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Toxic neuropathies result from exogenous substances damaging the peripheral nerves. There are numerous causes, including prescribed and recreational drugs, heavy metals, industrial agents and biological toxins. Timely recognition of these neuropathies gives better outcomes, as they usually improve or stabilise once the toxin is removed. Most toxic neuropathies are axonal, length-dependent and sensory predominant, although some have significant motor involvement or can present acutely or subacutely. Here, we outline our clinical approach and discuss the major causes of toxic neuropathy, while emphasising the clinical and neurophysiological features and the neuropathy phenotype. We also include an update on newer medications that can cause neuropathy, including immune checkpoint inhibitors and BRAF/MEK inhibitors.

Human prion diseases are remarkable for long incubation times followed typically by rapid clinical decline. Seed amplification assays and neurodegeneration biofluid biomarkers are remarkably useful in the clinical phase, but their potential to predict clinical onset in healthy people remains unclear. This is relevant not only to the design of preventive strategies in those at-risk of prion diseases, but more broadly, because prion-like mechanisms are thought to underpin many neurodegenerative disorders. Here, we report the accrual of a longitudinal biofluid resource in patients, controls and healthy people at risk of prion diseases, to which ultrasensitive techniques such as real-time quaking-induced conversion (RT-QuIC) and single molecule array (Simoa) digital immunoassays were applied for preclinical biomarker discovery. We studied 648 CSF and plasma samples, including 16 people who had samples taken when healthy but later developed inherited prion disease (IPD) (‘converters’; range from 9.9 prior to, and 7.4 years after onset). Symptomatic IPD CSF samples were screened by RT-QuIC assay variations, before testing the entire collection of at-risk samples using the most sensitive assay. Glial fibrillary acidic protein (GFAP), neurofilament light (NfL), tau and UCH-L1 levels were measured in plasma and CSF. Second generation (IQ-CSF) RT-QuIC proved 100% sensitive and specific for sporadic Creutzfeldt-Jakob disease (CJD), iatrogenic and familial CJD phenotypes, and subsequently detected seeding activity in four presymptomatic CSF samples from three E200K carriers; one converted in under 2 months while two remain asymptomatic after at least 3 years’ follow-up. A bespoke HuPrP P102L RT-QuIC showed partial sensitivity for P102L disease. No compatible RT-QuIC assay was discovered for classical 6-OPRI, A117V and D178N, and these at-risk samples tested negative with bank vole RT-QuIC. Plasma GFAP and NfL, and CSF NfL levels emerged as proximity markers of neurodegeneration in the typically slow IPDs (e.g. P102L), with significant differences in mean values segregating healthy control from IPD carriers (within 2 years to onset) and symptomatic IPD cohorts; plasma GFAP appears to change before NfL, and before clinical conversion. In conclusion, we show distinct biomarker trajectories in fast and slow IPDs. Specifically, we identify several years of presymptomatic seeding positivity in E200K, a new proximity marker (plasma GFAP) and sequential neurodegenerative marker evolution (plasma GFAP followed by NfL) in slow IPDs. We suggest a new preclinical staging system featuring clinical, seeding and neurodegeneration aspects, for validation with larger prion at-risk cohorts, and with potential application to other neurodegenerative proteopathies.

POEMS syndrome is a rare multisystem paraneoplastic disorder due to an underlying low-level plasma cell dyscrasia. Due to its rarity, there are limited data to guide treatment and there are no consensus guidelines. Therapy choices are dictated by patient characteristics, disease factors and local funding arrangements. The goals of therapy are to eradicate the underlying clone in order to improve quality of life and overall survival. Most evidence has been garnered in the front-line setting. Localised disease responds well to radiotherapy, whilst for those with systemic disease, the best outcomes are demonstrated with induction chemotherapy followed up with high-dose melphalan and stem cell rescue if eligible. For transplant-ineligible patients lenalidomide-dexamethasone remains a preferred treatment option. Data in the relapse setting are scarce. Supportive care including management of neuropathy, endocrinopathy, thrombotic risk and anti-infective agents is necessary. Future international collaboration is crucial to define optimal treatment strategies particularly in the relapse setting.

