Broader anti-EBV TCR repertoire in multiple sclerosis: disease specificity and treatment modulation.

Epstein-Barr virus (EBV) infection has long been associated with the development of multiple sclerosis (MS). MS patients have elevated titers of EBV-specific antibodies in serum and show signs of CNS damage only after EBV infection. Regarding CD8+ T-cells, an elevated but ineffective response to EBV was suggested in MS patients, who present with a broader MHC-I-restricted EBV-specific T-cell receptor beta chain (TRB) repertoire compared to controls. It is not known whether this altered EBV response could be subject to dynamic changes, e.g., by approved MS therapies, and whether it is specific for MS. 1317 peripheral blood TRB repertoire samples of healthy donors (n=409), patients with MS (n=710) before and after treatment, patients with neuromyelitis optica spectrum disorder (n=87), myelin-oligodendrocyte-glycoprotein antibody-associated disease (n=64) and Susac's syndrome (n=47) were analyzed. Apart from MS, none of the evaluated diseases presented with a broader anti-EBV TRB repertoire. In MS patients undergoing autologous hematopoietic stem-cell transplantation, EBV reactivation coincided with elevated MHC-I-restricted EBV-specific TRB sequence matches. Therapy with ocrelizumab, teriflunomide or dimethyl fumarate reduced EBV-specific, but not CMV-specific MHC-I-restricted TRB sequence matches. Together, this data suggests that the aberrant MHC-I-restricted T-cell response directed against EBV is specific to MS with regard to NMO, MOGAD and Susac's Syndrome and that it is specifically modified by MS treatments interfering with EBV host cells or activated lymphocytes.

Central intra-lesional iron deposits as a possible novel imaging marker at 7 Tesla MRI in Susac Syndrome - an exploratory study.

BACKGROUND: Susac syndrome (SuS) is a rare autoimmune disease that leads to hearing impairment, visual field deficits, and encephalopathy due to an occlusion of precapillary arterioles in the brain, retina, and inner ear. Given the potentially disastrous outcome and difficulties in distinguishing SuS from its differential diagnoses, such as multiple sclerosis (MS), our exploratory study aimed at identifying potential new SuS-specific neuroimaging markers. METHODS: Seven patients with a definite diagnosis of SuS underwent magnetic resonance imaging (MRI) at 7 Tesla (7T), including T2* weighted and quantitative susceptibility mapping (QSM) sequences. T2 weighted hyperintense lesions were analyzed with regard to number, volume, localization, central vein sign, T1 hypointensity, and focal iron deposits in the center of SuS lesions ("iron dots"). Seven T MRI datasets from the same institute, comprising 75 patients with, among others, MS, served as controls. RESULTS: The "iron dot" sign was present in 71.4% (5/7) of the SuS patients, compared to 0% in our control cohort. Thus, sensitivity was 71.4% and specificity 100%. A central vein sign was only incidentally detected. CONCLUSION: We are the first to demonstrate this type of "iron dot" lesions on highly resolving 7T T2*w and QSM images in vivo as a promising neuroimaging marker of SuS, corroborating previous histopathological ex vivo findings.

A broad spectrum of posterior reversible encephalopathy syndrome - a case series with clinical and paraclinical characterisation, and histopathological findings.

BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is clinical-neuroradiologically defined and potentially reversible, so there are limited data about histopathological findings. We aimed to describe the clinical and paraclinical features of patients with PRES with regard to its reversibility. METHODS: This retrospective case series encompasses 15 PRES cases out of 1300 evaluated patients from a single German center between January 1, 2010, and June 15, 2020. PRES was established according to the diagnostic criteria as proposed by the Berlin PRES Study 2012. One of the cases studied was subject to brain autopsy. RESULTS: From the 15 patients studied (median age 53 years, range 17-73; 11 female), 67 % presented with epileptic seizures, 40 % suffered from encephalopathy with reduced consciousness and 53 % developed delirium, while 47 % had headache and visual disturbances. Subcortical brain MRI abnormalities related to PRES were observed in all patients. One patient developed spinal ischemia and another Guillain-Barré syndrome in addition to PRES. Hypertensive blood pressure was the main underlying/trigger condition in all patients. Clinical symptoms and MRI changes were not reversible in 42 %, even progressive in 3 out of these 5 patients. Median time from symptom onset to diagnosis in these non-reversible cases was 7 days (range 0-13), while the median delay in diagnosis in the reversible group was 1 day (range 0-3). Cerebellar/brain stem involvement and status epilepticus were more frequently in patients with non-reversible disease course. Mortality due to PRES occurred in 13 % of these patients. Neuropathological examination of the brain of a 57-year-old female patient revealed major leukencephalopathic changes, fibrinoid necrosis of endothelial cells and fresh petechial hemorrhages in accordance with PRES. CONCLUSIONS: Our case series demonstrates that PRES was not reversible in 42 % of the studied patients. Delay in diagnosis seems to contribute to limited reversibility and poor outcome.

