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Background and Purpose: Functional outcome after stroke may be related to preexisting brain health. Several imaging markers of brain frailty have been described including brain atrophy and markers of small vessel disease. We investigated the association of these imaging markers with functional outcome after acute ischemic stroke. Methods: We retrospectively studied patients with acute ischemic stroke enrolled in the AXIS-2 trial (AX200 in Ischemic Stroke Trial), a randomized controlled clinical trial of granulocyte colony-stimulating factor versus placebo. We assessed the ratio of brain parenchymal volume to total intracerebral volumes (ie, the brain parenchymal fraction) and total brain volumes from routine baseline magnetic resonance imaging data obtained within 9 hours of symptom onset using the unified segmentation algorithm in SPM12. Enlarged perivascular spaces, white matter hyperintensities, lacunes, as well as a small vessel disease burden, were rated visually. Functional outcomes (modified Rankin Scale score) at day 90 were determined. Logistic regression was used to test associations between brain imaging features and functional outcomes. Results: We enrolled 259 patients with a mean age of 69±12 years and 46 % were female. Increased brain parenchymal fraction was associated with higher odds of excellent outcome (odds ratio per percent increase, 1.078 [95% CI, 1.008–1.153]). Total brain volumes and small vessel disease burden were not associated with functional outcome. An interaction between brain parenchymal fraction and large vessel occlusion on excellent outcome was not observed. Conclusions: Global brain health, as assessed by brain parenchymal fraction on magnetic resonance imaging, is associated with excellent functional outcome after ischemic stroke. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00927836.

BACKGROUND AND PURPOSE Myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) is an inflammatory autoimmune condition of the central nervous system. However, data on pain and depression have remained scarce. The aim of this study was to assess features of chronic pain and depression as well as their impact on health-related quality of life (hr-QoL) in MOGAD. METHODS Patients with MOGAD were identified in the Neuromyelitis Optica Study Group registry. Data were acquired by a questionnaire, including clinical, demographic, pain (PainDetect, Brief Pain Inventory-Short Form, McGill Pain Questionnaire-Short Form), depression (Beck Depression Inventory-II), and hr-QoL (Short Form-36 Health Survey) items. RESULTS Twenty-two of 43 patients suffered from MOGAD-related pain (11 nociceptive, eight definite neuropathic, three possible neuropathic) and 18 from depression. Patients with neuropathic pain had the highest pain intensity and most profound activities of daily living (ADL) impairment. Fifteen patients reported spasticity-associated pain, including four with short-lasting painful tonic spasms. Later disease onset, profound physical impairment, and depression were associated with chronic pain. Physical QoL was more affected in pain sufferers (p

Artificial intelligence (AI)‐based diagnostic algorithms have achieved ambitious aims through automated image pattern recognition. For neurological disorders, this includes neurodegeneration and inflammation. Scalable imaging technology for big data in neurology is optical coherence tomography (OCT). We highlight that OCT changes observed in the retina, as a window to the brain, are small, requiring rigorous quality control pipelines. There are existing tools for this purpose. Firstly, there are human‐led validated consensus quality control criteria (OSCAR‐IB) for OCT. Secondly, these criteria are embedded into OCT reporting guidelines (APOSTEL). The use of the described annotation of failed OCT scans advances machine learning. This is illustrated through the present review of the advantages and disadvantages of AI‐based applications to OCT data. The neurological conditions reviewed here for the use of big data include Alzheimer disease, stroke, multiple sclerosis (MS), Parkinson disease, and epilepsy. It is noted that while big data is relevant for AI, ownership is complex. For this reason, we also reached out to involve representatives from patient organizations and the public domain in addition to clinical and research centers. The evidence reviewed can be grouped in a five‐point expansion of the OSCAR‐IB criteria to embrace AI (OSCAR‐AI). The review concludes by specific recommendations on how this can be achieved practically and in compliance with existing guidelines.

ObjectiveTo update the consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results, thus revising the previously published Advised Protocol for OCT Study Terminology and Elements (APOSTEL) recommendations.MethodsTo identify studies reporting quantitative OCT results, we performed a PubMed search for the terms “quantitative” and “optical coherence tomography” from 2015 to 2017. Corresponding authors of the identified publications were invited to provide feedback on the initial APOSTEL recommendations via online surveys following the principle of a modified Delphi method. The results were evaluated and discussed by a panel of experts and changes to the initial recommendations were proposed. A final survey was recirculated among the corresponding authors to obtain a majority vote on the proposed changes.ResultsA total of 116 authors participated in the surveys, resulting in 15 suggestions, of which 12 were finally accepted and incorporated into an updated 9-point checklist. We harmonized the nomenclature of the outer retinal layers, added the exact area of measurement to the description of volume scans, and suggested reporting device-specific features. We advised to address potential bias in manual segmentation or manual correction of segmentation errors. References to specific reporting guidelines and room light conditions were removed. The participants' consensus with the recommendations increased from 80% for the previous APOSTEL version to greater than 90%.ConclusionsThe modified Delphi method resulted in an expert-led guideline (evidence Class III; Grading of Recommendations, Assessment, Development and Evaluations [GRADE] criteria) concerning study protocol, acquisition device, acquisition settings, scanning protocol, funduscopic imaging, postacquisition data selection, postacquisition analysis, nomenclature and abbreviations, and statistical approach. It will be essential to update these recommendations to new research and practices regularly.

Background: patients with anti-aquaporin-4 antibody seropositive (AQP4-IgG+) neuromyelitis optica spectrum disorders (NMOSDs) frequently suffer from optic neuritis (ON) leading to severe retinal neuroaxonal damage. Further, the relationship of this retinal damage to a primary astrocytopathy in NMOSD is uncertain. Primary astrocytopathy has been suggested to cause ON-independent retinal damage and contribute to changes particularly in the outer plexiform layer (OPL) and outer nuclear layer (ONL), as reported in some earlier studies. However, these were limited in their sample size and contradictory as to the localisation. This study assesses outer retinal layer changes using optical coherence tomography (OCT) in a multicentre cross-sectional cohort. Method: 197 patients who were AQP4-IgG+ and 32 myelin-oligodendrocyte-glycoprotein antibody seropositive (MOG-IgG+) patients were enrolled in this study along with 75 healthy controls. Participants underwent neurological examination and OCT with central postprocessing conducted at a single site. Results: no significant thinning of OPL (25.02 +/- 2.03 mu m) or ONL (61.63 +/- 7.04 mu m) were observed in patients who were AQP4-IgG+ compared with patients who were MOG-IgG+ with comparable neuroaxonal damage (OPL: 25.10 +/- 2.00 mu m; ONL: 64.71 +/- 7.87 mu m) or healthy controls (OPL: 24.58 +/- 1.64 mu m; ONL: 63.59 +/- 5.78 mu m). Eyes of patients who were AQP4-IgG+ (19.84 +/- 5.09 mu m, p=0.027) and MOG-IgG+ (19.82 +/- 4.78 mu m, p=0.004) with a history of ON showed parafoveal OPL thinning compared with healthy controls (20.99 +/- 5.14 mu m); this was not observed elsewhere. Conclusion: the results suggest that outer retinal layer loss is not a consistent component of retinal astrocytic damage in AQP4-IgG+ NMOSD. Longitudinal studies are necessary to determine if OPL and ONL are damaged in late disease due to retrograde trans-synaptic axonal degeneration and whether outer retinal dysfunction occurs despite any measurable structural correlates., Guthy Jackson Charitable Foundation (GJCF); German Research Foundation (DFG)