This study was undertaken to explore associations between plasma neurofilament light chain (pNfL) concentration (pg/ml) and disease activity in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and examine the usefulness of pNfL concentrations in determining disease remission.We examined pNfL concentrations in treatment-naïve CIDP patients (n = 10) before and after intravenous immunoglobulin (IVIg) induction treatment, in pNfL concentrations in patients on maintenance IVIg treatment who had stable (n = 15) versus unstable disease (n = 9), and in clinically stable IVIg-treated patients (n = 10) in whom we suspended IVIg to determine disease activity and ongoing need for maintenance IVIg. pNfL concentrations in an age-matched healthy control group were measured for comparison.Among treatment-naïve patients, pNfL concentration was higher in patients before IVIg treatment than healthy controls and subsequently reduced to be comparable to control group values after IVIg induction. Among CIDP patients on IVIg treatment, pNfL concentration was significantly higher in unstable patients than stable patients. A pNFL concentrationgt; 16.6 pg/ml distinguished unstable treated CIDP from stable treated CIDP (sensitivity = 86.7%, specificity = 66.7%, area under receiver operating characteristic curve = 0.73). Among the treatment withdrawal group, there was a statistically significant correlation between pNfL concentration at time of IVIg withdrawal and the likelihood of relapse (r = 0.72, p lt; 0.05), suggesting an association of higher pNfL concentration with active disease.pNfL concentrations may be a sensitive, clinically useful biomarker in assessing subclinical disease activity.

BackgroundArterial and venous thromboembolic events (TEEs) have been associated with intravenous Ig use, but the risk has been poorly quantified. We aimed to calculate the risk of TEEs associated with exposure to intravenous Ig.MethodsWe included participants from UK Biobank recruited over 3 years, data extracted September 2020.The study endpoints were incidence of myocardial infarction, other acute ischaemic heart disease, stroke, pulmonary embolism and other venous embolism and thrombosis.Predictors included known TEE risk factors: age, sex, hypertension, smoking status, type 2 diabetes mellitus, hypercholesterolaemia, cancer and past history of TEE. Intravenous Ig and six other predictors were added in the sensitivity analysis.Information from participants was collected prospectively, while data from linked resources, including death, cancer, hospital admissions and primary care records were collected retrospectively and prospectively. Findings14 794 of 502 492 individuals had an incident TEE during the study period. The rate of incident events was threefold higher in those with prior history of TEE (8 .7%) than those without previous history of TEE (3.0%).In the prior TEE category, intravenous Ig exposure was independently associated with increased risk of incident TEE (OR=3.69 (95% CI 1.15 to 11.92), p=0.03) on multivariate analysis. The number needed to harm by exposure to intravenous Ig in those with a history of TEE was 5.8 (95% CI 2.3 to 88.3).Intravenous Ig exposure did not increase risk of TEE in those with no previous history of TEE.InterpretationIntravenous Ig is associated with increased risk of further TEE in individuals with prior history of an event with one further TEE for every six people exposed. In practice, this will influence how clinicians consent for and manage overall TEE risk on intravenous Ig exposure.

Reliable and responsive tools for monitoring disease activity and treatment outcomes in patients with neuropathies are lacking. With the emergence of ultrasensitive blood bioassays, proteins released with nerve damage are potentially useful response biomarkers for many neurological disorders, including polyneuropathies. In this review, we provide an overview of the existing literature focusing on potential applications in polyneuropathy clinical care and trials. Whilst several promising candidates have been identified, no studies have investigated if any of these proteins can serve as response biomarkers of longitudinal disease activity, except for neurofilament light (NfL). For NfL, limited evidence exists supporting a role as a response biomarker in Guillain-Barré syndrome, vasculitic neuropathy, and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Most evidence exists for NfL as a response biomarker in hereditary transthyretin-related amyloidosis (hATTR). At the present time, the role of NfL is therefore limited to a supporting clinical tool or exploratory endpoint in trials. Future developments will need to focus on the discovery of additional biomarkers for anatomically specific and other forms of nerve damage using high-throughput technologies and highly sensitive analytical platforms in adequality powered studies of appropriate design. For NfL, a better understanding of cut-off values, the relation to clinical symptoms and long-term disability as well as dynamics in serum on and off treatment is needed to further expand and proceed towards implementation. Supplementary Information The online version contains supplementary material available at 10.1007/s13311-021-01136-0.