Diagnostic criteria for Susac syndrome.

BACKGROUND: Susac syndrome is characterised by the triad of encephalopathy with or without focal neurological signs, branch retinal artery occlusions and hearing loss. Establishment of the diagnosis is often delayed because the triad is complete only in a minority of patients at disease onset. This leads to a critical delay in the initiation of appropriate treatment. Our objective was to establish criteria for diagnosis of either definite or probable Susac syndrome. METHOD: The establishment of diagnostic criteria was based on the following three steps: (1) Definition of a reference group of 32 patients with an unambiguous diagnosis of Susac syndrome as assessed by all interdisciplinary experts of the European Susac Consortium (EuSaC) team (EuSaC cohort); (2) selection of diagnostic criteria, based on common clinical and paraclinical findings in the EuSaC cohort and on a review of the literature; and (3) validation of the proposed criteria in the previously published cohort of all Susac cases reported until 2012. RESULTS: Integrating the clinical presentation and paraclinical findings, we propose formal criteria and recommend a diagnostic workup to facilitate the diagnosis of Susac syndrome. More than 90% of the cases in the literature fulfilled the proposed criteria for probable or definite Susac syndrome. We surmise that more patients could have been diagnosed with the recommended diagnostic workup. CONCLUSIONS: We propose diagnostic criteria for Susac syndrome that may help both experts and physicians not familiar with Susac syndrome to make a correct diagnosis and to prevent delayed treatment initiation.

RETINAL LESION EVOLUTION IN SUSAC SYNDROME.

PURPOSE: To describe retinal lesion development in Susac syndrome during acute, postacute, and late phases of the disease. METHODS: Cross-sectional study of four patients with Susac syndrome and longitudinal short-interval case study of one additional patient. Retinal changes were analyzed with high-resolution spectral domain optical coherence tomography and retinal fluorescein angiography. RESULTS: Retinal Susac syndrome lesions comprise four different lesion sections, which can be distinguished in acute and postacute phases of the disease: a primary section at the site of branch retinal artery occlusion, which spans more layers than supplied by the affected vessel; hypoxic sections from superficial and deep capillary networks; and an axonal damage section with degenerating axons from perished ganglion cells in the main and hypoxic sections. In the later stages, main and hypoxic lesion sections can no longer be distinguished, and both show degeneration from outer plexiform to retinal nerve fiber layers. CONCLUSION: The dynamics of lesion development and morphologically distinct lesion sections suggest more complex mechanisms of lesion evolution beyond an isolated endothelial immune reaction and subsequent hypoxic tissue damage. The characteristic lesion morphology assists in differentiating the diagnosis of acute visual loss in neuroinflammatory disease. Specificity of the identified changes has to be determined in future studies also including patients with other retinal vascular diseases.

Clinical, paraclinical and serological findings in Susac syndrome: an international multicenter study.