Background and ObjectivesTo evaluate the long-term safety and efficacy of tocilizumab (TCZ), a humanized anti–interleukin-6 receptor antibody in myelin oligodendrocyte glycoprotein–IgG–associated disease (MOGAD) and neuromyelitis optica spectrum disorders (NMOSD).MethodsAnnualized relapse rate (ARR), Expanded Disability Status Scale score, MRI, autoantibody titers, pain, and adverse events were retrospectively evaluated in 57 patients with MOGAD (n = 14), aquaporin-4 (AQP4)-IgG seropositive (n = 36), and seronegative NMOSD (n = 7; 12%), switched to TCZ from previous immunotherapies, particularly rituximab.ResultsPatients received TCZ for 23.8 months (median; interquartile range 13.0–51.1 months), with an IV dose of 8.0 mg/kg (median; range 6–12 mg/kg) every 31.6 days (mean; range 26–44 days). For MOGAD, the median ARR decreased from 1.75 (range 0.5–5) to 0 (range 0–0.9; p = 0.0011) under TCZ. A similar effect was seen for AQP4-IgG+ (ARR reduction from 1.5 [range 0–5] to 0 [range 0–4.2]; p < 0.001) and for seronegative NMOSD (from 3.0 [range 1.0–3.0] to 0.2 [range 0–2.0]; p = 0.031). During TCZ, 60% of all patients were relapse free (79% for MOGAD, 56% for AQP4-IgG+, and 43% for seronegative NMOSD). Disability follow-up indicated stabilization. MRI inflammatory activity decreased in MOGAD (p = 0.04; for the brain) and in AQP4-IgG+ NMOSD (p < 0.001; for the spinal cord). Chronic pain was unchanged. Regarding only patients treated with TCZ for at least 12 months (n = 44), ARR reductions were confirmed, including the subgroups of MOGAD (n = 11) and AQP4-IgG+ patients (n = 28). Similarly, in the group of patients treated with TCZ for at least 12 months, 59% of them were relapse free, with 73% for MOGAD, 57% for AQP4-IgG+, and 40% for patients with seronegative NMOSD. No severe or unexpected safety signals were observed. Add-on therapy showed no advantage compared with TCZ monotherapy.DiscussionThis study provides Class III evidence that long-term TCZ therapy is safe and reduces relapse probability in MOGAD and AQP4-IgG+ NMOSD.

Introduction Acute kidney injury (AKI) after high dose methotrexate (HD-MTX) is associated with delayed MTX-excretion and life-threatening toxicity. Glucapridase, the recommended therapy, is expensive and not always available. Case series We describe 3 cases (69, 67, 73 years) with diffuse large B-cell lymphoma who developed AKI and early-onset severely delayed MTX elimination after HD-MTX. MTX serum concentrations were 101 and 69 μmol/L at 24 h after administration in two patients and 34 μmol/L at 32 h in the third. Management and outcome Since glucarpidase was unavailable, we performed daily high-flux hemodialysis (HF-HD) or online hemodiafiltration (HDF) sessions (median duration, 6 h). The median serum MTX elimination half-life during HDF/HF-HD sessions was similar in all patients (median, 4.4 h; IQR, 3.8–5.3 h), but serum MTX concentrations rebounded after each dialysis by a median of 40% of the trough concentrations. The three patients underwent multiple dialysis sessions, until MTX serum concentrations remained sufficiently low to be neutralized by leucovorin. Only 1 patient developed severe pancytopenia, and renal function normalized in all patients after 3–6 weeks. Discussion In conclusion, when glucarpidase is unavailable or delayed, early, repeated and prolonged HDF/HF-HD effectively enhance MTX elimination and prevent toxicity in patients with AKI and severely delayed MTX elimination after HD-MTX.

In recent years, considerable progress has been made in frontline therapy for elderly/physically unfit patients with CLL. The combination of obinutuzumab and chlorambucil (O-Clb) has been shown to prolong progression free survival (PFS, median PFS-31.5 months) and overall survival (OS) compared to chlorambucil alone. More recently, obinutuzumab given in combination with either ibrutinib or venetoclax improved PFS but not OS when compared to O-Clb. In this retrospective multinational, multicenter co-operative study, we evaluated the efficacy and safety of frontline treatment with O ± Clb in unfit patients with CLL, in a “real-world” setting. Patients with documented del (17p13.1)/TP53 mutation were excluded. A total of 437 patients (median age, 75.9 years; median CIRS score, 8; median creatinine clearance, 61.1 mL/min) were included. The clinical overall response rate was 80.3% (clinical complete and partial responses in 38.7% and 41.6% of patients, respectively). Median observation time was 14.1 months and estimated median PFS was 27.6 months (95% CI, 24.2-31.0). In a multivariate analysis, high-risk disease [del (11q22.3) and/or IGHV-unmutated], lymph nodes of diameter > 5 cm, obinutuzumab monotherapy and reduced cumulative dose of obinutuzumab, were all independently associated with shorter PFS. The median OS has not yet been reached and estimated 2-year OS is 88%. In conclusion, in a “real-world” setting, frontline treatment with O-Clb achieves PFS comparable to that reported in clinical trials. Inferior outcomes were noted in patients with del (11q22.3) and/or unmutated IGHV and those treated with obinutuzumab-monotherapy. Thus, O-Clb can be still considered as legitimate frontline therapy for unfit CLL patients with low-risk disease.

BACKGROUND Assessment of motor symptoms in Huntington's disease (HD) is based on the Unified-HD-Rating-Scale-Total-Motor-Score (UHDRS-TMS). Its categorical and rater-dependent nature reduces the ability to detect subtle changes and often placebo effects have been observed in trials. We have previously shown that impairments in isometric force matching can be detected by quantitative motor (Q-Motor) assessments of tongue protrusion forces (glossomotography) in HD. OBJECTIVE We aimed to investigate whether similar impairments in isometric force matching can be detected in tasks assessing hand and foot force coordination and whether correlations with clinical measures and the disease burden score can be found. METHODS Using a pre-calibrated force transducer, the ability of subjects to generate and maintain isometric forces at different target levels displayed on a monitor was assessed. Target forces applied in the hand were 1.5 and 5 Newton [N] and in feet 1, 5, and 10 N. Subjects with HD (n = 31) and age-matched controls (n = 22) were recruited from the HD out-patient clinic. RESULTS All paradigms distinguished controls from HD. The static coefficient of variability (%) was the most robust measure across all matching tasks. Correlations with clinical measures, such as the UHDRS-TMS, TFC, and the DBS were found. CONCLUSIONS Assessment of hand and foot force matching tasks was feasible and provided quantitative objective measures for severity of motor phenotype in HD. Since both upper and lower extremity motor function are relevant for everyday activities, these measures should be further assessed as candidates for developing functionally meaningful quantitative motor tasks.

