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Practical yet reliable diagnostic tools for small-fiber neuropathy are needed. We aimed to establish a histopathologic protocol for estimating intraepidermal nerve fiber density (eIENFD) on formalin-fixed, paraffin-embedded tissue (FFPE), evaluate its reliability through intraobserver and interobserver analyses, and provide normative reference values for clinical use. Sixty-eight healthy participants underwent nerve conduction studies and quantitative sensory testing. Skin biopsies from the distal and proximal leg were taken and processed using routine immunohistochemistry (anti-PGP9.5 antibodies) on thin 5 µm sections. eIENFD was assessed with a modified counting protocol. Interobserver and intraobserver reliabilities were excellent (ICC=0.9). eIENFD was higher in females than males (fibers/mm, 14.3±4.4 vs. 11.6±5.8, P <0.05), decreased with age ( r s =-0.47, P <0.001), and was higher proximally than distally (15.0±5.5 vs. 13.0±5.3, P =0.002). Quantile regression equations for the fifth percentile of distal and proximal eIENFD were presented: 13.125-0.161×age (y)-0.932×sex (male=1; female=0) and 17.204-0.192×age (y)-3.313×sex (male=1; female=0), respectively. This study introduces a reliable and reproducible method for estimating epidermal nerve fiber density through immunostaining on 5-µm thin FFPE tissue samples. Normative data on eIENFD is provided. Regression equations help identify abnormal decreases in small nerve fiber density., Competing Interests: K.P. obtained funding from Region Stockholm Innovation Fund. The remaining author declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Systemic capillary leak syndrome (SCLS) is a rare condition associated with episodes of hypotension, hemoconcentration, hypoalbuminemia, and rhabdomyolysis. We describe a middle-aged man presenting with several distinct SCLS-like episodes, the last being fatal. In addition, in the year before the final event, he developed rapid cognitive decline with contrast-enhancing lesions on MRI and highly elevated neurofilament light protein levels in CSF., Methods: Data and imaging were obtained from patient medical records., Results: At the time, the SCLS-like episodes were interpreted as myositis secondary to viral infection. A thorough workup for other causes, including genetic testing, was negative. As for the rapid cognitive decline, despite an extensive workup for infectious and inflammatory causes, no definitive diagnosis was made. Whole genome sequencing however identified a C9orf72 hexanucleotide expansion., Discussion: The C9orf72 expansion is associated with frontotemporal dementia and amyotrophic lateral sclerosis but has also been shown to increase susceptibility to neuroinflammation. Recent findings also suggest C9orf72 to exert functions in the immune system, in particular regulation of type I interferon responses, in turn shown to be associated with SCLS. This case suggests a possible link between SCLS, cerebral inflammation, dysregulated type I interferon signaling, and expansions in C9orf72 ., Competing Interests: The authors report no relevant disclosures. Go to Neurology.org/NG for full disclosures., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Several studies have investigated the histopathology of mechanically retrieved thrombi from stroke patients. Thrombi with unusual components constitute about 1-2% of all stroke thrombi in clinical practice. Knowledge about these rare components is limited., Objectives: To characterize the histopathology of unusual stroke thrombi from a real-world setting with relation to clinical presentation, patient characteristics and procedural aspects of mechanical thrombectomy., Methods: One-thousand and eight thrombi retrieved from stroke patients with mechanical thrombectomy at three different hospitals were retrospectively reviewed for unusual histological components. Fifteen thrombi were included in the study for further histopathological analysis. Clinical data and data on procedural aspects were collected., Results: We identified six cases with large amounts of extracellular DNA, of which three were calcified. All six cases except one received anticoagulant therapy. We describe two types of calcifications that differ with respect to general calcification morphology, von Kossa staining pattern, macrophage immunophenotype and presence of multinucleated giant cells. Cholesterol-rich ( n = 3), adipocyte-like pattern-rich ( n = 2), collagen-rich ( n = 2) and myxomatous ( n = 1) thrombi were also identified and are discussed with regard to pathogenesis and clinical and intervention characteristics. Finally, a thrombus with parts of a vascular wall is described. Suggestions for future studies are made and clinical and technical aspects of the management for these rare but important patients are discussed., Conclusion: In our retrospective multicenter study, we characterized stroke thrombi histopathologically and found subgroups of thrombi defined by presence of rarely seen components. These defined subgroups showed relation to underlying cardiovascular disease, patient characteristics, and mechanical thrombectomy technique. Knowledge about these components may increase our understanding of stroke pathophysiology and influence interventional procedures., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Aspegren, Staessens, Vandelanotte, Desender, Cordonnier, Puy, Bricout, De Meyer, Andersson and Arnberg.)

Acute ischemic stroke caused by large vessel occlusion is treated with endovascular thrombectomy, but treatment failure may occur when clot composition and thrombectomy technique mismatch. In this proof-of-concept study, diffuse reflectance spectroscopy (DRS) is evaluated for identification of clot composition ex vivo. DRS spectra and histology were acquired from 45 clot units retrieved from 29 stroke patients. DRS spectra correlated to clot RBC content, R= 81, p < .001, and could discriminate between RBC-rich and fibrin-rich clots, p < 0.001. Sensitivity and specificity for detection of RBC-rich clots were 0.722 and 0.846 respectively. Applied in an intravascular device, DRS could potentially provide intraprocedural information on clot composition that could increase endovascular thrombectomy efficiency., Competing Interests: T.A. holds equity for Ceroflo and is a consultant for Amnis Therapeutics, Anaconda, Cerenovus-Neuravi, Medtronic, Rapid Medical and Stryker. None of the authors who are affiliated with clinical institutions or universities (S.S, G.B, E.E, O.A, A.E.-T, F.A, T.A.) have financial interests in the subject matter, materials, or equipment or with any competing materials and did not receive any payments from Philips. Karolinska University hospital and Philips have a major collaboration agreement. The authors affiliated with Philips Research (M.M, G.L.) have financial interests in the subject matter, materials, and equipment, in the sense that they are employees of Philips. Philips provided support in the form of salaries but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Authors without conflicts of interest had full control of all data labelling, data analysis and information submitted for publication and over all conclusions drawn in the manuscript., (© 2022 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.)