Human prion diseases are remarkable for long incubation times followed by typically rapid clinical decline. Seed amplification assays and neurodegeneration biofluid biomarkers are remarkably useful in the clinical phase, but their potential to predict clinical onset in healthy people remains unclear. This is relevant not only to the design of preventive strategies in those at-risk of prion diseases, but more broadly, because prion-like mechanisms are thought to underpin many neurodegenerative disorders. Here we report the accrual of a longitudinal biofluid resource in patients, controls and healthy people at-risk of prion diseases, to which ultrasensitive techniques such as real-time quaking-induced conversion (RT-QuIC), and single molecule array (Simoa) digital immunoassays were applied for preclinical biomarker discovery. We studied a total of 648 CSF and plasma samples, including importantly, 16 people who had samples taken when healthy but later developed inherited prion disease (IPD) (“converters,” range from 9.9 prior to, and 7.4 years after onset). A second generation (IQ-CSF) RT-QuIC assay was used to screen symptomatic IPD samples, followed by optimisation for other IPDs, before the entire collection of at-risk samples was screened using the most sensitive assay. Glial fibrillary acidic protein (GFAP), neurofilament light (NfL), tau and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) levels were measured in plasma and CSF. IQ-CSF RT-QuIC proved 100% sensitive and specific for sporadic Creutzfeldt-Jakob disease (sCJD), iatrogenic (iCJD) and familial CJD phenotypes, and subsequently detected seeding activity in four CSF samples from threePRNPE200K carriers in the presymptomatic phase, one of whom converted shortly after but the other two remain asymptomatic after two and three years of follow up. A bespoke HuPrP P102L RT-QuIC showed partial sensitivity for P102L disease and was positive in a CSF sample from an individual at risk of P102L IPD. No compatible RT-QuIC assay iterations were discovered for classical 6-OPRI, A117V and D178N, and these at-risk samples tested negative with bank vole RT-QuIC. Plasma GFAP and NfL, and CSF NfL levels emerged as proximity markers of neurodegeneration in slowly progressive forms of IPDs, with highly statistically significant differences in mean values segregating normal control (together with IPD > 2 years to onset) from IPD < 2 years to onset and symptomatic IPD cohorts. The trajectories of biomarker change appeared to correspond to expected fast and slow clinical phenotypes of progression in IPD with plasma GFAP changes preceding NfL changes. We propose patterns of preclinical biomarker changes in prion diseases based on the presence of clinical, seeding and neurodegeneration features.

Guillain-Barre syndrome is sometimes a severe and disabling postinfectious neuromuscular paralysis that is causally associated with a number of well defined infections, and occasionally with immunization. The severe acute respiratory syndrome coronavirus 2 (Sars-CoV-2) pandemic and the worldwide immunization programme provoked fears of an epidemic of coronavirus disease 2019 (COVID-19) related disease. As we emerge from the pandemic this review summarises some of the huge volume of publications about Guillain-Barre syndrome (GBS), COVID-19 and immunisation against it.In the early months of COVID-19, there were concerns of significant numbers of cases of GBS resulting from SARS-CoV-2 infection. Large epidemiological studies have provided reassurance that the association of GBS with COVID-19 is small or absent. Despite considerable efforts, plausible pathogenic mechanisms aligned with our understanding of GBS causation have not been identified. Reliable data from national surveillance of COVID-19 vaccinations have shown GBS to occur at about 5.8 cases per million first doses of adenovirus vectored COVID-19 vaccines, otherwise not distinguishable from incident naturally occurring cases. However, this risk is far outweighed by the protective benefits of vaccination in the at-risk older deciles of age.With no obvious link of GBS to COVID-19 epitopes, in particular the spike (S-)protein, but a clearly demonstrable causation in some susceptible individuals from the global rollout of novel adenovirus vectored vaccine technologies, adenoviruses are of significant interest in the pathogenesis of GBS as well as vectors in their many expanding pharmaceutical applications.