Autologous stem cell transplantation (ASCT), intensifying anti-leukemic effects without significant treatment-related mortality (TRM), is particularly appealing in AML with favorable genetic/molecular profile. This study retrospectively evaluated the outcomes of post-remission treatment in consecutive favorable-risk AML patients. Sixty-six patients were included: 32 had mutated NPM1/wild-type FLT-ITD, 16 had t(8:21) and 18 - inv(16). Forty patients received chemotherapy alone, 26 underwent ASCT upfront. In time-dependent analysis, the ASCT group demonstrated higher relapse-free (RFS) (

Patients with lymphoma, especially those treated with anti-CD20 monoclonal antibodies, suffer high COVID-19-associated morbidity and mortality. The goal of this study was to assess the ability of lymphoma patients to generate a sufficient humoral response after two injections of BNT162b2 Pfizer vaccine and to identify factors influencing the response. Antibody titers were measured with the SARS-CoV-2 IgG II Quant (Abbott ) assay in blood samples drawn from lymphoma patients 4 2 weeks after the second dose of vaccine. The cutoff for a positive response was set at 50 AU/mL. Positive serological responses were observed in 51% of the 162 patients enrolled in this cross-sectional study. In a multivariate analysis, an interval of 1 year after this therapy. The latter percentage was equal to that of patients never exposed to monoclonal antibodies. In conclusion, lymphoma patients, especially those recently treated with anti- CD20 monoclonal antibodies, fail to develop sufficient humoral response to BNT162b2 vaccine. While a serological response is not the only predictor of immunity, its low level could make this population more vulnerable to COVID-19, which implies the need for a different vaccination schedule for such patients.

ObjectivesTo evaluate prevalence, clinical characteristics, and predictors of pain, depression, and their impact on the quality of life (QoL) in a large neuromyelitis optica spectrum disorder (NMOSD) cohort.MethodsWe included 166 patients with aquaporin-4–seropositive NMOSD from 13 tertiary referral centers. Patients received questionnaires on demographic and clinical characteristics, PainDetect, short form of Brief Pain Inventory, Beck Depression Inventory–II, and Short Form 36 Health Survey.ResultsOne hundred twenty-five (75.3%) patients suffered from chronic NMOSD-associated pain. Of these, 65.9% had neuropathic pain, 68.8% reported spasticity-associated pain and 26.4% painful tonic spasms. Number of previous myelitis attacks (OR = 1.27, p = 0.018) and involved upper thoracic segments (OR = 1.31, p = 0.018) were the only predictive factors for chronic pain. The latter was specifically associated with spasticity-associated pain (OR = 1.36, p = 0.002). More than a third (39.8%) suffered from depression, which was moderate to severe in 51.5%. Pain severity (OR = 1.81, p < 0.001) and especially neuropathic character (OR = 3.44, p < 0.001) were associated with depression. Pain severity and walking impairment explained 53.9% of the physical QoL variability, while depression and walking impairment 39.7% of the mental QoL variability. No specific medication was given to 70.6% of patients with moderate or severe depression and 42.5% of those with neuropathic pain. Two-thirds (64.2%) of patients with symptomatic treatment still reported moderate to severe pain.ConclusionsMyelitis episodes involving upper thoracic segments are main drivers of pain in NMOSD. Although pain intensity was lower than in previous studies, pain and depression remain undertreated and strongly affect QoL. Interventional studies on targeted treatment strategies for pain are urgently needed in NMOSD.

Background and ObjectivesTo determine optic nerve and retinal damage in aquaporin-4 antibody (AQP4-IgG)-seropositive neuromyelitis optica spectrum disorders (NMOSD) in a large international cohort after previous studies have been limited by small and heterogeneous cohorts.MethodsThe cross-sectional Collaborative Retrospective Study on retinal optical coherence tomography (OCT) in neuromyelitis optica collected retrospective data from 22 centers. Of 653 screened participants, we included 283 AQP4-IgG–seropositive patients with NMOSD and 72 healthy controls (HCs). Participants underwent OCT with central reading including quality control and intraretinal segmentation. The primary outcome was thickness of combined ganglion cell and inner plexiform (GCIP) layer; secondary outcomes were thickness of peripapillary retinal nerve fiber layer (pRNFL) and visual acuity (VA).ResultsEyes with ON (NMOSD-ON, N = 260) or without ON (NMOSD-NON, N = 241) were assessed compared with HCs (N = 136). In NMOSD-ON, GCIP layer (57.4 ± 12.2 μm) was reduced compared with HC (GCIP layer: 81.4 ± 5.7 μm, p < 0.001). GCIP layer loss (−22.7 μm) after the first ON was higher than after the next (−3.5 μm) and subsequent episodes. pRNFL observations were similar. NMOSD-NON exhibited reduced GCIP layer but not pRNFL compared with HC. VA was greatly reduced in NMOSD-ON compared with HC eyes, but did not differ between NMOSD-NON and HC.DiscussionOur results emphasize that attack prevention is key to avoid severe neuroaxonal damage and vision loss caused by ON in NMOSD. Therapies ameliorating attack-related damage, especially during a first attack, are an unmet clinical need. Mild signs of neuroaxonal changes without apparent vision loss in ON-unaffected eyes might be solely due to contralateral ON attacks and do not suggest clinically relevant progression but need further investigation.

Objective: The timing of brain atrophy after stroke is not well understood. We investigated the associations between age and imaging features and brain volume change in the first month after stroke. Methods: We retrospectively studied patients with acute ischemic stroke enrolled in the AXIS-2 trial. Total brain volume change from hyperacute MRI data to the first month after stroke was assessed using unified segmentation in SPM12. We hypothesized that age, ischemic brain lesion size and white matter changes were associated with larger brain volume change. Enlarged perivascular spaces (EPVS) and white matter hyperintensities (WMH) were rated visually and the presence of lacunes was assessed. Results: We enrolled 173 patients with a mean age of 67±11 years, 44 % were female. There was a median 6 mL decrease in volume (25th percentile -1mL-75th percentile 21mL) over time, equivalent to a median 0.5% (IQR-0.07% - 1.4%), decrease in brain volume. Age was associated with larger brain volume loss (per 10 years of age, 5 mL 95% CI 2 mL-8 mL). Baseline DWI lesion volume was not associated with greater volume loss (per 10 mL of lesion volume, change by 0 mL (95% CI -0.1 mL-0.1mL). Increasing Fazekas scores of deep white matter hyperintensity were associated with greater tissue loss (5 mL, 95% CI 1 mL-10 mL). Brain volume change was associated with ordinal change on the modified Rankin scale at 90 days (per 10 ml, OR 1.085, 95% CI 1.031-1.141) but the association was not present when adjusting for age, baseline diffusion lesion volume and NIHSS score (OR 1.044, 95% CI 0.990-1.010).Interpretation-Global brain volume loss occurs over 1 month after stroke and is associated with age and deep white matter disease. We did not find evidence that more severe strokes lead to increased early tissue loss.