BACKGROUND: Susac syndrome (SuS) is a rare disorder thought to be caused by autoimmune-mediated occlusions of microvessels in the brain, retina and inner ear leading to central nervous system (CNS) dysfunction, visual disturbances due to branch retinal artery occlusions (BRAO), and hearing deficits. Recently, a role for anti-endothelial cell antibodies (AECA) in SuS has been proposed. OBJECTIVES: To report the clinical and paraclinical findings in the largest single series of patients so far and to investigate the frequency, titers, and clinical relevance of AECA in SuS. PATIENTS AND METHODS: A total of 107 serum samples from 20 patients with definite SuS, 5 with abortive forms of SuS (all with BRAO), and 70 controls were tested for AECA by immunohistochemistry employing primate brain tissue sections. RESULTS: IgG-AECA >1:100 were detected in 25% (5/20) of patients with definite SuS and in 4.3% (3/70) of the controls. Median titers were significantly higher in SuS (1:3200, range 1:100 to 1:17500) than in controls (1:100, range 1:10 to 1:320); IgG-AECA titers >1:320 were exclusively present in patients with SuS; three controls had very low titers (1:10). Follow-up samples (n = 4) from a seropositive SuS patient obtained over a period of 29 months remained positive at high titers. In all seropositive cases, AECA belonged to the complement-activating IgG1 subclass. All but one of the IgG-AECA-positive samples were positive also for IgA-AECA and 45% for IgM-AECA. SuS took a severe and relapsing course in most patients and was associated with bilateral visual and hearing impairment, a broad panel of neurological and neuropsychological symptoms, and brain atrophy in the majority of cases. Seropositive and seronegative patients did not differ with regard to any of the clinical or paraclinical parameters analyzed. CONCLUSIONS: SuS took a severe and protracted course in the present cohort, resulting in significant impairment. Our finding of high-titer IgG1 and IgM AECA in some patients suggest that humoral autoimmunity targeting the microvasculature may play a role in the pathogenesis of SuS, at least in a subset of patients. Further studies are warranted to define the exact target structures of AECA in SuS.

Susac syndrome treated with subcutaneous immunoglobulin.

BACKGROUND: Susac syndrome is a rare disease characterized by the triad of encephalopathy, branch retinal artery occlusion, and sensorineural hearing loss mainly affecting young women. The finding of antibodies against the endothelium in the sera of these patients has supported the hypothesis of an autoimmune endotheliopathy of the brain, inner ear and retina. Because of the rarity of the disease, treatment is based on the knowledge of case reports and small case series. Medical therapy consists of glucocorticoids, immunosuppressants, acetyl salicylic acid, and immunomodulatory agents such as intravenous immunoglobulin. METHODS: We present the case histories of 2 young women with Susac syndrome presenting with several episodes of encephalopathy, branch retinal artery occlusions, and hearing loss that were treated with different immunosuppressive drugs, glucocorticoids and intravenous immunoglobulin. In the course of the disease, the treatment was successfully switched to subcutaneous immunoglobulin without any further relapse in both patients. CONCLUSION: We conclude that the application of subcutaneous immunoglobulin is easy to learn, helps to reduce in-hospital costs and enables a more flexible everyday life. The treatment with subcutaneous immunoglobulin helps to reduce immunosuppressants and appears to prevent relapses.

Clinical Characterization and Ancillary Tests in Susac Syndrome: A Systematic Review.

Susac syndrome (SuS) is an orphan microangiopathic disease characterized by a triad of encephalopathy, visual disturbances due to branch retinal artery occlusions, and sensorineuronal hearing loss. Our previous systematic review on all cases of SuS reported until 2012 allowed for a better understanding of clinical presentation and diagnostic findings. Based on these data, we suggested diagnostic criteria in 2016 to allow early diagnosis and treatment of SuS. In view of the accumulation of new SuS cases reported in the last 10 years and improved diagnostic tools, we here aimed at updating the demographic and clinical features of SuS and to review the updated ancillary tests being used for SuS diagnosis. Therefore, based on the 2016 criteria, we systematically collected and evaluated data on SuS published from January 2013 to March 2022.

Endovascular thrombectomy for childhood stroke (Save ChildS Pro): an international, multicentre, prospective registry study.