After extensive evaluation, one-third of patients affected by polyneuropathy remain undiagnosed and are labelled as having chronic idiopathic axonal polyneuropathy, which refers to a sensory or sensory-motor, axonal, slowly progressive neuropathy of unknown origin. Since a sensory neuropathy/neuronopathy is identified in all patients with genetically confirmed RFC1 cerebellar ataxia, neuropathy, vestibular areflexia syndrome, we speculated that RFC1 expansions could underlie a fraction of idiopathic sensory neuropathies also diagnosed as chronic idiopathic axonal polyneuropathy. We retrospectively identified 225 patients diagnosed with chronic idiopathic axonal polyneuropathy (125 sensory neuropathy, 100 sensory-motor neuropathy) from our general neuropathy clinics in Italy and the UK. All patients underwent full neurological evaluation and a blood sample was collected for RFC1 testing. Biallelic RFC1 expansions were identified in 43 patients (34%) with sensory neuropathy and in none with sensory-motor neuropathy. Forty-two per cent of RFC1-positive patients had isolated sensory neuropathy or sensory neuropathy with chronic cough, while vestibular and/or cerebellar involvement, often subclinical, were identified at examination in 58%. Although the sensory ganglia are the primary pathological target of the disease, the sensory impairment was typically worse distally and symmetric, while gait and limb ataxia were absent in two-thirds of the cases. Sensory amplitudes were either globally absent (26%) or reduced in a length-dependent (30%) or non-length dependent pattern (44%). A quarter of RFC1-positive patients had previously received an alternative diagnosis, including Sjögren’s syndrome, sensory chronic inflammatory demyelinating polyneuropathy and paraneoplastic neuropathy, while three cases had been treated with immune therapies., Currò et al. investigate the prevalence of RFC1 expansions in a cohort of patients with chronic idiopathic axonal polyneuropathy. RFC1 expansions were found in 34% of patients with sensory neuropathy, but in none with sensory-motor neuropathy. Clinical features and diagnostic clues that should lead to suspicion of RFC1 neuropathy are discussed.

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.

In clinical neurology practice, there are few sensitive, specific and responsive serological biomarkers reflecting pathological processes affecting the peripheral nervous system. Instead, we rely on surrogate multimodality biomarkers for diagnosis and management. Correct use and interpretation of the available tests is essential to ensure that appropriate treatments are used and adjusted in a timely fashion. The incorrect application or interpretation of biomarkers can result in misdiagnosis and delays in appropriate treatment. Here, we discuss the uses and limitations of such biomarkers and discuss possible future developments.

Individualized dosing is an established approach in intravenous immunoglobulin (IVIg) treatment for inflammatory neuropathies. There is less experience in effective dosing strategies for subcutaneous (SC) immunoglobulin. We conducted a retrospective cohort study of patients with inflammatory neuropathies transferring from IVIg to SCIg in two UK peripheral nerve services. I-RODS and grip strength were used to measure outcome. Dose and clinical progress were documented at 1 year and at last review. 44/56 patients remained on maintenance SCIg beyond 1 year (mean 3.3 years, range 1–9 years) with stable clinical outcomes. Clinical deteriorations were corrected by small increases in SCIg dose in 20 patients at 1 year, a further 9 requiring subsequent further up-titrations. Sixteen tolerated dose reduction. Mean dose change was + 2.4% from baseline. Two patients required IVIg bolus rescue (2 g/kg). Three patients successfully discontinued Ig therapy. Nine patients returned to IVIg due to clinical relapse or patient preference. Overall tolerance was good. Dose titration to clinical response is an effective approach in SCIg maintenance therapy.

Objective The objective of this study was to evaluate patients with ganglionic acetylcholine receptor antibody (gAChR-Ab) positive autoimmune autonomic ganglionopathy using a multimodal testing protocol to characterize their full clinical phenotype and explore biomarkers to quantify immunotherapy response. Methods We conducted a cohort study of 13 individuals (7 women, 21-69 years of age) with autonomic failure and gAChR-Ab >100 pM identified between 2005 and 2019. From 2018, all patients were longitudinally assessed with cardiovascular, pupillary, urinary, sudomotor, lacrimal and salivary testing, and Composite Autonomic Symptom Score (COMPASS-31) autonomic symptom questionnaires. The orthostatic intolerance ratio was calculated by dividing change in systolic blood pressure over time tolerated on head-up tilt. Eleven patients received immunotherapy. Results At first assessment, all 13 patients had cardiovascular and pupillary impairments, 7 of 8 had postganglionic sudomotor dysfunction, 9 of 11 had urinary retention and xeropthalmia, and 6 of 8 had xerostomia. After immunotherapy, there were significant improvements in orthostatic intolerance ratio (33.3 [17.8-61.3] to 5.2 [1.4-8.2], p = 0.007), heart rate response to deep breathing (1.5 [0.0-3.3] to 4.5 [3.0-6.3], p = 0.02), pupillary constriction to light (12.0 [5.5-18.0] to 19.0 [10.6-23.8]%, p = 0.02), saliva production (0.01 [0.01-0.05] to 0.08 [0.02-0.20] g/min, p = 0.03), and COMPASS-31 scores (52 to 17, p = 0.03). Orthostatic intolerance ratio correlated with autonomic symptoms at baseline (r = 0.841, p = 0.01) and following immunotherapy (r = 0.889, p = 0.02). Immunofluorescence analyses of skin samples from a patient 32 years after disease onset showed loss of nerve fibers supplying the dermal autonomic adnexa and epidermis, with clear improvements following immunotherapy. Interpretation Patients with autoimmune autonomic ganglionopathy demonstrated objective evidence of widespread sympathetic and parasympathetic autonomic failure, with significant improvements after immunotherapy. Quantitative autonomic biomarkers should be used to define initial deficits, guide therapeutic decisions, and document treatment response. ANN NEUROL 2021;89:753-768.