Background: Endovascular thrombectomy has revolutionized the management of acute ischemic stroke and proven superior to stand-alone intravenous thrombolysis for large vessel occlusions. However, failed or delayed revascularization may occur as a result of a mismatch between removal technique and clot composition. Determination of clot composition before thrombectomy provides the possibility to adapt the technique to improve clot removal efficacy. We evaluated the application of diffuse reflectance spectroscopy (DRS) for intravascular determination of clot composition in vivo., Methods: Three clot types, enriched in red blood cells or fibrin or with a mixed content, were prepared from porcine blood and injected into the external carotids of a domestic pig. A guidewire-like DRS probe was used to investigate the optical spectra of clots, blood and vessel wall. Measurement positions were confirmed with angiography. Spectra were analyzed by fitting an optical model to derive physiological parameters. To evaluate the method's accuracy, photon scattering and blood and methemoglobin contents were included in a decision tree model and a random forest classification., Results: DRS could differentiate between the three different clot types, blood and vessel wall in vivo (p<0.0001). The sensitivity and specificity for detection was 73.8% and 98.8% for red blood cell clots, 80.6% and 97.8% for fibrin clots, and 100% and 100% for mixed clots, respectively., Conclusion: Intravascular DRS applied via a custom guidewire can be used for reliable determination of clot composition in vivo. This novel approach has the potential to increase efficacy of thrombectomy procedures in ischemic stroke., Competing Interests: Competing interests: TA holds equity for Ceroflo and is a consultant for Amnis Therapeutics, Anaconda, Cerenovus-Neuravi, Medtronic, Rapid Medical and Stryker. None of the authors who are affiliated with clinical institutions or universities (SS, GB, EE, OA, AE-T, FA, TA) have financial interests in the subject matter, materials, or equipment or with any competing materials and did not receive any payments from Philips. Karolinska University hospital and Philips Healthcare have a major collaboration agreement. The authors affiliated with Philips Research and Philips Healthcare (MM, GL) have financial interests in the subject matter, materials, and equipment, in the sense that they are employees of Philips. Philips provided support in the form of salaries but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. Authors without conflicts of interest had full control of all data labeling, data analysis and information submitted for publication and over all conclusions drawn in the manuscript., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We present a 53-year-old woman who presented simultaneously with acute inflammatory demyelinating polyneuropathy, Graves' disease, leukocytoclastic vasculitis, elevated acetylcholine antibody receptor antibodies and a mediastinal mass. Thymectomy was performed and revealed a type A thymoma and the clinical picture and paraclinical findings were consistent with a thymoma-associated multi-autoimmune syndrome (TAMA). Beside prednisolone and plasmapheresis, the patient was treated with tocilizumab and rituximab. After surgical and immunomodulatory treatment with tocilizumab and rituximab the patient's condition slowly started to improve. TAMA is associated with a spectrum of autoantibodies and immune-mediated damage to multiple organs. Even if thymectomy is crucial for long term prognosis, aggressive immunomodulation should be considered early in the disease course, especially in cases showing involvement of the peripheral and/or central nervous system., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: Retinopathy is a result of pathologic angiogenesis influenced by insulinlike growth factor (IGF)-1. The authors examined the local expression of the IGF/insulin family., Methods: In retinas with and without oxygen-induced retinopathy, the authors assessed with real-time RT-PCR mRNA expression of the IGF-1 receptor (IGF-1R), insulin receptor (IR), IGF-1, IGF-2, insulin (Ins2), and IGF-binding protein 1 (IGFBP1) to IGFBP6 in total retina from postnatal day (P) 7 to P33 to examine changes over time with the induction of retinopathy and at P17 on laser-captured retinal components to quantitatively localize mRNA expression in the ganglion cell layer, the outer nuclear layer, the inner nuclear layer, normal blood vessels, and neovascular tufts., Results: IGF-1R and IR are expressed predominantly in photoreceptors and in vessels, with scant expression in the rest of the neural retina. IGF-1R expression is more than 100-fold greater than IR. The major local growth factor (expressed in photoreceptors and in blood vessels) is IGF-2 (approximately 1000-fold greater than IGF-1). IGF-1 (approximately 600 copies/10(6) cyclophilin) is expressed throughout the retina. IGFBP2, IGFBP4, and IGFBP5 expression is unchanged with increasing retinal development and with the induction of retinopathy. In contrast, IGFBP3 expression increased more than 5-fold with hypoxia, found in neovascular tufts., Conclusions: IGF-1R, IR, and the ligand IGF-2 are expressed almost exclusively in photoreceptors and blood vessels. IGFBP3 and IGFBP5 expression increases in neovascular tufts compared with normal vessels. IGF-1 is expressed throughout the retina at much lower levels. These results suggest cross-talk between vessels and photoreceptors in the development of retinopathy and retinal vasculature.