In ischemic stroke, the study of edema, measurable as fluid attenuated inversion recovery (FLAIR) signal increase, has mainly focused on the ischemic core and less on the surrounding penumbra. To the naked eye, no FLAIR changes are present in the penumbra. However, changes in perfusion status could induce physiological changes resulting in subtle penumbral FLAIR signal alterations. To investigate penumbral FLAIR changes, we included subjects from the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) and Granulocyte Colony-Stimulating Factor in Patients With Acute Ischemic Stroke (AXIS 2) trial with perfusion- and diffusion-weighted imaging (PWI, DWI) and FLAIR at baseline. We used RAPID software to calculate the core and perfusion lesion on DWI and PWI and selected subjects with a minimal mismatch volume (15 ml) and ratio (1.2). We created voxel-based relative FLAIR signal intensity (rFLAIR SI) maps at baseline and follow up (FU) by calculating the ratio of the FLAIR intensity in one voxel and the median FLAIR intensity in a sphere with 15 mm radius around a contralateral homologues voxel. We studied rFLAIR SI in two regions of interest: the baseline penumbra (baseline perfusion lesion - [core lesion + voxels with apparent diffusion coefficient -6 mm 2 /s]) and the non-infarcted penumbra (baseline perfusion lesion - FU FLAIR lesion) at 24 hours (WAKE-UP) or 30 days (AXIS 2). Severity of hypoperfusion was defined as the time to maximum of the residue function. In the baseline penumbra, rFLAIR SI was elevated (ratio=1.04, p=1.7*10 -13 , n=126) and correlated with severity of hypoperfusion (Pearson’s r 0.03, p-4 , n=126). At 24 hours in a subgroup from WAKE-UP, rFLAIR SI in the non-infarcted penumbra further increased (ratio=1.05 at 24h vs 1.03 at baseline, p=7.1*10 -3 , n=43). In a different subgroup from AXIS 2, this increase in rFLAIR SI was reversible (ratio=1.02 at 30d vs 1.04 at baseline, p=1.5*10 -3 n=26) since it was no longer different from 1 at 30 days (ratio=1.01 at 30 days, p=0.099, n=26). Increases in rFLAIR SI, likely representing edema, are not restricted to the ischemic core and correlate with severity of hypoperfusion in the penumbra. They appear early after stroke onset, further increase at 24 hours and are reversible by 30 days.

Background and purpose: Functional outcome after stroke may be related to preexisting brain health. Several imaging markers of brain frailty have been described including brain atrophy and markers of small vessel disease. We investigated the association of these imaging markers with functional outcome after acute ischemic stroke. Methods: We retrospectively studied patients with acute ischemic stroke enrolled in the AXIS-2 trial, an international, multicenter, randomized controlled clinical trial of Granulocyte Colony Stimulating Factor versus placebo. We assessed the ratio of brain parenchymal volume to total intracerebral volumes (i.e., the brain parenchymal fraction [BPF]) and total brain volumes from routine baseline MRI data obtained within 9 hours of symptom onset using the unified segmentation algorithm in SPM12. Enlarged perivascular spaces (EPVS), white matter hyperintensities (WMH), lacunes as well as a small vessel disease (SVD) burden were rated visually. Functional outcomes (modified Rankin Scale [mRS] score) at day 90 were determined. Logistic regression was used to test associations between brain imaging features and functional outcomes. As there was no significant effect of G-CSF on any outcomes in AXIS-2, placebo and active groups were combined for these analyses. Results: We enrolled 259 patients with a mean age of 69±12 years and 46 % were female. Increased BPF was associated with higher odds of excellent outcome (OR per percent increase: 1.081, 95%CI: 1.012-1.155). Total brain volumes and SVD burden were not associated with functional outcome. An interaction between BPF and large vessel occlusion on excellent outcome was not observed. Conclusions: Global brain health, as assessed by brain parenchymal fraction on magnetic resonance imaging, is associated with excellent functional outcome after ischemic stroke. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00927836.

Neurology: Neuroimmunology & Neuroinflammation ; official journal of the American Academy of Neurology 8(6), e1062 (2021). doi:10.1212/NXI.0000000000001062, Published by Lippincott Williams & Wilkins, Philadelphia, Pa.

Background and Purpose: We aimed to investigate fluid-attenuated inversion recovery changes in the penumbra. Methods: We determined core and perfusion lesions in subjects from the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke) and AXIS 2 trial (Granulocyte Colony-Stimulating Factor in Patients With Acute Ischemic Stroke) with perfusion- and diffusion-weighted imaging at baseline. Only subjects with a mismatch volume >15 mL and ratio >1.2 were included. We created voxel-based relative fluid-attenuated inversion recovery signal intensity (rFLAIR SI) maps at baseline and follow-up. We studied rFLAIR SI in 2 regions of interest: baseline penumbra (baseline perfusion lesion−[core lesion+voxels with apparent diffusion coefficient −6 mm 2 /s]) and noninfarcted penumbra (baseline perfusion lesion−follow-up fluid-attenuated inversion recovery lesion) at 24 hours (WAKE-UP) or 30 days (AXIS 2). We analyzed the association between rFLAIR SI and severity of hypoperfusion, defined as time to maximum of the residue function. Results: In the baseline penumbra, rFLAIR SI was elevated (ratio, 1.04; P =1.7×10 − 13 ; n=126) and correlated with severity of hypoperfusion (Pearson r, 0.03; P − 4 ; n=126). In WAKE-UP, imaging at 24 hours revealed a further increase of rFLAIR SI in the noninfarcted penumbra (ratio, 1.05 at 24 hours versus 1.03 at baseline; P =7.1×10 −3 ; n=43). In AXIS 2, imaging at 30 days identified reversibility of the rFLAIR SI (ratio, 1.02 at 30 days versus 1.04 at baseline; P =1.5×10 −3 ; n=26) since it was no longer different from 1 (ratio, 1.01 at 30 days; P =0.099; n=26). Conclusions: Penumbral rFLAIR SI increases appear early after stroke onset, correlate with severity of hypoperfusion, further increase at 24 hours, and are reversible by 30 days. Registration: URL: https://clinicaltrials.gov ; Unique identifier: NCT01525290. URL: https://clinicaltrials.gov ; Unique identifier: NCT00927836.