BACKGROUND: Emerging evidence suggests that endovascular thrombectomy is beneficial for treatment of childhood stroke, but the safety and effectiveness of endovascular thrombectomy has not been compared with best medical treatment. We aimed to prospectively analyse functional outcomes of endovascular thrombectomy versus best medical treatment in children with intracranial arterial occlusion stroke. METHODS: In this prospective registry study, 45 centres in 12 countries across Asia and Australia, Europe, North America, and South America reported functional outcomes for children aged between 28 days and 18 years presenting with arterial ischaemic stroke caused by a large-vessel or medium-vessel occlusion who received either endovascular thrombectomy plus best medical practice or best medical treatment alone. Intravenous thrombolysis was considered part of best medical treatment and therefore permitted in both groups. The primary outcome was the difference in median modified Rankin Scale (mRS) score between baseline (pre-stroke) and 90 days (±10 days) post-stroke, assessed by the Wilcoxon rank test (α=0·05). Efficacy outcomes in the endovascular thrombectomy and best medical treatment groups were compared in sensitivity analyses using propensity score matching. The Save ChildS Pro study is registered at the German Clinical Trials Registry, DRKS00018960. FINDINGS: Between Jan 1, 2020, and Aug 31, 2023, of the 241 patients in the Save ChildS Pro registry, 208 were included in the analysis (115 [55%] boys and 93 [45%] girls). 117 patients underwent endovascular thrombectomy (median age 11 years [IQR 6-14]), and 91 patients received best medical treatment (6 years [3-12]; p<0·0001). The median Pediatric National Institutes of Health Stroke Scale (PedNIHSS) score on admission was 14 (IQR 10-19) in the endovascular thrombectomy group and 9 (5-13) in the best medical treatment group (p<0·0001). Both treatment groups had a median pre-stroke mRS score of 0 (IQR 0-0) at baseline. The change in median mRS score between baseline and 90 days was 1 (IQR 0-2) in the endovascular thrombectomy group and 2 (1-3) in the best medical treatment group (p=0·020). One (1%) patient developed a symptomatic intracranial haemorrhage (this patient was in the endovascular thrombectomy group). Six (5%) patients in the endovascular thrombectomy group and four (5%) patients in the best medical treatment group had died by day 90 (p=0·89). After propensity score matching for age, sex, and PedNIHSS score at hospital admission (n=79 from each group), the change in median mRS score between baseline and 90 days was 1 (IQR 0-2) in the endovascular thrombectomy group and 2 (1-3) in the best medical treatment group (p=0·029). Regarding the primary outcome for patients with suspected focal cerebral arteriopathy, endovascular thrombectomy (n=18) and best medical treatment (n=33) showed no difference in 90-day median mRS scores (2 [IQR 1-3] vs 2 [1-4]; p=0·074). INTERPRETATION: Clinical centres tended to select children with more severe strokes (higher PedNIHSS score) for endovascular thrombectomy. Nevertheless, endovascular thrombectomy was associated with improved functional outcomes in paediatric patients with large-vessel or medium-vessel occlusions compared with best medical treatment. Future studies need to investigate whether the positive effect of endovascular thrombectomy is confined to older and more severely affected children. FUNDING: None.

Encephalopathic Susac's Syndrome associated with livedo racemosa in a young woman before the completion of family planning.

BACKGROUND: Susac's Syndrome (SS) consists of the triad of encephalopathy, branch retinal artery occlusions (BRAO) and hearing loss (HL). Histopathologically, SS is characterised by a microangiopathy, and some observations suggest that an immune-mediated damage of endothelial cells might play a role. These findings also implicate a similarity between SS and other autoimmune diseases, most notably juvenile dermatomyositis (JDM). However, SS and JDM are commonly thought to affect distinct and non-overlapping sets of organs, and it is currently not clear how these specificities arise. Moreover, in the absence of clinical trials, some authors suggest that therapeutic approaches in SS should rely on the model of other autoimmune diseases such as JDM. CASE PRESENTATION: Here, we report a case of SS in a 32-year-old pregnant woman. She initially was admitted to the hospital with subacute severe encephalopathy and multifocal neurologic signs. As cranial magnetic resonance imaging (MRI) revealed multifocal white matter lesions including the corpus callosum, erroneously a diagnosis of multiple sclerosis (MS) was made, and intravenous methylprednisolone (IVMP) therapy was initiated. A few days later, an exanthema appeared on the trunk and extremities, which was diagnosed as livedo racemosa (LR). Several weeks later, the patient was readmitted to the clinic with an obscuration of her left visual hemifield and a bilateral HL. Ophthalmologic examination revealed extensive ischemic damage to both retinae. Now the correct diagnosis of SS was established, based on the above triad of clinical symptoms in conjunction with typical MRI and fundoscopic findings. When SS was diagnosed, the standard therapy with intravenous cyclophosphamide (IVCTX) was not instituted because of a significant risk of permanent infertility. Instead, sustained control of disease activity could be achieved with a therapeutic regime combining prednisolone, intravenous immunoglobulins (IVIG), mycophenylate mofetil (MM), and methotrexate (MTX). CONCLUSIONS: An association with LR has only been described in very few cases of SS before and further underlines the pathogenetic relationship between SS and other autoimmune diseases such as JDM. In young women with SS and the desire for a child the combination of MM and MTX may represent a reasonable alternative to IVCTX.

