute intervals. Once the scenario was complete, the in-room tutor graphically presented these scores against time. During debriefing, students were asked to examine the graph produced: fluctuations in anger levels were identified, discussion was held regarding possible precipitants for the changes seen and strategies were developed for tackling future such incidents. Teaching communication skills using role-play addresses an important learning need for medical students Results Examples of graphs produced during the session are presented, including annotations highlighting the discussion topics that arose. Feedback on the session from both students and actor was positive, with no reports that the scoring process interfered with the fidelity of the scenario. Discussion We believe that actor-reported ‘anger scores’ provide a quick, simple and cheap method of producing a visual aid to the debriefing process that, in the context of a challenging communication scenario, provided a stimulus for discussion.

Doctors in training are allowed to apply to go ‘Out Of Progamme’ (OOP) to perform research, develop their clinical experience or take a career break. New replacement numbers are not released when a trainee takes an OOP. From 1 January 2016, Locum Appointments for Training (LAT) posts, across all specialties, ended in England. There is now a mismatch between trainee numbers wanting to take time out of programme and those in clinical training programmes. A survey was conducted into OOP preferences of neurology trainees throughout the North London training programme. 48 of 52 trainees responded to the email questionnaire to ascertain the following; 1. What proportion of trainees had already taken time OOP, 2. How many were looking to apply and what year, 3. How many years will trainees apply for OOP, and 4. Do trainees feel taking time OOP is a valuable experience, Neurology is a particularly academic speciality, where time OOP to develop research skills and experience is frequently requested; our survey demonstrates that the majority of trainees in the North London programme will have a research degree by the time they complete training. The survey also demonstrates the considerable benefits that trainees obtain from a period of OOP for research. We postulate that Health Education England should allow ‘mortgaging’ of training numbers in neurology to accommodate demand for OOPs without compromising adequate fill rates in clinical training programmes

Introduction POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin changes) syndrome is a rare multi-system disorder characterised by a monoclonal plasma cell disorder and peripheral neuropathy in combination with a myriad of other clinical features. Several patient cohorts have previously been described leading to the formulation of diagnostic criteria. For the purposes of establishing a specialist centre in the United Kingdom we collected data of our patient cohort and compared it with previous reports. Methods Demographic data for patients currently known to our clinic with an established diagnosis of POEMS (n=52) was extracted from an already existing database. Clinic letters for these patients were retrospectively screened for clinical features, diagnostic criteria, treatments given and response to treatment, occasionally supplemented by review of historical investigation results. The data was collected in a newly established database designed to facilitate future prospective data collection. Results Our cohort currently consists of 52 patients from a mixed ethnic background, with a male to female ratio of 4.2:1 (n=42 vs 10 respectively) and a median age of 57; median age at diagnosis was 49. The majority of patients were referred to our centre from across the United Kingdom between 2009 and 2015. The prevalence of diagnostic criteria broadly resembles previously published cohorts (see table). 17 patients received radiotherapy for limited disease while 31 patients underwent autologous haematopoietic stem cell transplant (ASCT); 18 patients received at least one line of systemic chemotherapy. A subgroup review of patients who underwent ASCT showed sustained clinical improvements in 83% of patients reviewed; 61% of patients who received radiotherapy had a documented sustained improvement. Patients receiving chemotherapy showed a more variable response; of note, 4 out of 6 patients treated with a combination of lenalidomide and dexamethasone were documented to have had significant clinical improvement. 3 patients died during the period of follow-up at the ages of 70, 63 and 63, respectively. Death occurred between 4 and 15 months following diagnosis; none of the deceased patients underwent ASCT or radiotherapy. Discussion We report the basic demographic and clinical outcomes of a new cohort of patients with this rare condition. Our cohort broadly resembles other previously published reports, as does our experience with therapeutic options. Radiotherapy appears to be effective in stabilising or improving limited disease confined to a solitary plasmacytoma or few lytic foci, while autologous stem cell transplantation achieves sustained improvement in the majority of patients with more diffuse disease. Chemotherapy offers further treatment options for patients not suitable for either of those, with lenalidomide becoming an increasingly promising agent. Retrospective data collection and the establishment of a database for prospective study will enable us to further investigate this group with a view to expand our understanding of this poorly understood disease. Disclosures Yong: Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding.

Aims and Objectives: To review the pathophysiology, accuracy, effectiveness and use of Licox for brain tissue oxygen monitoring in traumatic brain injury (TBI). Background: The Licox monitoring system allows continuous monitoring of partial pressure of brain tissue oxygen (PbO2), brain tissue temperature and intracranial pressure (ICP). The application and effectiveness of the use of Licox in TBI is not clearly explored within the literature. Inclusion Criteria: A date limit of 1995–2009, English language, all animal and human studies and the following terms were searched: Licox, brain tissue oxygenation, cerebral oxygenation and TBI. MEDLINE database was the primary data source. Exclusion Criteria: All paediatric papers were excluded from the search. Studies not related to pathophysiology and management of TBI and brain tissue oximetry in adults were excluded. Data relevant to the subject under consideration were extracted by three independent clinicians to form a narrative report. Studies were critically evaluated using the NHS Public Health Resource Unit's checklist for each study analysed. Conclusions: Licox offers new insights into cerebral pathology and physiology. The continuous bedside monitoring provides real-time data that can be used to improve patient management and prognosis in specialist units by trained and experienced staff. More research is required to understand the limitations of this technology and why it is not in widespread use. Relevence to Clinical Practice: A clinical tool that could be utilized more often in the right setting to improve care to patients suffering from TBI by disseminating more information on this unique tool.

Disparity exists between clinical practice and guidelines on discussion of Sudden death in epilepsy (SUDEP) with patients. This study examined how patients were informed about SUDEP; the impact of such discussion, and their views on the discussion.MethodsA quantitative/qualitative questionnaire was given to 50 consenting patients attending epilepsy clinics. Exclusions were patients with intellectual disability, and/or those deemed at risk of negative consequences on completing the study.Results98% of patients were aware of the importance of medication adherence, 78% of driving regulations in epilepsy, and 84% of factors influencing seizure frequency. Only 50% of patients were aware of SUDEP and 38% of status epilepticus.42% of patients preferred SUDEP information at diagnosis and 36% only after three clinic appointments.Negative emotional responses (in 38%), and not behavioural changes, resulted from SUDEP discussions.ConclusionsIn this small in-depth study, only half the patients recalled information about SUDEP. More than one-third of patients reported adverse consequences. There was no improvement in self-management.We suggest a paradigm shift: embedding SUDEP discussion with all potential complications of epilepsy; and emphasising optimal healthcare and self-management. This model has been successfully applied in other areas to empower patients and improve outcome.