Neurology: Neuroimmunology & Neuroinflammation ; official journal 8(6), 1-15 (2021). doi:10.1212/NXI.0000000000001086, Published by Wolters Kluwer, Philadelphia, Pa.

PURPOSE: Optical coherence tomography (OCT) captures retinal damage in neuromyelitis optica spectrum disorders (NMOSD). Previous studies investigating OCT in NMOSD have been limited by the rareness and heterogeneity of the disease. The goal of this study was to establish an image repository platform, which will facilitate neuroimaging studies in NMOSD. Here we summarise the profile of the Collaborative OCT in NMOSD repository as the initial effort in establishing this platform. This repository should prove invaluable for studies using OCT to investigate NMOSD. PARTICIPANTS: The current cohort includes data from 539 patients with NMOSD and 114 healthy controls. These were collected at 22 participating centres from North and South America, Asia and Europe. The dataset consists of demographic details, diagnosis, antibody status, clinical disability, visual function, history of optic neuritis and other NMOSD defining attacks, and OCT source data from three different OCT devices. FINDINGS TO DATE: The cohort informs similar demographic and clinical characteristics as those of previously published NMOSD cohorts. The image repository platform and centre network continue to be available for future prospective neuroimaging studies in NMOSD. For the conduct of the study, we have refined OCT image quality criteria and developed a cross-device intraretinal segmentation pipeline. FUTURE PLANS: We are pursuing several scientific projects based on the repository, such as analysing retinal layer thickness measurements, in this cohort in an attempt to identify differences between distinct disease phenotypes, demographics and ethnicities. The dataset will be available for further projects to interested, qualified parties, such as those using specialised image analysis or artificial intelligence applications.

We thank Dr. Chen for his comment. We included neuromyelitis optica spectrum disorder (NMOSD) patients with longitudinal visual-evoked potential (VEP) data covering ≥3 months. We calculated the changes per year using regression analysis. For eyes with

Background New-generation cell-based assays have demonstrated a robust association of serum autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis, and brainstem encephalitis, as well as with neuromyelitis optica (NMO)-like or acute-disseminated encephalomyelitis (ADEM)-like presentations. However, only limited data are yet available on cerebrospinal fluid (CSF) findings in MOG-IgG-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD). Objective To describe systematically the CSF profile in MOG-EM. Material and methods Cytological and biochemical findings (including white cell counts and differentiation; frequency and patterns of oligoclonal bands; IgG/IgM/IgA and albumin concentrations and CSF/serum ratios; intrathecal IgG/IgA/IgM fractions; locally produced IgG/IgM/IgA concentrations; immunoglobulin class patterns; IgG/IgA/IgM reibergrams; Link index; measles/rubella/zoster (MRZ) reaction; other anti-viral and anti-bacterial antibody indices; CSF total protein; CSF l-lactate) from 163 lumbar punctures in 100 adult patients of mainly Caucasian descent with MOG-EM were analyzed retrospectively. Results Most strikingly, CSF-restricted oligoclonal IgG bands, a hallmark of multiple sclerosis (MS), were absent in almost 90% of samples (N = 151), and the MRZ reaction, the most specific laboratory marker of MS known so far, in 100% (N = 62). If present, intrathecal IgG (and, more rarely, IgM) synthesis was low, often transient and mostly restricted to acute attacks. CSF WCC was elevated in > 50% of samples (median 31 cells/μl; mostly lymphocytes and monocytes; > 100/μl in 12%). Neutrophils were present in > 40% of samples; activated lymphocytes were found less frequently and eosinophils and/or plasma cells only very rarely (< 4%). Blood–CSF barrier dysfunction (as indicated by an elevated albumin CSF/serum ratio) was present in 48% of all samples and at least once in 55% of all patients (N = 88) tested. The frequency and degree of CSF alterations were significantly higher in patients with acute myelitis than in patients with acute ON and varied strongly depending on attack severity. CSF l-lactate levels correlated significantly with the spinal cord lesion load in patients with acute myelitis (p < 0.0001). Like pleocytosis, blood–CSF barrier dysfunction was present also during remission in a substantial number of patients. Conclusion MOG-IgG-positive EM is characterized by CSF features that are distinct from those in MS. Our findings are important for the differential diagnosis of MS and MOG-EM and add to the understanding of the immunopathogenesis of this newly described autoimmune disease.

Introduction. Emergency department (ED) triage regarding infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is challenging. During the coronavirus disease 2019 (COVID-19) outbreak in Germany, the diagnostic outcomes of critically ill patients admitted to the resuscitation room in the ED of our academic 754-bed hospital should be analyzed. Methods. All resuscitation room patients between March 1st and April 15th 2020 were included in this retrospective study. Every patient with suspicion of SARS-CoV-2 infection received a pharyngeal swab for real-time polymerase chain reaction (rt-PCR), divided in the clinical subgroups of “highly suspicious for COVID-19” and “COVID-19 as differential diagnosis.” All respiratory and infectious symptoms were included as at least “differential diagnosis” as an expanded suspicion strategy. Results. Ninety-five patients were included (trauma n=14, critically ill n=81). Of 3 highly suspicious patients, 2 had rt-PCR positive pharyngeal swabs. In 39 patients, COVID-19 was defined as differential diagnosis, and 3 were positive for SARS-CoV-2. Of them, pharyngeal swabs were positive in 1 case, while in 2 cases, only tracheal fluid was rt-PCR positive while the pharyngeal swabs were negative. In one of these 2 cases, chest computed tomography (CT) was also negative for ground-glass opacities but showed a pulmonary abscess and pulmonary embolism. Conclusion. We recommend an expanded suspicion strategy for COVID-19 due to unexpected diagnostic outcomes. Personal protective equipment should be used in every resuscitation room operation due to unexpected cases and initial knowledge gaps. Furthermore, tracheal fluid should be tested for SARS-CoV-2 in every intubated patient due to cases with negative pharyngeal swabs and negative chest CT.

Selection of resistant clones following intensive chemotherapy is a common obstacle for cure in many cancers, particularly in acute myeloid leukemia (AML). In AML, clone-specific sensitivity to chemotherapy varies even within the same patient. Multiple mutations and genetic aberrations are associated with clones surviving chemotherapy. The current study explored the role of activated signaling pathways in chemoresistance as a function of cell maturation, reflected by CD34 expression. In-vitro, Kasumi-1 leukemic cell line, sorted by CD34 expression, showed increased apoptosis only in the CD34− subpopulation after exposure to cytosine arabinoside (Ara-C) or daunorubicin. The resistant CD34+ subset demonstrated higher expression of ERK1/2 and BCL-2 proteins than CD34− cells. MEK1/2 inhibition elevated Ara-C ability to induce apoptosis in CD34+ cells, suggesting that MEK1/2-ERK1/2 is surviving signaling, which correlates to cell maturation levels and plays a role in chemoresistance. Deep sequencing of sorted CD34+/− populations, both derived from the same patient samples, demonstrated various subclonal distribution of NPM1, DNMT3A and FLT3-ITD mutations. Interestingly, in these samples, p-ERK levels and apoptosis rates following chemotherapy exposure significantly differed between CD34+/− populations. Hence, clones may be selected due to their ability to escape apoptosis rather than a direct effect of chemotherapy on a specific mutated clone.