Sodium-dependent vitamin C transporter 2 deficiency causes hypomyelination and extracellular matrix defects in the peripheral nervous system.

Ascorbic acid (vitamin C) is necessary for myelination of Schwann cell/neuron cocultures and has shown beneficial effects in the treatment of a Charcot-Marie-Tooth neuropathy 1A (CMT1A) mouse model. Although clinical studies revealed that ascorbic acid treatment had no impact on CMT1A, it is assumed to have an important function in peripheral nerve myelination and possibly in remyelination. However, the transport pathway of ascorbic acid into peripheral nerves and the mechanism of ascorbic acid function in peripheral nerves in vivo remained unclear. In this study, we used sodium-dependent vitamin C transporter 2-heterozygous (SVCT2(+/-)) mice to elucidate the functions of SVCT2 and ascorbic acid in the murine peripheral nervous system. SVCT2 and ascorbic acid levels were reduced in SVCT2(+/-) peripheral nerves. Morphometry of sciatic nerve fibers revealed a decrease in myelin thickness and an increase in G-ratios in SVCT2(+/-) mice. Nerve conduction velocities and sensorimotor performance in functional tests were reduced in SVCT2(+/-) mice. To investigate the mechanism of ascorbic acid function, we studied the expression of collagens in the extracellular matrix of peripheral nerves. Here, we show that expression of various collagen types was reduced in sciatic nerves of SVCT2(+/-) mice. We found that collagen gene transcription was reduced in SVCT2(+/-) mice but hydroxyproline levels were not, indicating that collagen formation was regulated on the transcriptional and not the posttranslational level. These results help to clarify the transport pathway and mechanism of action of ascorbic acid in the peripheral nervous system and may lead to novel therapeutic approaches to peripheral neuropathies by manipulation of SVCT2 function.

Lesion morphology at 7 Tesla MRI differentiates Susac syndrome from multiple sclerosis.

BACKGROUND: Although an orphan disease with still obscure aetiopathogenesis, Susac syndrome has to be considered as differential diagnosis in multiple sclerosis (MS), since its clinical presentation and paraclinical features including routine magnetic resonance imaging (MRI) findings partially overlap. OBJECTIVE: We aimed to study a potential benefit of 7T MRI for (i) the differentiation between Susac syndrome and MS and (ii) the clarification of pathogenesis of Susac syndrome. METHODS: Five patients suffering from Susac syndrome, 10 sex- and age-matched patients with relapsing-remitting MS (median Expanded Disability Status Scale (EDSS) score 1.5) and 15 matching healthy controls were investigated at 7 Tesla MRI. The protocol included T1-weighted MPRAGE, T2*-weighted FLASH, and TIRM sequences. RESULTS: Almost all T2* FLASH lesions in patients with MS were centred by a small central vein (325 lesions; 92%) and often showed a small hypointense rim (145 lesions; 41%). In contrast, white matter lesions in Susac syndrome exhibited a perivascular setting significantly less frequently (148 lesions; 54%, p=0.002), and very rarely exhibited a hypointense rim (12 lesions; 4%, p=0.004). Furthermore, in addition to callosal atrophy, Susac patients showed cerebrospinal fluid-isointense lesions within the central part of corpus callosum that are not commonly seen in MS. CONCLUSION: At 7T MRI, plaques in MS patients and patients with Susac syndrome differed substantially with respect to morphology and pattern. Thus, lesion morphology at 7T (i) may serve as a marker to distinguish Susac syndrome from MS and (ii) reflects a different pathophysiological mechanism underlying Susac syndrome, for example microinfarction rather than demyelination.

Point-of-Care Testing Using a Neuropsychology Pocketcard Set: A Preliminary Validation Study.