This special commentary refers to ‘Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome’ by Keddie et al. (doi:10.1093/brain/awaa433).

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.

BACKGROUND: There is limited data on cerebrospinal fluid (CSF) biomarkers in sporadic amyloid-β (Aβ) cerebral amyloid angiopathy (CAA). OBJECTIVE: To determine the profile of biomarkers relevant to neurodegenerative disease in the CSF of patients with CAA. METHODS: We performed a detailed comparison of CSF markers, comparing patients with CAA, Alzheimer’s disease (AD), and control (CS) participants, recruited from the Biomarkers and Outcomes in CAA (BOCAA) study, and a Specialist Cognitive Disorders Service. RESULTS: We included 10 CAA, 20 AD, and 10 CS participants (mean age 68.6, 62.5, and 62.2 years, respectively). In unadjusted analyses, CAA patients had a distinctive CSF biomarker profile, with significantly lower (p

Immunoglobulin (Ig) is used to treat chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy with conduction block (MMNCB). Regular infusions may be used for symptom control. Disease activity is monitored with clinical outcome measurements. We examined outcome measure variation during clinically stable periods in Ig-treated CIDP and MMNCB patients. We explored utility of serial outcome measurement in long-term outcome prediction. Retrospective longitudinal analysis of a single neuroscience centre's Ig-treated CIDP and MMNCB patients, 2009-2020, was performed. Mean and percentage change for grip strength, Rasch-built overall disability scales (RODS) and MRC sum scores (MRC-SS) during periods of clinical stability were compared to score-specific minimal clinically important differences (MCID). Latent class mixed modelling (LCMM) was used to identify longitudinal trends and factors influencing long-term outcome. We identified 85 CIDP and 23 MMNCB patients (1423 datapoints; 5635 treatment-months). Group-averaged outcome measures varied little over time. Intra-individual variation exceeded MCID for RODS in 44.2% CIDP and 16.7% MMNCB datapoints, grip strength in 10.6% (CIDP) and 8.8%/27.2% (MMNCB right/left hand) and MRC-SS in 43.5% (CIDP) and 20% (MMNCB). Multivariate LCMM identified subclinical trends towards improvement (32 patients) and deterioration (73 patients) in both cohorts. At baseline, CIDP 'deteriorators' were older than 'improvers' (66.2 vs 57 years, P = .025). No other individual factors predicted categorisation. The best model for 'deteriorator' identification was contiguous sub-MCID decline in more than one outcome measure (CIDP: sensitivity 74%, specificity 59%; MMNCB: sensitivity 73%, specificity 88%). Outcome measure interpretation determines therapeutic decision-making in Ig-dependent neuropathy patients, but intra-individual variation is common, often exceeding MCID. Here we show sub-MCID contiguous changes in more than one outcome measurement are a better predictor of long-term outcome.

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.

Epidemics and pandemics in human history are not the exception but the rule. Bill Gates was prophetic in 2015 ‘if anything kills ten million people in the next few decades, it is likely to be an infectious virus rather than a war. Not missiles, microbes’. The Black Death (1347), the Great Plague of London (1665) and the Spanish Flu outbreak which killed 50 million people occurred in 1918. In 1997, the H5N1 bird flu epidemic occurred and was followed, in 2002, by the coronavirus outbreaks of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012. These were followed by the re-emerging pathogen epidemic; Ebola virus, unexpectedly, exploded in West Africa in 2013. While the world was celebrating the success of victory over Ebola, in 2015, the Zika epidemic reared its head. Significant neurological complications only featured in the Zika outbreak: congenital microcephaly, Guillain-Barre syndrome, myelitis and meningoencephalitis.1 The most well-studied coronavirus is the betacoronavirus, mouse hepatitis virus, that has provided model systems for the study of encephalitis and multiple sclerosis. In humans, coronaviruses usually cause common cold symptoms. However, the emergence of two zoonotic betacoronaviruses, SARS-CoV and MERS-CoV, revealed their full pathogenic potential.2 In December 2019, Zhu et al 3 described patients with pneumonia epidemiologically linked to a seafood and wet animal market in Wuhan, China. A novel coronavirus, SARS-CoV-2, was identified. WHO labelled the disease as COVID-2019. Further genomic analysis reveals that SARS-CoV-2 is similar to the betacoronavirus detected in bats but is a distinctly separate clade from SARS-CoV and MERS-CoV. A metallopeptidase, angiotensin-converting enzyme 2 (ACE2), has been identified as the functional cellular …