Neuromyelitis Optica Spectrum Disorder (NMOSD) is an inflammatory demyelinating disease of the central nervous system (CNS) primarily affecting the optic nerves and spinal cord, but also involving other regions of the CNS including the area postrema, periaqueductal gray matter, and hypothalamus. Knowledge related to pediatric manifestations of NMOSD has grown in recent years, particularly in light of newer information regarding the importance of not only antibodies to aquaporin 4 (AQP4-IgG) but also myelin oligodendrocyte glycoprotein (MOG-IgG) in children manifesting clinically with this syndrome. In this review, we describe the current state of the knowledge related to clinical manifestations, diagnosis, and chronic therapies for children with NMOSD, with emphasis on literature that has been published in the last 5 years. Following the review, we propose recommendations for the assessment/follow up clinical care, and treatment of this population.

ObjectiveTo assess possible adverse effects on breastfed infants of mothers receiving monoclonal antibodies (MAbs) during pregnancy and/or lactation.MethodsWe identified 23 patients from the German Multiple Sclerosis and Pregnancy Registry (DMSKW) who received MAbs (17 natalizumab and 6 anti-CD20) during lactation. Thirteen were already exposed to natalizumab during the third trimester of pregnancy, and 1 received ocrelizumab during pregnancy. Data were obtained from standardized, telephone-administered questionnaires completed by the mother during pregnancy and at 1, 3, 6, and 12 months postpartum. Natalizumab concentration in mother’s milk was analyzed in 3 patients and natalizumab serum concentration in 2 of these patients and their breastfed infants.ResultsWe did not observe a negative impact on infant health and development attributable to breast milk exposure after a median follow-up of 1 year. Infants exposed to natalizumab during the third trimester had a lower birth weight and more hospitalizations in the first year of life. The concentration of natalizumab in breast milk and serum of infants was low; B cells normal in infants breastfed under anti-CD20.ConclusionMore data on the effect of Mab exposure during pregnancy are needed. Otherwise, our data suggest that treatment with natalizumab, ocrelizumab, or rituximab during lactation might be safe for breastfed infants.

ObjectiveWe aimed to evaluate racial differences in the clinical features of neuromyelitis optica spectrum disorder.MethodsThis retrospective review included 603 patients (304 Asian, 207 Caucasian, and 92 Afro-American/Afro-European), who were seropositive for anti–aquaporin-4 antibody, from 6 centers in Denmark, Germany, South Korea, United Kingdom, United States, and Thailand.ResultsMedian disease duration at last follow-up was 8 years (range 0.3–38.4 years). Asian and Afro-American/Afro-European patients had a younger onset age than Caucasian patients (mean 36, 33, and 44 years, respectively; p < 0.001). During the disease course, Caucasian patients (23%) had a lower incidence of brain/brainstem involvement than Asian (42%) and Afro-American/Afro-European patients (38%) (p < 0.001). Severe attacks (visual acuity ≤0.1 in at least one eye or Expanded Disability Status Scale score ≥6.0 at nadir) at onset occurred more frequently in Afro-American/Afro-European (58%) than in Asian (46%) and Caucasian (38%) patients (p = 0.005). In the multivariable analysis, older age at onset, higher number of attacks before and after immunosuppressive treatment, but not race, were independent predictors of severe motor disabilities at last follow-up.ConclusionA review of a large international cohort revealed that race affected the clinical phenotype, age at onset, and severity of attacks, but the overall outcome was most dependent on early and effective immunosuppressive treatment.

Das Susac-Syndrom (SuS) ist eine seltene Erkrankung. Eine wahrscheinlich durch autoreaktive CD8+-Zellen (CD: „cluster of differentiation“) vermittelte Immunreaktion fuhrt uber die Beeintrachtigung von Gefasendothelzellen zu okklusiven Mikroangiopathien in Gehirn, Retina und Innenohr. Klinisch ausert sich dies in einer subakuten Enzephalopathie mit variabel ausgepragten kognitiven Storungen, Verhaltensveranderungen, fokal-neurologischen Beeintrachtigungen, Seh- und Horstorungen. Bildmorphologisch lassen sich oft eindruckliche Befunde erheben. Das SuS ist eine wichtige Differenzialdiagnose zu vielen neurologischen, psychiatrischen, ophthalmologischen und HNO-Erkrankungen (HNO: Hals-Nasen-Ohren). Fehldiagnosen sind sehr haufig, beinahe regelhaft wird das SuS initial als Multiple Sklerose verkannt, was Verzogerungen in der Therapie und Fehlbehandlungen begunstigt. Meist ist eine fruhzeitige und konsequente Immuntherapie erforderlich und fur die langfristige Prognose entscheidend.

New software solutions emerged to support radiologists in image interpretation in acute ischemic stroke. This study aimed to validate the performance of computer-aided assessment of the Alberta Stroke Program Early CT score (ASPECTS) for detecting signs of early infarction. ASPECT scores were assessed in 119 CT scans of patients with acute middle cerebral artery ischemia. Patient collective was differentiated according to (I) normal brain, (II) leukoencephalopathic changes, (III) infarcts, and (IV) atypical parenchymal defects (multiple sclerosis, etc.). ASPECTS assessments were automatically provided by the software package e-ASPECTS (Brainomix®, UK) (A). Subsequently, three neuroradiologists (B), (C), and (D) examined independently 2380 brain regions. Interrater comparison was performed with the definite infarct core as reference standard after best medical care (thrombolysis and/or thrombectomy). Interrater comparison revealed higher correlation coefficient of (B) 0.71, (C) 0.76, and of (D) 0.80 with definite infarct core compared to (A) 0.59 for ASPECTS assessment in the acute ischemic stroke setting. While (B), (C), and (D) showed a significant correlation for individual patient groups (I), (II), (III), and (IV), except for (D) (II), (A) was not significant in patient groups with pre-existing changes (II), (III), and (IV). The following sensitivities, specificities, PPV, NPV, and accuracies given in percent were achieved: (A) 83, 57, 55, 82, and 67; (B) 74, 76, 69, 83, and 77; (C) 80.8, 85.2, 76, 84, and 80; (D) 63, 90.7, 82, 79, and 80, respectively. For ASPECTS assessment, the examined software may provide valid data in case of normal brain. It may enhance the work of neuroradiologists in clinical decision making. A final human check for plausibility is needed, particularly in patient groups with pre-existing cerebral changes.