Neurocognitive screening instruments usually require printed sheets and additional accessories, and can be unsuitable for low-threshold use during ward rounds or emergency workup, especially in patients with motor impairments. Here, we test the utility of a newly developed neuropsychology pocketcard set for point-of-care testing. For aphasia and neglect assessment, modified versions of the Language Screening Test and the Bells Test were validated on 63 and 60 acute stroke unit patients, respectively, against expert clinical evaluation and the original pen-and-paper Bells Test. The pocketcard aphasia test achieved an excellent area under the curve (AUC) of 0.94 (95% CI: 0.88−1, p < 0.001). Using an optimal cut-off of ≥2 mistakes, sensitivity was 91% and specificity was 81%. The pocketcard Bells Task, measured against the clinical neglect diagnosis, achieved higher sensitivity (89%) and specificity (88%) than the original paper-based instrument (78% and 75%, respectively). Separately, executive function tests (modified versions of the Trail Making Test [TMT] A and B, custom Stroop color naming task, vigilance 'A' Montreal Cognitive Assessment item) were validated on 44 inpatients with epilepsy against the EpiTrack® test battery. Pocketcard TMT performance was significantly correlated with the original EpiTrack® versions (A: r = 0.64, p < 0.001; B: r = 0.75, p < 0.001). AUCs for the custom Stroop task, TMT A and TMT B for discriminating between normal and pathological EpiTrack® scores were acceptable, excellent and outstanding, respectively. Quick point-of-care testing using a pocketcard set is feasible and yields diagnostically valid information.

Report of a novel mutation in the PMP22 gene causing an axonal neuropathy.

INTRODUCTION: Point mutations in the peripheral myelin protein 22 (PMP22) gene rarely cause the hereditary neuropathies Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP), both of which show a demyelinating phenotype. METHODS: In this study we characterized a family with an axonal neuropathy. RESULTS: Three family members carried a heterozygous point mutation of the PMP22 gene, resulting in amino acid substitution R159C. Screening of 185 healthy controls did not reveal the R159C allele in any case. DISCUSSION: The novel R159C mutation represents a very rare case of a dominant PMP22 mutation causing an axonal neuropathy.

Susac syndrome and pregnancy: a review of published cases and considerations for patient management.

Susac syndrome (SuS) is a rare autoimmune endotheliopathy leading to hearing loss, branch retinal artery occlusions and encephalopathy. Young females are more frequently affected than males, making counselling for family planning an important issue. We reviewed published cases on SuS during pregnancy or in the postpartum period, and selected 27 reports describing the details of 33 patients with SuS. Treatment options and implications for pregnancy and breastfeeding are discussed. We propose new areas for research and suggest a management strategy.

Mechanical Thrombectomy in Acute Terminal Internal Carotid Artery Occlusions Using a Large Manually Expandable Stentretriever (Tiger XL Device): Multicenter Initial Experience.

BACKGROUND: The recently introduced Tigertriever XL Device for treatment of cerebral vessel occlusions combines manual adjustability and maximum length in one device. In this study, we report our initial experience with the Tigertriever XL in terminal ICA occlusions. METHODS: Retrospective multicenter analysis of acute terminal ICA occlusions treated by mechanical thrombectomy using the Tigertriever XL Device. RESULTS: 23 patients were treated using the Tigetriever XL due to an acute occlusion of the terminal ICA. The overall successful reperfusion rate after a median of two maneuvers using the Tigertriever XL Device was 78.3% (mTICI 2b-3). In 43.5% (10/23) additional smaller devices were applied to treat remaining occlusions in downstream territories, which resulted in a final successful reperfusion rate of 95.7%. Device related complications did not occur. Two symptomatic intracerebral hemorrhages (sICH) were observed. CONCLUSIONS: The Tigertriever XL Device might be a helpful tool in the treatment of ICA terminus occlusions with large clot burden resulting in high reperfusion rates. This is mainly related to the manual adjustability of the device combined with the maximum length.

Cardiac Imaging Within Emergency CT Angiography for Acute Stroke Can Detect Atrial Clots.