Our objective was to evaluate whether IV immunoglobulin (IVIg) increases the risk of thromboembolic events in neurology outpatients with inflammatory neuropathies, as there is conflicting evidence supporting this hypothesis, mainly from non-neurologic cohorts. We investigated this question over 30 months in our cohort of patients with inflammatory neuropathies receiving regular IVIg and found a greater incidence of arterial and venous thromboembolic events than population-based rates determined by hospital admissions data. Vascular risk factors were more common in the event group but there were no IVIg administration factors that contributed to the risk. This study suggests that IVIg may have a small but contributory role in determining thromboembolic risk in the inflammatory neuropathy cohort and more evidence is required before it is clear whether the current primary prevention guidelines are appropriate in this group of patients.

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.

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

Supplemental Digital Content is available in the text., OBJECTIVES: Multiple mechanisms have been proposed to explain disease severity in coronavirus disease 2019. Therapeutic approaches need to be underpinned by sound biological rationale. We evaluated whether serum levels of a range of proposed coronavirus disease 2019 therapeutic targets discriminated between patients with mild or severe disease. DESIGN: A search of ClinicalTrials.gov identified coronavirus disease 2019 immunological drug targets. We subsequently conducted a retrospective observational cohort study investigating the association of serum biomarkers within the first 5 days of hospital admission relating to putative therapeutic biomarkers with illness severity and outcome. SETTING: University College London, a tertiary academic medical center in the United Kingdom. PATIENTS: Patients admitted to hospital with a diagnosis of coronavirus disease 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eighty-six patients were recruited, 44 (51%) with mild disease and 42 (49%) with severe disease. We measured levels of 10 cytokines/signaling proteins related to the most common therapeutic targets (granulocyte-macrophage colony-stimulating factor, interferon-α2a, interferon-β, interferon-γ, interleukin-1β, interleukin-1 receptor antagonist, interleukin-6, interleukin-7, interleukin-8, tumor necrosis factor-α), immunoglobulin G antibodies directed against either coronavirus disease 2019 spike protein or nucleocapsid protein, and neutralization titers of antibodies. Four-hundred seventy-seven randomized trials, including 168 different therapies against 83 different pathways, were identified. Six of the 10 markers (interleukin-6, interleukin-7, interleukin-8, interferon-α2a, interferon-β, interleukin-1 receptor antagonist) discriminated between patients with mild and severe disease, although most were similar or only modestly raised above that seen in healthy volunteers. A similar proportion of patients with mild or severe disease had detectable spike protein or nucleocapsid protein immunoglobulin G antibodies with equivalent levels between groups. Neutralization titers were higher among patients with severe disease. CONCLUSIONS: Some therapeutic and prognostic biomarkers may be useful in identifying coronavirus disease 2019 patients who may benefit from specific immunomodulatory therapies, particularly interleukin-6. However, biomarker absolute values often did not discriminate between patients with mild and severe disease or death, implying that these immunomodulatory treatments may be of limited benefit.

Paraproteinaemic neuropathies comprise a heterogeneous group of neuro-haematological conditions with some distinct neurological, haematological and systemic phenotypes. The spectrum of disease varies from mild to severe, indolent to rapidly progressive and from small fibre sensory involvement to dramatic sensorimotor deficits. The haematological association may be overlooked, resulting in delayed treatment, disability, impaired quality of life and increased mortality. However, the presence of an irrelevant benign paraprotein can sometimes lead to inappropriate treatment. In this review, we outline our practical approach to paraproteinaemic disorders, discuss the utility and limitations of diagnostic tests and the distinctive clinical phenotypes and touch on the complex multidisciplinary management approaches.