Objective Studies using conventional full‐field visual evoked potentials (ffVEP) have reported subtle abnormalities in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). We hypothesize that these abnormalities can be detected in the majority of CIDP patients using enhanced methods. Methods We performed a cross‐sectional noninterventional study comparing 18 CIDP patients and 18 matched healthy controls using multifocal VEP (mfVEP) as a technique with enhanced sensitivity to detect conduction abnormalities across the spectrum of optic nerve fibers. Patients with confounding diseases (ophthalmologic, diabetes mellitus) were excluded. Results The mean amplitude and latency, as well as the low‐contrast visual acuity, did not differ between CIDP patients and controls. Subanalyses revealed latency differences concerning the superior sector of the visual field. Severity markers of CIDP (ODSS, motor nerve conduction velocity) were associated with mfVEP latency delay. Interpretation We could not adduce evidence for clinically or diagnostically relevant visual pathway involvement in CIDP. The latency differences identified were very subtle and restricted to the superior visual field which cannot be readily explained biologically, anatomically, or pathologically. In summary, we conclude that our study revealed no relevant differences in mfVEP parameters between CIDP patients and controls.

We performed a genome-wide association study in 1,194 controls and 150 patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR, n = 96) or anti-leucine-rich glioma-inactivated1 (anti-LGI1, n = 54) autoimmune encephalitis. Anti-LGI1 encephalitis was highly associated with 27 single-nucleotide polymorphisms (SNPs) in the HLA-II region (leading SNP rs2858870 p = 1.22 × 10-17 , OR = 13.66 [7.50-24.87]). Potential associations, below genome-wide significance, were found with rs72961463 close to the doublecortin-like kinase 2 gene (DCLK2) and rs62110161 in a cluster of zinc-finger genes. HLA allele imputation identified association of anti-LGI1 encephalitis with HLA-II haplotypes encompassing DRB1*07:01, DQA1*02:01 and DQB1*02:02 (p < 2.2 × 10-16 ) and anti-NMDAR encephalitis with HLA-I allele B*07:02 (p = 0.039). No shared genetic risk factors between encephalitides were identified. Ann Neurol 2018;83:863-869.

To examine radiation dose levels of CT-guided interventional procedures of chest, abdomen, spine and extremities on different CT-scanner generations at a large multicentre institute. 1,219 CT-guided interventional biopsies of different organ regions ((A) abdomen (n=516), (B) chest (n=528), (C) spine (n=134) and (D) extremities (n=41)) on different CT-scanners ((I) SOMATOM-Definition-AS+, (II) Volume-Zoom, (III) Emotion6) were included from 2013–2016. Important CT-parameters and standard dose-descriptors were retrospectively examined. Additionally, effective dose and organ doses were calculated using Monte-Carlo simulation, following ICRP103. Overall, radiation doses for CT interventions are highly dependent on CT-scanner generation: the newer the CT scanner, the lower the radiation dose imparted to patients. Mean effective doses for each of four procedures on available scanners are: (A) (I) 9.3mSv versus (II) 13.9mSv (B) (I) 7.3mSv versus (III) 11.4mSv (C) (I) 6.3mSv versus (II) 7.4mSv (D) (I) 4.3mSv versus (II) 10.8mSv. Standard dose descriptors [standard deviation (SD); CT dose indexvol (CTDIvol); dose-length product (DLPbody); size-specific dose estimate (SSDE)] were also compared. Effective dose, organ doses and SSDE for various CT-guided interventional biopsies on different CT-scanner generations following recommendations of the ICRP103 are provided. New CT-scanner generations involve markedly lower radiation doses versus older devices. • Effective dose, organ dose and SSDE are provided for CT-guided interventional examinations. • These data allow identifying organs at risk of higher radiation dose. • Detailed knowledge of radiation dose may contribute to a better individual risk-stratification. • New CT-scanner generations involve markedly lower radiation doses compared to older devices.

Introduction - Data regarding efficacy and toxicity of different bridging strategies prior to CAR-T therapy are scanty. Tisagenlecleucel (Kymriah TM, Novartis) and axictagene ciloleucel (Yescarta TM, Kite/Gilead) were commercially approved for relapsed/refractory (R/R) DLBCL since 2019. We analyzed real-life data of CAR-T therapy among all consecutive patients who were treated in 4 different CAR-T centers in Israel. Methods - From May 2019, 144 R/R DLBCL patients underwent apheresis and continued to receive bridging therapy that included chemo/immunotherapy (n=78, 54%), radiation (n=11, 7.6%), chemoradiation (n=22, 15%), steroids only (n=5, 3.5%) and none (n=28, 19.4%). All patients were evaluated after bridging therapy and prior to CAR-T infusion by PETCT (96%) or CT scan (4%). Results - Median age was 68 (20-88) years and Median follow-up was 13 (4-26) months. All 144 patients underwent successful apheresis. Reasoning for choosing specific bridging therapy was based on low tumor mass (n= 23, 16%), high tumor mass (n=73, 51%), frailty of the patient (n=27, 19%), ongoing significant prior regimen's toxicities (n=14, 10%) and local disease (n=7, 4%). In patients given radiation therapy median dose was 23 (range, 8-30) Gy. In patients given chemo/immunotherapy or chemoradiation, sepsis was the main complications (9% of all patients) during bridging therapy. However, none of the patients had a fatal event. 14 patients (9.7%) did not proceed to CAR-T infusion; 6 (4.2%) had disease progression and died; 8 (5.6%) had manufacture failure). Among the 130 patients that received CAR-T infusion, PET-CT prior to preparative regimen demonstrated CR/PR status in 38%, 50%, 40%, 17%, and 16% of patients given chemotherapy, radiation, chemoradiation, steroids only, or no bridging therapy, respectively (p=.15), Figure 1. Any bridging therapy was associated with a better disease control compared to either steroids only or no treatment (p=.012). There were no differences in the incidences of overall CRS (p=.692), grade 3-4 CRS (p=.196), overall ICANS (p=.941), grade 3-4 ICANS (p=.281), acute kidney disease (p=.244), and liver dysfunction (p=.45) between the 5 different bridging strategies. Cardiovascular complications were more common after chemoradiation (36%), chemotherapy (19%) and radiation (13%), compared with steroids (0%) or no bridging therapy (4%), p=.05. Non-relapse mortality was 0 in all subgroups. PETCT at 1-month post CAR-T infusion demonstrated an increase in CR status percentage across all subgroups with no statistically significant difference in the incidence between the subgroups (p=.27), Figure 1. There was no difference in both progression-free survival (Figure 2) and overall survival between the 5 subgroups (p=.7, and p=.23). Cox regression model identified preinfusion lower ECOG status (HR=0.8, p=.04), preinfusion CR/PR status (HR=.46, p=.037) and 1-month post infusion CR status as a time dependent co-variate (HR=.14, p Conclusions - Bridging to CAR-T should be tailored based on patient's and disease's characteristics with the aim to achieve the best disease control prior to CAR-T. However the chosen strategy per-se does not impact long-term outcomes. Intensive bridging therapy is associated with more cardiovascular events after CAR-T infusion. A prospective-controlled-trial allocating patients to different bridging strategies is needed to verify these results. Figure 1 Figure 1. Disclosures Ram: Gilead: Honoraria; Novartis: Honoraria. Yehudai-Ofir: Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees. Avivi: Novartis: Speakers Bureau; Kite, a Gilead Company: Speakers Bureau. Zuckerman: Cellect Biotechnology: Honoraria; Gilead Sciences: Honoraria, Speakers Bureau; Novartis: Honoraria; Janssen: Honoraria; BioSight Ltd: Honoraria; Orgenesis Inc.: Honoraria; AbbVie: Honoraria. Yeshurun: Astellas: Consultancy; Janssen: Consultancy. Gurion: Medison; Gilead Sciences; Takeda Pharmaceuticals: Consultancy; JC Health CARE; Roche: Honoraria. Levi: AbbVie: Consultancy, Research Funding.