Cardiac embolism is presumed to cause a significant portion of cryptogenic strokes. Transesophageal echocardiography may detect intracardiac thrombi, but this remains a rare finding, possibly because remnant clots dissolve spontaneously or following thrombolysis. Cardiac imaging within cerebral CT angiography might offer an alternative method for thrombus detection within hyperacute stroke assessment. In a proof-of-concept study we analyzed records of patients aged ≥ 60 years that presented with suspected stroke and underwent extended cerebral CT angiography as part of their emergency assessment. CT imaging of patients with ischemic stroke or transient ischemic attack (TIA) and atrial fibrillation and of those with embolic strokes of undetermined source (ESUS) was reviewed for intracardiac clots and other cardiac or aortic pathology. Over a period of 3 months 59 patients underwent extended CT angiography for suspected stroke, 44 of whom received a final diagnosis of ischemic stroke or TIA. Of those, 17 had atrial fibrillation, and four fulfilled ESUS criteria. Thrombi were detected within atrial structures on CT angiography in three cases. In two ESUS patients complex atheromatosis of the proximal ascending aorta with irregular and ulcerating plaques was detected. Cardiac imaging within emergency cerebral CT angiography is feasible and can provide valuable diagnostic information in a patient group that might not routinely undergo transesophageal echocardiography. A small change to emergency assessment could potentially uncover cardioembolic pathology in cases that would have remained cryptogenic otherwise.

CD8+ T cell-mediated endotheliopathy is a targetable mechanism of neuro-inflammation in Susac syndrome.

Neuroinflammation is often associated with blood-brain-barrier dysfunction, which contributes to neurological tissue damage. Here, we reveal the pathophysiology of Susac syndrome (SuS), an enigmatic neuroinflammatory disease with central nervous system (CNS) endotheliopathy. By investigating immune cells from the blood, cerebrospinal fluid, and CNS of SuS patients, we demonstrate oligoclonal expansion of terminally differentiated activated cytotoxic CD8+ T cells (CTLs). Neuropathological data derived from both SuS patients and a newly-developed transgenic mouse model recapitulating the disease indicate that CTLs adhere to CNS microvessels in distinct areas and polarize granzyme B, which most likely results in the observed endothelial cell injury and microhemorrhages. Blocking T-cell adhesion by anti-α4 integrin-intervention ameliorates the disease in the preclinical model. Similarly, disease severity decreases in four SuS patients treated with natalizumab along with other therapy. Our study identifies CD8+ T-cell-mediated endotheliopathy as a key disease mechanism in SuS and highlights therapeutic opportunities.

The role of aquaporin-4 polymorphisms in the development of brain edema after middle cerebral artery occlusion.

BACKGROUND AND PURPOSE: Some patients develop severe brain edema after complete middle cerebral artery occlusion, whereas others do not. Aquaporin-4 (AQP4) is the main water channel in the brain and has been shown to be critical for the development of brain edema after ischemia. We asked whether genetic variation in the AQP4 gene is related to the severity of brain edema after middle cerebral artery occlusion. METHODS: We genotyped 10 single nucleotide polymorphisms distributed across the AQP4 gene in 41 patients with middle cerebral artery occlusion with and without severe brain edema and assessed single marker association as well as the linkage dysequilibrium structure across AQP4. RESULTS: One single nucleotide polymorphism (rs9951307) at the 3' end of AQP4 was associated with severe brain edema (dominant model, P=0.01; OR, 0.10; 95% CI, 0.02 to 0.49 for the protective G-allele). Linkage dysequilibrium across AQP4 was low; no clear haplotype blocks could be identified for the assessment of haplotype association. CONCLUSIONS: This explorative study shows that genetic variation in AQP4 might contribute to brain edema formation after middle cerebral artery occlusion and warrants further investigation.

Inhibition of N-cadherin and beta-catenin function reduces axon-induced Schwann cell proliferation.

N-cadherin and beta-catenin are involved in cell adhesion and cell cycle in tumor cells and neural crest. Both are expressed at key stages of Schwann cell (SC) development, but little is known about their function in the SC lineage. We studied the role of these molecules in adult rat derived SC-embryonic dorsal root ganglion cocultures by using low-Ca(2+) conditions and specific blocking antibodies to interfere with N-cadherin function and by using small interfering RNA (siRNA) to decrease beta-catenin expression in both SC-neuron cocultures and adult rat-derived SC monocultures. N-cadherin blocking conditions decreased SC-axon association and reduced axon-induced SC proliferation. In SC monocultures, beta-catenin reduction diminished the proliferative response of SCs to the mitogen beta1-heregulin, and, in SC-DRG cocultures, beta-catenin reduction inhibited axon-contact-dependent SC proliferation. Stimulation of SC cultures with beta1-heregulin increased total beta-catenin protein amount, phosphorylation of GSK-3beta and beta-catenin presence in nuclear extracts. In conclusion, our findings suggest a previously unrecognized contribution of beta-catenin and N-cadherin to axon-induced SC proliferation.