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

BackgroundDaclizumab is an anti-CD25 monoclonal antibody developed for the treatment of relapsing remitting multiple sclerosis, which was withdrawn worldwide in March 2018, due to emerging serious immune-mediated systemic andcentral nervous system adverse events. We report a case of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis occurring 14 weeks after stopping daclizumab, which responded to the proteasome inhibitor bortezomib.MethodsFollowing lack of effective clinical response to first line (corticosteroid, plasma exchange, intravenous immunoglobulin) and second line (rituximab) treatments, bortezomib therapy was commenced. The patient received six cycles of bortezomib treatment.ResultsClinical improvement was noted 4 weeks after the first of six cycles of bortezomib and the patient experienced sustained clinical improvement.ConclusionOur case provides further class IV evidence of the use of bortezomib therapy for treatment refractory anti-NMDAR encephalitis.

Anti-viral vaccination has rarely been associated with Guillain-Barré syndrome(GBS). We performed a population-based study of NHS England data and a UK multicentre surveillance study to investigate the relationship between COVID-19 vaccination and GBS.We linked GBS cases from England’s National Immunoglobulin Database(NID) with COVID-19 vaccina- tion data from December 2020–July 2021. GBS temporally associated within a 6-week risk window of any COVID-19 vaccine was identified.We prospectively collected incident UK GBS cases January–November 2021 regardless of vaccine exposure.The NID recorded 996 English GBS cases January–October 2021. A spike of cases above the 2016-2020 average occurred March–April 2021. 198 cases occurred within 6 weeks of first-dose COVID-19 vaccina- tion (0.618cases/100,000vaccinations: 176 ChAdOx1 nCoV-19, 21 tozinameran, 1 mRNA-1273). First-dose ChAdOx1 nCoV-19 accounted for the excess of 98-140 GBS cases with a peak 24 days post-vaccination. First-dose tozinameran and second-dose any vaccination showed no excess GBS risk. The UK multicen- tre surveillance dataset (121 patients) identified no phenotypic or demographic differences between vaccine-linked and unlinked cases.First-dose ChAdOx1 nCoV-19 vaccination is associated with excess GBS risk 0.576 (95%CI 0.481-0.691) cases/100,000 doses. No specific features are associated with vaccination-related GBS cases. The mechanism of immunogenicity of ChAdOx1 nCoV-19- warrants further study.

Neurological syndromes associated with glutamic acid decarboxylase (GAD) antibodies provide a challenge in understanding disease pathogenesis, interpreting antibody results, and deciding manage- ment. We retrospectively reviewed 277 patients with positive anti-GAD antibodies (≥ 10 IU/mL) at our centre between 2012-2020. 154 (56%) had one or more neurological disorders including 27 stiff person spectrum disorders (SPSD) (18%), 20 cerebellar ataxia (13%), 18 epilepsy (12%), 18 encephalitis (12%),12 ‘mixed’ (8%), and 59 other neurological disorders (38%). Co-existing autoimmunity was common; 57 (33%) had diabetes and 46 autoimmune thyroid disease (30%). A wide range of GAD titres was seen, but serum GAD antibody titres were significantly higher in patients with ‘classical’ GAD antibody syndromes than other neurological disorders (p

BackgroundPlasma Exchange (PLEX) is an increasingly used therapy for various immune-mediated neu- rological diseases. Treatment can be complicated by potentially life-threatening clots and bleeds but there is limited data available regarding these risks.Method and Intervention: A retrospective audit of the records of patients receiving PLEX in the NHNN for neurological disease from May 2019 – October 2020 was performed to identify thrombotic and haemor- rhagic complications. A multi-disciplinary PLEX working group was created to set guidelines for all aspects of the PLEX process including mode of vascular access, use of prophylactic heparin and fluid replace- ment. The service was subsequently re-audited.Results46 patients were treated with plasma exchange between May 2019 and Oct 2020. 11% developed a thrombus requiring anticoagulation. 41% developed a haemorrhage, 42% of which required intervention.Following protocol change a review of 32 patients between November 2020 to October 2021 showed that there was a reduction of 27% in the incidence of thrombus and a 17% reduction in the incidence of haemorrhage.ConclusionPLEX is integral to the treatment of disabling and potentially fatal immune-mediated neuro-logical diseases. Careful consideration of all aspects of the PLEX process, reduces risks associated with treatment and improves patient safety.