Introduction: In patients with hematological malignancies, COVID-19 is considered to be associated with a high risk of severe morbidity and mortality. While anti-COVID-19 vaccination of such patients has become the standard of care, many of them fail to generate protective serological response due to either the nature of their underlying disease or exposure to therapy. Surprisingly, none of the Hodgkin lymphoma (HL) patients treated or followed at our tertiary care center, has been hospitalized for severe COVID-19. Nevertheless, the vulnerability of this patient population to infections highlights the need for efficacious protection against this life-threatening disease. The current non-interventional single-center study has aimed to evaluate the serological response in HL patients vaccinated against the virus in comparison to those HL patients who had a history of COVID-19 infection. The impact of an additional background disease or use of lymphodepleting agents on the evaluated serological response of HL patients has also been assessed. Methods: The BNT162b2 vaccine (Pfizer) was available in Israel from January 2021 and all costs were covered by the National Health Service. Thus, all patients with hematological malignancies were recommended to undergo vaccination with 2 doses of this vaccine, injected 21 days apart. The serology test was performed at least two weeks after the second vaccination. The SARS-CoV-2 IgG II Quant (Abbott©) assay was used to measure the levels of IgG antibodies against the SARS-CoV-2 spike protein. The result was considered positive if the IgG level was ≥50 AU/ml, which was defined as an adequate serological response. Results: Fifty-two HL patients were offered to have their serological response evaluated. Six declined. Sixteen patients had early-stage HL, stage I-II, and 30 had advanced disease, including 4 patients with stage IIB bulky, 9 - with stage III and 17 - with stage IV disease. Study participants received 1-9 lines of therapy (median 1 line). Twelve patients were being treated for active disease when their serology was tested. The study was approved by the Institutional Review Board (Approval #0883-20-RMB) and patients signed informed consent. Ten patients were diagnosed with COVID-19, with none of them being hospitalized. Forty-two other patients received two vaccine doses. One patient who had been diagnosed with COVID-19 and was later vaccinated with a single dose was analyzed with vaccinated patients. Serology tests were performed at a median of 132 days from COVID-19 diagnosis or 108 days from vaccination, with no statistical difference in test timing between the groups. Similarly, the median age did not differ between the groups [41 (28-64) and 43 (18-80) years, respectively; p=0.98]. Data on antibody levels were available for 7/10 patients who recovered from COVID-19, with a median antibody level equating to 113 (0-1576) AU/ml (Table 1). In the group of 39 vaccinated patients, the median antibody level was 2054 AU/ml (0-21174; p=0.007). An additional analysis was performed to compare the evaluated parameters in a subgroup of patients (n=7) who had another background disease along with HL, such as chronic lymphocytic leukemia, s/p kidney transplantation, solid tumor, or those who were heavily pretreated, including therapy with bendamustine, versus the values observed in the rest of the patients (n=39). The median age in the above subgroup was found to be 60 (38-80) years, which was significantly older than in the remaining patients [median age 41 (18-78) years; p=0.029)]. Likewise, median IgG antibody levels demonstrated significant difference between these two subgroups, equating to 2 (0-7539) AU/ml and 1993 (0-21174) AU/ml, respectively (p=0.007). Of the 36 vaccinated HL patients with no background disease 92% had adequate anti-spike antibody levels at a median of 100 days post-vaccination. Conclusions: The results of the current study suggest that at least 87% of Hodgkin lymphoma patients develop a high titer of anti-spike antibodies after vaccination with two doses of BNT162b2. Among HL patients, the antibody titer levels in vaccinated individuals are found to be 18-fold higher than in those who have recovered from COVID-19. Only a minority of HL patients who had additional background diseases or were heavily pretreated, failed to develop an adequate serological response. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

While complement-dependent cytotoxicity (CDC) is a known effector mechanism in aquaporin-4-immunoglobulin (Ig)G-positive (AQP4-IgG+) neuromyelitis optica spectrum disorder (NMOSD), the role of CDC in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is less clear. We determined complement C3 and C4 plasma concentrations in patients with clinically stable AQP4-IgG+ NMOSD (n = 16), MOGAD (n = 15), early multiple sclerosis (MS, n = 19) and in healthy controls (HC, n = 18). C4 was lower in AQP4-IgG+ NMOSD than in MOGAD, MS and HC (p 0.05, pairwise comparisons). C3 was lower in AQP4-IgG+ NMOSD than in MS (p = 0.034). These findings suggest subtle complement consumption in clinically stable AQP4-IgG+ NMOSD, but not in MOGAD.

Background and ObjectivesChronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease primarily affecting the peripheral nervous system. However, several noncontrolled studies have suggested concomitant inflammatory CNS demyelination similar to multiple sclerosis. The aim of this study was to investigate an involvement of the visual pathway in patients with CIDP.MethodsIn this prospective cross-sectional study, we used high-resolution spectral-domain optical coherence tomography to compare the thickness of the peripapillary retinal nerve fiber layer and the deeper macular retinal layers as well as the total macular volume (TMV) in 22 patients with CIDP and 22 age-matched and sex-matched healthy control (HC) individuals. Retinal layers were semiautomatically segmented by the provided software and were correlated with clinical measures and nerve conduction studies.ResultsIn patients with CIDP compared with healthy age-matched and sex-matched controls, we found slight but significant volume reductions of the ganglion cell/inner plexiform layer complex (CIDP 1.86 vs HC 1.95 mm3, p = 0.015), the retinal pigment epithelium (CIDP 0.38 vs HC 0.40 mm3, p = 0.02), and the TMV (CIDP 8.48 vs HC 8.75 mm3, p = 0.018). The ganglion cell layer volume and motor nerve conduction velocity were positively associated (B = 0.002, p = 0.02).DiscussionOur data reveal subtle retinal neurodegeneration in patients with CIDP, providing evidence for visual pathway involvement, detectable by OCT. The results need corroboration in independent, larger cohorts.